Øystein Fischer Bjelland
Physiology FALL 2007
Disclaimer: i take no responsibility whatsoever for the information you’ll find in this collection of lecture notes. Be aware of spelling mistakes! 1
Øystein Fischer Bjelland
Physiolecture 19.09.07 The immune system Purpose of the immune system - protects the body from infection and invasion by foreign substances. - Recognizes & destroys altered cells Organs of the immune system - bone marrow - thymus - spleen - lymph nodes Cells of the immune system - all the cells of the immune system are leucocytes and originate in the bone marrow from a common precursor, the pluripotent stem cell. There are 2 kinds of immunity: - innate immunity (non-specific immunity) - adaptive immunity (specific immunity) Antigen: - a substance that reacts with antibody molecules and antigen receptors on lymphocytes - high molecular weight ( > 8000 Da) - complex - recognized as non-self The portion of an antigen that reacts with receptors on B and T lymphocytes and antibodies is called an epitope. Examples of the innate immunity: - anatomical barriers o skin, mucus membranes and bony encasements - mechanical removal o mucus and cilia; the cough and sneeze reflex; vomiting and diarrhea; and the physical flushing action of body fluids. 2
Øystein Fischer Bjelland
- bacterial antagonism o normal body flora keep potentially harmful pathogens in check and also inhibit the colonization of pathogens. - cytokines o intercellular regulatory proteins, including interleukins (IL), tumor necrosis factors (TNF), colony-stimulating factors (CSF), chemokines, and interferons (IF). Complement system - 11 complement proteins (C1 q,r,s-C9) in serum in an inactivated form sequentially activated upon recognition of certain Ag-Ab complexes. Contribution of complement components occurs in 3 phases: - recognition (c1 components) - activation (c4, c2, c3 in that order) - attack (c5-c9)=complement fixation- bind to victim cell membrane & destroy it. Adaptive immunity - adaptive immunity is a collection of antigen-specific defense mechanisms that take several days to become protective and is designed to remove a specific antigen. This type of immunity develops throughout life and involves: o antigen-presenting cells (APCs) such as macrophages and dendritic cells. o The activation and proliferation of antigen-specific Blymphocytes o The activation and proliferation of antigen-specific Tlymphocytes. o The production of antibody molecules, cytotoxic Tlymphocytes (CTLs), activated macrophages, NK (natural killer) cells and cytokines. MHC-molecules - Major histocompatibility complex molecules (MHC), are products of a gene cluster known as the major histocompatibility complex. - They are present on various human cells and enable T-lymphocytes to recognize epitopes and discriminate self from non-self. - The T-cell receptors of T-lymphocytes can only recognize epitopes after they are bound to MHC molecules.
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Two types of adaptive immunity - humoral o humoral immunity involves the production of antibody molecules in response to an antigen and is mediated by Blymphocytes. - cell-mediated o cell-mediated immunity involves the production of cytotoxic T-lymphocytes, activated macrophages, activated NK cells, and cytokines in response to an antigen. o mediated by T-lymphocytes. Humoral immunity - humoral immunity refers to the production of antibody molecules in response to an antigen. - Humoral immunity is most effective against bacteria, bacterial toxins, and viruses prior to these agents entering the cells. Antibodies - antibodies or immunoglobulins are produced by B-lymphocytes and plasma cells in response to a specific antigen - antibodies are Y-shaped glycoproteins that bind to and destroy specific antigens. - IgG, IgA, IgM, IgD, IgE - Consists of one heavy, and one light chain - There is a variable and a constant region of the chains Cell-mediated immunity - cell-mediated immunity (CMI) involves the production of cytotoxic T-lymphocytes, activated macrophages, activated NK cells, and cytokines in response to an antigen and is mediated by Tlymphocytes. - CMI is most effective in removing virus-infected cells, but also defends against fungi, protozoans, cancers, and intracellular bacteria. Immunological memory - the adapive immunesystem generally gives rise to immunity - T & B cells differentiate after meeting ”their” antigen, although most cells produced are effector cells. Some ”memory”-cells that are long lived are also made. - On later encounters with the same pathogen the memory cells are activated. 4
Øystein Fischer Bjelland
Developmental aspects of the lymphatic system and body defenses - except for thymus and spleen, the lymphoid organs are poorly developed before birth. - A newborn has no functioning lymphocytes at birth, only passive immunity from the mother. - If lymphatic vessels/nodes are blocked or removed/lost, severe edema results, but vessels can grow back in time - Nervous system helps to control the activity of the immune response - Immune system function decreases with age
Physiolecture 20.09.07 Blood groups Blood type - classification of blood based on the presence of surface antigens on red blood cells, and the presence of antibodies to surface antigens other than one’s own. Human blood groups - RBC membranes have glycoprotein antigens on their external surfaces. These antigens are: - unique to the individual - recognized as foreign if transfused into another individual - promoters of agglutination and are referred to as agglutinogens Presence or absence of these antigens is used to classify blood groups. Humans have 30 varieties of naturally occurring RBC antigens. The antigens of the ABO and Rh blood groups cause vigorous transfusion reactions when they are improperly transfused. Other blood groups (M, N, Dufy, Kell, and Lewis) are mainly used for legalities. ABO blood groups - The ABO blood groups consists of: o Two antigens (A and B) on the surface of the RBCs 5
Øystein Fischer Bjelland
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o Two antibodies in the plasma (anti-A and anti-B) an individual with ABO blood may have various types of antigens and spontaneously preformed antibodies. Agglutinogens and their corresponding antibodies cannot be mixed without serious hemolytic reactions.
The H Antigen: - base structure (e.g glycoprotein) - galactose - n-acetyl glucosamine - fucose The A antigen - base structure (e.g glycoprotein) - galactose - n-acetyl glucosamine - fucose - n-acetyl galactosamine The B antigen - base structure (e.g glycoprotein) - galactose - n-acetyl glucosamine - fuctose The ABO group - Your ABO blood type is determined by presence or absence of antigens (agglutinogens) A & B on RBCs - Blood type A person has A antigens, blood type B person has B antigens, AB has both, & blood type O has neither. - Blood type O is the most common; AB the least common. ABO blood groups Antigen (RBC) A A agglutinogen B B agglutinogen AB A & B agglutinogen O neither A nor B agg.
Antibody (plasma) ___ anti-B agglutinin 41% anti-A agglutinin 10% neither anti-AorB 4% anti-A and anti-B 45%
Antibodies (agglutinins) appear 2-8 months after birth & are at maximum concentration between 8 and 10 years.
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You do not have those antibodies that would react against your own antigens. Each antibody can attach to several antigens at the same time, causing agglutination (clumping)
Rh Blood group - there are eight different Rh agglutinogens, three of which are common - The three most common agglutinogens exist in two different variants, commonly known as C/c, D/d and E/e. - presence of the D-agglutinogen on RBCs is indicated as Rh+ - presence of the d-agglutinogen on RBCs in indicated as Rh- anti-Rh antibodies are not spontaneously formed in Rhindividuals - however, if an Rh- individual receives Rh+ blood, anti-Rh+ antibodies will form - a second exposure of Rh+ blood will result in a typical transfusion reaction.
Rh+ (D+) Rh(D-)
Antigen (RBC) Rh agglutinogen
Antibody (plasma) Rh agglutinin is never present
There is no Rh agglutinogen
normally Rh agglutinins is not present
Hemolytic disease of newborn - Mother’s antibodies attack fetal blood causing severe anemia & kernicterus (toxic brain syndrome) from excessive bilirubin in blood o treatment is phototherapy to degrade bilirubin or exchange transfusion to completely replace infant’s blood Blood typing - when serum containing anti-a of anti-b agglutinins are added to blood, agglutination will occur between the agglutinin and the corresponding agglutinogens - positive reactions indicate agglutination
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Øystein Fischer Bjelland
Physiolecture 21.09.07 Heart & circulation Chronotop: Heart rate Inotrop: strength of contraction Dromotrop: velocity of contraction Bathmotrop: excitability Terms: Atrium Ventricle Tricuspidal - Having three points, prongs, or cusps, as the tricuspid valve of the heart. - the valve closing the orifice between the right atrium and right ventricle of the heart; its three cusps are called anterior, posterior, and septal. Bicuspidal - Having two points, prongs, or cusps. - the valve closing the orifice between the left atrium and left ventricle of the heart; its two cusps are called anterior and posterior. Automatia Syncytium Eberth (lines) - lines appearing between the cells of the myocardium (muscle tissue of the heart) when stained with silver nitrate. Heart has dual circulation - pulmonary - systematic mean heartrate/min is about 70 cardiac output: 5500ml/min blood volume: 5500ml systole: contraction of the heart diastole: resting of the heart 8
Øystein Fischer Bjelland
during heavy work, systole duration decrease, but only minimal. From about 370ms (resting) to 209ms (maximal effect) refractory periods - absolute - relative absolute refractory period - the period following excitation when no response is possible regardless of the intensity of the stimulus. relative refractory period - the period between the effective refractory period and the end of the refractory period; fibers then respond only to high-intensity stimuli and the impulses conduct more slowly than normally. Fibrillation: flattening of the heart no direction of stimulation Continuous contraction: tetanus Heart muscle cannot be tetanized! (failure question) From heart: arteries To heart: veins In frogs: Sinus venosus In humans: Sinus nodes Atrioventricular node (AV node) - a small node of modified cardiac muscle fibers located near the ostium of the coronary sinus; it gives rise to the atrioventricular bundle of the conduction system of the heart. Extrasystolia (extrasystole) - an ectopic (in an abnormal place or position) beat from any source in the heart.
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Extra heartbeat (extrasystole) is followed by a compensatory pause (because of the absolute refractory period). The sinusnode is also called the sinoatrial (SA) node
Physiolecture 24.09.07 Heart Sinoatrial node is found on the lateroposterior side of the right atrium, just beneath the superior vena cava. main pacemaker of the heart. Bundle of his: - between the AV node and the branching of the AV-bundle. Between SA and AV-node, fibers are found. These fibers are known as the ”internodal pathways” main axis of excitation follows the axis of the heart. Sinus node: - pacemaker potential ”prepotential, diastolic potential” sinus-like potential - in repolarization phase, K+ channels are open makes inside negative again. Action potential generation in sinoatrial-node cells. Threshold is -30mV in the sinoatrial node. Parasympathetic stimulation releases acetylcholin which decrease the number of action potentials (APs) Sympathetic stimulation releases norepinephrine, which increase the number of action potentials. Sinoatrial node (endogenous frequency) = 100freq/min 10
Øystein Fischer Bjelland
Atrial myocardium = none Atrioventricular node, 40-55/min Velocity of conduction m/s Sinoatrial node Atrial myocardium Atrioventricular node Atrioventricular bundle Purkinje fibers Ventricular myocardium
< 0.01 1.0-1.2 0.02-0.05 1.2-2.0 2.0-4.0 0.3-10
in micrometers Sinoatrial node Atrial myocardium AV fibers His bundle branch Ventricular myocardium
2-7 3-17 3-11 9-18 10-12
The whole cardiac cycle takes about 800ms. Systole takes about 270-300ms, diastole about 500ms. The heart muscle cannot be re-excitated within the systole. 3 different ways of taking an ECG. - einthover´s leads - goldberger´s leads - wilson´s leads the lower electrode is connected to the right leg, to ground the person. Einthovers leads I: right arm, left arm II: right arm, left leg III: left arm, left leg Unipolar (monopolar) goldbergers leads only one active electrode aVR: right arm active (result negative!) aVL: left arm active aVF: left leg active 11
Øystein Fischer Bjelland
chestrecording: wilsons leads 12 different electrodes on the chest, but only 6 are usually used. V1,....V6 no active electrodes in the extremities, only on the chest.
Physiolecture 26.09.07 Heart The heart as an organ: - automaticity (e.g. frog isolated heart) - rhythmicity (systole – diastole) - impulse generation and conduction - contractility - excitability (irritability) - adaptability impulse generation and conduction - in frog heart : stannius ligatures o 1st: between the sinus venosus and the right atrium o 2nd: between atria and ventricle o 3rd: cut the apex of the ventricle intrinsic cardiac conduction system - approximately 1% of cardiac muscle cells are autorhythmic rather that contractile. Function of SA-node: initiate & distribute impulses so the heart depolarizes & contracts in orderly manner from atria to ventricles. Bachman pathway – anterior Winckebach pathway - (?) Thorel pathway – (?) Cellular level of the heart - the heart consists of single cells, each with a nucleus, connected to each other by gap junctions 12
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the heart contain contractile proteins arranged regularly (myosin & actin) cells are joined end to end – the membranes in contact form intercalated discs. Cells also branch to form a network i 3 dimensions. This arrangement of cells is called a syncytium. Any stimulus applied, the impulse in one cell will be conducted to all others – functional syncytium
All myocardial cells - gap junctions at intercalated discs autorhythmic myocardial cells - (pacemakers) are small myocardial cells with few contractile fibers - spontaneously generate action potentials - enables the heart to contract without any outside signal - the heart is myogenic: signal for contraction originates from heart muscle itself most myocardial cells - remaining myocardial cells are striated - have sarcomers - much smaller than skeletal muscle fibers - connected by gap junctions at intercalated discs - lots of mitochondria - extensive blood flow to myocardial cells the membranes of the two cells forming the intercalated discs are - very close together but o separated by extracellular fluid o bridged by gap junctions & held mechanically by desmosomes cells -
two kinds of cells: o impulse generators and conductors o working muscle cells
The hearts main pacemaker is the sinoatrial node. Electrical changes 13
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electrical changes occur at the level of the membrane and these changes are summarized as changes of excitability of the muscle cell. The changes occurring inside the cell will produce the contraction (the mechanical activity of the heart)
How are the electrical properties of the membrane changing? - resting heart - we apply a threshold stimulus: contraction - we apply a second stimulus 1. if the time interval is very short: no response – absolute refractory period (arp) 2. if the time is longer between the 2 stimuli: local electrical potential – effective refractory period (erp) 3. if the time is longer again, stimulation with higher intensity of stimulus: contraction – relative refractory period (rrp) arp, erp, rrp together: - total refractory period Extrasystole: A new systole is initiated before the current systole is finished. Working muscle cells: 5 components: 1. sarcolemma - 2 major functions - electrical properties - elastic properties organiation of sarcolemma: t-tubules oriented in vertical direction to the axis of the muscle 2. nucleus 3. mitochondria 4. sarcoplasmic reticulum - L-tubules, terminal cisterna, triad - diad 5. myofibrils Ca2+ signaling in cardiac muscle 1. action potential enters from adjacent cell 2. voltage-gated Ca2+ channels open. Ca2+ enters cell. 3. Ca2+ induces Ca2+ release through ryanodine receptor-channel (RyR) 14
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4. Local release causes Ca2+ spark 5. Summed Ca2+ sparks create a Ca2+ signal 6. Ca2+ ions bind to troponin to initiate contraction 7. Relaxation occurs when Ca2+ unbinds from troponin 8. Ca2+ is pumped back into sarcoplasmic reticulum for storage 9. Ca2+ is exchanged with Na+ 10. Na+ gradient maintained by Na+/K+ ATPase. Excitation-contraction coupling - APs come and enter the cells at the t-tubules - ion channels are opened - Ca2+ are mobilized from terminal cisterna - Ca2+ binds to troponin C, which turns tropomyosin away from the actin - Actin binding place will now be free, so myosin can bind. Ca2+-ion movements in cardiac muscle cells 1. slow inward flow during the slow repolarization phase of the AP 2. exchange of 2Ca2+ by 3Na+ through the membrane 3. active pump Ca2+ is exchanged by 2 H+ 4. mitochondria: exchange with 2 Na+ 5. sarcoplasmic reticulum 6. around the membrane there is a large store of Ca2+. 5+6 is the main storage places for Ca2+.
Physiolecture 27.09.07 Mechanical activity of the heart -
the different components of the muscle cells are grouped in an excellent model prepared by HILL - the three component model of the muscle
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parallel elastic elements (sarcolemma, extracellular elastic components, such as connective tissue) contractile element (actin, myosin, modulator proteins) series elastic elements (intercalated discs, intracellular elastic components, such as the sarcoplasmic reticulum)
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Length-tension relationships - there is an optimal sarcomere length for generating a maximal force during contraction. - As blood enters the ventricle, it expands and the sarcomere length increases - The stroke volume increases when the force of contraction increases. Starlings heart-lung preparation - the relationship between stretch and force in the intact heart. - the force of contraction (stroke volume) is proportional to the end-diastolic volume. - Within physiological limits, the heart pumps all the blood that returns to it. - The more cardiac muscle is stretched within physiological limits, the more forcibly it will contract. - Increasing volume of blood in ventricles increase the stretch & thus the force generated by ventricular wall contraction. - Greater stretch means more blood volume is pumped out, up to certain limits. Increased blood volume = increased stretch of myocardium = increased strength to pump blood out Cardiac cycle - pressure - volume - electrical changes (during systole and diastole) refers to the repeating pattern of contraction and relaxation of the heart. - systole : 230ms o phase of contraction - diastole: 570ms o phase of relaxation - end-diastolic volume (EDV) 145ml o total volume of blood in the ventricles at the end of diastole - stroke volume (SV) 80ml o amount of blood ejected from ventricles during systole 16
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end-systolic volume (ESV) 65ml o amount of blood left in the ventricles at the end of systole.
Phase 1: atrial contraction 2: isovolumetric contraction 3: rapid ejection 4: reduced ejection 5: isovolumetric relaxation 6: rapid ventricular filling 7: slow ventricular filing (diastasis) atrial contraction: (110ms) - ventricle are full of blood - pressure low in the ventricle - P wave on the ECG Isovolumetric contraction (50ms) - the ventricle contracts - pressure rises in the ventricle - mitral valve closes - QRS complex on the ECG - 1st heart sound - and upward deflection is called an R wave whether it is preceded by a Q wave or not - any deflection below the baseline following an R wave is called an S wave whether there has been a preceding Q wave or not. rapid ejection (90ms) reduced ejection(130ms) - the aortic valve opens - blood ejected into the aorta - T wave at the end of the period on the ECG Isovolumetric relaxation (80ms) - the ventricle relaxes - aortic valve closes - pressure falls in the ventricle - 2nd heart sound rapid ventricular filling (110ms) slow ventricular filling (190ms) - the ventricle has relaxed 17
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pressure is now lower in the ventricle than in the atrium, which causes the mitral valve to open ventricles fill with blood slow filling phase is also called diastasis a 3rd heart sound would be from the rapid filling.
70% of the blood flows passively from the atria to the ventricles. Of three heart sounds, only two are generally heard with the stethoscope. S1 is generally the longest and loudest. It occurs at the beginning of systole. S2 occurs at the end of systole S3 is low pitched and occurs during early ventricular filling. The normal PR interval is 0.12-0.20s, represented by 3-5 small squares. Most of the time is taken up by the delay in the AV node, or there is abnormally fast conduction from the atria to the ventricles. The duration of the QRS complex shows how long excitation takes to spread through the ventricles. The QRS duration is normally 0.12s or less, but any abnormality of conduction takes longer, and causes widened QRS complexes. The ECG machine is arranged so that when a depolarization wave spreads towards a lead the stylus moves upward, and when it spreads away from the lead the stylus moves downwards. QRS complex in the V leads: - the septum between the ventricles is depolarized before the walls of the ventricles and the depolarization wave spreads across the septum from left to right. - In the normal heart there is more muscle in the wall of the left ventricle than in that of the right ventricle, and so the left ventricle exerts more influence on the ECG pattern than the right ventricle does. First-degree heart block: If each wave of depolarization that originates in the SA node is conducted to the ventricles, but there is delay somewhere along the conduction pathway, then the PR interval is prolonged. It might be a sign of coronary artery disease, acute rheumatic carditis... Second degree heart block:
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Sometimes excitation completely fails to pass through the AV node or the bundle of His. This occurs at irregular intervals. There are 3 variations: - most beats are conducted with a constant PR interval, but occasionally there is an atrial contraction without a subsequent ventricular contraction. - There may be progressive lengthening of the PR interval and then failure of conduction of an atrial beat, followed by a conducted beat with a shorter PR interval and then a repetition of this cycle. - There may be alternate conducted and non-conducted atrial beats, giving twice (or three times) as many P waves as QRS complexes. This is called 2:1 (two to one) conduction. The extra P wave may show itself as a distortion of the T wave. Third degree heart block: Complete heart block is said to occur when atrial contraction is normal but no beats are conducted to the ventricles. When this occurs, the ventricles are excited by a slow ”escape mechanism” (ventricular escape) from a depolarizing focus within the ventricular muscle. No relationship between P waves and QRS complexes!
Physiolecture 28.09.07 Heart sounds -
Auscultation stethoscope phonocardiography
first heart sound - results from closure of atrioventricular valves at the beginning of ventricular systole second heart sound - results from closure of aortic and pulmonary semilunar valves at the beginning of ventricular diastole, lasts longer third heart sound (occasional) - turbulent blood flow in rapid filling of heart abnormal heart sounds 19
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heart murmur o extra sounds heard during cardiac cycle. Associated with valve disorder stenotic valve: abnormally narrow valve that does not fully open insufficient valve: a valve that does not fully close
punctum maximums: points of auscultation 2nd intercostal space, right to the sternum: aortic 2nd intercostal space, left to the sternum: pulmonary 4th intercostal space right to sternum: bicuspid v. Tricuspid is found at the point of the apex, in the midclavicular line. The first heart sound appears at the R wave, the second at the last part of the T wave. 2L3 2 is the second intercostal space L is left of sternum 3 is 3cm away from sternum 1st heart sound - atrial systole - closure of the cuspidal valves - opening of the semilunar valves - vibration of the ventricular wall and the blood stream 2nd heart sound - relaxation of the wall of the ventricle - closure of the semilunar valves - vibration of the wall of the aorta - opening of the cuspidal valves 3rd heart sound - rapid ventricular filling sometimes your can hear a 4th heart sound, not physiological! Separated from the other 3 heart sounds. A 5th sound is also possible to hear, but not under physiological conditions. Cardiac output (CO) - the amount of blood pumped by a ventricle per minute. - Heart rate: number of cardiac cycles per minutes = 70 ±10/min 20
Øystein Fischer Bjelland
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Stroke volume: amount of blood pumped out of a ventricle each beat. Average resting stroke volume = 80ml CO = heart rate x stoke volume = 5-6 L/min
Factors affecting heart rate - autonomic innervation - sympathetic stimulus increases heart rate - parasympathetic stimulation decreases heart rate. - Hormones o Epinephrine: increase heart rate o Tachycardia = resting HR > 100b/min o Bradycardia = resting HR 2000 in vivo Re > 1000 Turbulent flow - needs larger pressure, more energy (v2) - noise/murmur o valve errors o narrowing of arteries o measure blood pressure 23
Øystein Fischer Bjelland
peripheral resistance % arterioles 47 arteries 19 veins 7 capillaries 27 sympathetic stimulation - critical closing pressure is just above 15 Hgmm, it will block the vessels. Blood is a non nutonic liquid. Viscosity is not constant, directly proportional with the hematocrit. It is inverse proportional to the flow velocity. Viscosity is proportional to the diameter of the vessel. What are these good for? - understand mechanism of diseases - understand possible therapies ex: poisevilles law : arterioles hypertony bernoullis law : stenosis closure aneurism rupture laplace law: ventricular hypertrophy arterial pressure - systolic, diastolic, pulse, mean pressure - determinants of ABP - fluctuations of ABP by time - normal values - factors affecting ABP ABP = arterial blood pressure pulse pressure - the variation in blood pressure occurring in an artery during the cardiac cycle; it is the difference between the systolic or maximum and diastolic or minimum pressures. how quick to measure the bloodpressure? 24
Øystein Fischer Bjelland
depending on the heartrate; not more than 5 mmHg down per heartbeat changes of arterial blood pressure by time: - during inspiration there is a rise in blood pressure - during expiration there is a drop in blood pressure primary waves: (systole/diastole) 70/min secondary waves: (inspiration/expiration)20/min tertiary waves: (chemoreceptors) 3/min daily blood pressure changes; sleeping 90/60 waking up 120/80 boss comes in 140/80 drop in the early afternoon (tired, hungry) rise around 16-17 heavy muscular exercise in the afternoon, 150/80 sex 160/80 sleep 90/60 experiments on arterial blood pressure TPR rise: systolic rise, diastolic pressure rise Mean arterial pressure rises Determinants of arterial blood pressure - cardiac output - total peripheral resistance - elasticity of aorta - isovolemy (beginning of circulatory system must be overfilled, about 7 mmHg) effect of gravity: 1g : 1cm = 0.1kPa = 0.77 mmHg Top of head if you stand up : -40cm: 100-30 mmHg In legs: +100 cm: 100 + 77 mmHg Blood pressure Baby: 80/50 Child 90/60 Adolescent 105/70 Adult 120/80 < 60 / 40 hypotonia, low blood pressure 25
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border > 140/90 hypertonia, high blood pressure factors affecting arterial blood pressure - age - part of the day, sleeping - body position - muscular work - psychological stress - painful stimuli - under/overnourished - climate arterial pulse - wave type - pulse curve; shape & parts - palpation locations - pulse qualities - central and peripheral pulse curves anacrot = rising pulse wave velocity of pulse wave aorta 4-6 m/sec a.radialis 10-12 m/sec by ageing, arteriosclerosis: 10-15 m/sec velocity of blood flow < 30 cm/sec locations of pulse palpation: - temporal art. - Carotid art. - Axillary art - Cubital art - Radial art - Femoral art - Popliteal art - Dorsal pedis art Pulse qualities: - regularity - rate - width - amplitude
regular / irregular rapid / slow filled / thin large / small 26
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- quickness - hardness
fast / slow (how fast to max amplitude) hard / soft
what type of pulse qualities would you observe in a fainted person? < 60 bradycardia >100 tachycardia
Physiolecture 03.10.07 Circulation in the capillaries Largest drop in blood pressure is found in the arteries. In the postcapillaries circulation the pressure is almost zero. Metarterioles have no continuous smooth muscle cover. Precapillary sphincter is responsible for control of microcirculation. True capillaries are highly anastomosed. - Vasomotion (change in caliber of a blood vessel) does not require innervation In demand for oxygen increases, the frequency (open/close) is changed by vasomotion. This is also true for the opposite. Transfer of substances through the capillary wall - filtration - diffusion - pinocytosis (The cellular process of actively engulfing liquid, a phenomenon in which minute invaginations are formed in the surface of the cell membrane and close to form fluid-filled vesicles; it resembles phagocytosis.) diffusible substances - lipid-soluble (e.g. O2, CO2) o diffuse directly through the capillary wall - water-soluble (e.g. glucose) o only through pores structure of capillaries 27
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systemic o r = 3µ, length: 750µ
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pulmonary o r = 4µ, length: 350µ
How can we estimate? - number of capillaries? - Total surface area for exchange between capillaries and surrounding tissue A1V1 = A 2V2 How can capillary withstand 100Hgmm pressure? Structure of the capillary wall - continuous, e.g. brain - fenestrated, e.g. kidney - non continuous, e.g. liver, spleen capillary pores - intra-cellular: 20-25nm - inter-cellular: 4-4.5nm - basement membrane: 20-60nm CO2 is about 10 times more diffusible than O2. Regulation of microcirculation - paracrine o bradykinin o prostacyclin o thromboxane o histamine o serotonine o NO - Endocrine o Adrenal medulla - Neurocrine o Axon reflex o Sympathic α1 axon reflex Regulation of bloodflow is due to the smooth muscles in the vessels. There is no way to directly regulate bloodflow in the capillaries 28
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Control of microcirculation - effect of metabolite o hypoxia o hypercapnia (increased level of CO2) o adenosine o lactate o [H+] o [K+]
Physiolecture 04.10.07 Microcirculation cGMP is responsible for vasodilation. Phosphodiester-5 inactivates cGMP. Bradykinin is another vasodilator. It also does visceral smooth muscle contraction. Prostaglandin forms prostanoid, which either makes thromboxane (which is a constrictor), or prostacyclin, bradykinin and NO (which relax smooth muscle and increase blood flow). Another vasoconstrictor is insulin. Calcium is very important for smooth muscle contraction. NO will inhibit the influx of Ca2+. Effective filtration pressure - dependent on osmotic pressure and hydrostatic pressure being in equilibrium. - Removal of fluid causes changes in osmotic pressure, additional fluid causes hydrostatic pressure (reabsorption and filtration) 30 mmHg / 10 mmHg (arterial part / venous part of the capillaries) In the venous side there is a net reabsorption. In the arterial side there is a net filtration. Q = CFC x Peff CFC = capillary filtration coefficient Peff = effective pressure (?) 29
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Q= Oncotic pressure (osmotic pressure exerted by colloids in solution) is due to the proteins
Physiolecture 05.10.07 Microcirculation Filtration and reabsorbtion in the capillaries is in equilibrium at 17 mmHg. Resistance is 4 times greater in the arterioles than in the venules. What is the role of the lymphatic system? - recycling the excess of water to the circulation, which was filtered but not reabsorbed. - Recycling of useful substances (proteins, ions..) - Immunological functions Large lymph vessels are built up of pores, valves, and collecting ducts. Type of edema - Pitting (one presses the skin over the edematous area and suddenly removes the finger, small depression is called ”pit” remains. - Due to translocation of water - Non pitting o The fluid can not be mobilized (e.g. infected or damaged tissue) Causes of edema - cardiac edema - obstruction of vein o thrombosis - renal edema - obstruction of lymph vessels o cancer - increased permeability of capillaries o inflammation, allergic reaction - decreased oncotic pressure o malnutrition 30
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composition of the lymph - protein (20-40 g/l) - ions (Na+, K+, Cl-, Ca2+, Mg2+, phosphate) - WBC, RBC, thrombocyte - Globulins, antibodies - Lipoproteins - Blood clotting factors - Tissue debris, bacteria Of venous return - vis a tergo (a force acting from behind; a pushing or accelerating force.) o the work of the heart pressure gradient from the left ventricle to the right atrium - vis a fronte (a force acting from in front; an obstructive, restraining, or impeding force.) o suckling effect on large veins due to the contraction of heart muscle (negative pressure) - vis a laterale o muscle pump o thoracoabdominal pump o arterial pulsation distribution of blood - high pressure compartments = 86 % - low pressure compartments = 14%
Physiolecture 08.10.07 pulmonary circulation pulmonary circulation and systemic circulation are interconnected Resting cardiac output is the same for pulmonary circulation as for the systemic circulation = 5-5.5L/min = total amount of blood in the body
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During inspiration the right atria filling is greater than the left atria filling. During expiration the left atria filling is greater than the right atria filling. In general: - the blood vessels of the lesser circulation are thinner as far as the wall is concerned, but their diameter is usually bigger, compared to their counterpart in the systemic circulation. - Thinner because of less smooth muscle in the wall. Pulmonary arteries: - bigger compliance, and much larger amount of smooth muscles, there are no real arterioles in the pulmonary circulation. - The total vascular resistance consists of the arterioles, capillaries ..... (?) Pulmonary capillaries: - diameter is close to 8 micrometers (7-10); major difference from systemic circulation (5-6). - Also shorter than in systemic circulation, about 350 micrometers long. - Transit time is less than one second. (750ms as mean) The capillaries surround the alveoli of the lungs. Actual alveolar surface, and the total surface of the pulmonary capillaries are equal = 60-80sq.meters The blood volume in resting condition found in the pulmonary capillaries is 67ml, but can increase 3 times when needed. In extreme needs of oxygen, the transit time decrease substantially, from 750ms to 350ms. About ¼ of the total blood amount is found in the pulmonary circulation. Why is the pulmonary circulation considered a low-pressure circulation? - because of the .... (?) mean arterial pressure is about 93 mmHg 32
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systolic pressure once, diastolic pressure twice, divide by 3 270 ms systole = 120 mmHg 530 ms diastole = 80 mmHg 2-3 mmHg in the right atrium pressure drop in the systemic circulation = mean art pressure - pressure in right atrium = 90 mmHg systolic blood pressure in pulmonary artery is about 24 mmHg. Diastolic pressure is 9 mmHg. Mean arterial blood pressure is 14 mmHg. (1 systole + 2 diastole / 3) Pressure drop in the pulmonary circulation is 14-8 = 6 mmHg 15 times different from the systemic circulation! Pulmonary veins = 9 mmHg Pulmonary capillaries = 10 mmHg Left atrium = 8 mmHg Pressure in the left atrium is higher than in the right atrium. Much smaller resistance is found in the pulmonary arteries than in the systemic arteries. Influence of the gravity on the lesser circulation: Gravity and hydrostatic pressure makes .. (?) Intermediate hilar zone of the lung Total height of the lung is about 34-35 cm; the apex is remarkably higher than the heart, while the base is found lower than the heart. The actual perfusion pressure in the apical zone of the lung is substantially large compared to either the intermediate or basal zone of the lung. The hydrostatic pressure has to be subtracted from the mean arterial pressure (?) In case of the basal zone, the situation is the opposite. Due to gravity, the pressure values are 5-8 mmHg higher compared to the pressure levels as that of the heart. Lung is divided into 3 zones: apical, intermediate and basal zone. 33
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In the very apical zone, due to the effect of the hydrostatic pressure, the alveoli pressure can exceed the arteriolar pressure. The capillaries can be compressed by the alveoli, and the blood flow can be temporarily stopped. In the intermediate zone, there is no problem of the arterial pressure, but the alveolar pressure can exceed the pressure in the venous end of the capillaries. It is only the apical part of the lung where the blood flow is discontinuous during diastole. (?) Apical zone has a poorer perfusion than the 2 other zones. can result in accommodation of microorganisms, infection agents... more susceptible to getting infections the oncotic pressure is more or less the same in the circulations. hydrostatic pressure is larger in the pulmonary circulation. Increased outflow of the capillaries increased interstitial volume; gets into the alveoli pulmonary edema no gas exchange can take place in the alveoli! pulmonary edema is fatal! Left ventricular failure, development of mitral stenosis, Regulation of the blood flow in the pulmonary circulation: - sharply different from the systemic circulation in that hypoxia and hypercapnia results in vasoconstriction in the pulmonary circulation. What is the consequence of vasoconstriction in the pulmonary circulation? Poorly ventilated parts of the lung gets closed of from the rest of the circulation, ¼ of total blood volume is found in pulmonary circ. = more than 1 liter. Can function as a blood reservoir in case of special needs of the organism. Very rapidly mobilizable. (e.g. standing up)
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filtering function: - atherosclerotic plac which comes of in the pulmonary circulation can cause big problems in the systemic circulation, (e.g. closing coronary blood vessels, necrosis of relatively big parts of heart muscle.) - blocking of major pulmonary arteries can be fatal, but smaller arterial branches blocked may be without major consequences. BRAIN Weight: 1400-1500grams = 2-3% of total body weight Cerebral circulation requires about 15% of resting cardiac output. Oxygen requirement is 20-25% of total. Neurons of the brain use glucose as fuel for metabolic needs. A temporary stop in blood flow cause serious pathological alterations. 5 seconds of total stop in cerebellar blood flow causes functional disturbances. 10 seconds of stop result in loss of consciousness. More than 3 minutes; irreversible consequences, loss of neurons etc Cerebral circulation - In resting condition, the cerebral circulation is free of influence of the autonomic nervous system. - Existence of blood-brain barrier. - Autoregulation capacity of cerebral blood flow. ( - interstitial fluid and the cerebral spinal fluid are results of special secretory processes ) - the brain is located in the skull, whose capacity is constant, the whole brain/fluid has to coexist in this constant space of the skull. - Monro - Kellis doctrine which states that: the cranial cavity is a closed rigid box and that therefore a change in the quantity of intracranial blood can occur only through the displacement of or replacement by cerebrospinal fluid the perfusion of the brain is constant. Blood supply of the brain: The rostral part (2/3) is supplied by the internal carotid artery Vertebral arteries supply the posterior part. 35
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Posterior interconnecting small arteries make connection between internal carotid arteries and vertebral arteries.
Physiolecture 10.10.07 Cerebral circulation Internal carotid + vertebral artery supplies the brain Blood supply is unilateral for the hemispheres. TIA : transient ischemic attack 1. The lack of direct influence of sympathetic and parasympathetic innervation on the cerebral blood vessels 3. Existence of the blood-brain barrier: - interstitial fluid and cerebral fluid are the product of special secretory mechanism. 4. the brain is found in a closed compartment whose capacity is constant. 75ml blood is found in the brain cerebral spinal fluid = 140ml 1400-1500g brain itself intracranial pressure never exceeds 10 mmHg. When intracranial pressure increases, (appearance of brain tumors) symptoms of the cushing-reflex develop, - shock - rapid increase of blood pressure - decrease of heart rate - decrease of rate of respiration (the blood volume increases due to hemorrhages) increase in cerebral blood flow may result in loss of consciousness. Higher concentration of K+, adenosine, H+ vasodilation
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Active regions of the brain receive more blood than the inactive region. functional hyperemia Blood-brain barrier: - separation of the blood compartment of the extracellular space of the brain from the interstitial space of the brain. - ”windows barrier” circumventricular region/ organs of the brain - this is where this blood-brain barrier doesn’t exist. - This barrier is especially important in medication. Endothelial cells of the brain is tightly bound by tight junction, only water diffusion is possible Glucose cannot diffuse freely through the endothelium, but need help from special compounds. Na-ions are transported to the brain interstitium by 2 methods: NaCl-transporter + Na-K pump Membrane of glial cells can take up K+-ions very easily K+ concentration In the plasma : 4mmol/liter In interstitial fluid: less than 3mmol/liter
Physiolecture 11.10.07 Cerebral circulation Cerebral-spinal fluid is produced by endothelium of choroid plexuses. CSF (constant volume of cerebral fluid) = 140-150ml The brain ”floats” in the cerebral fluid ”cushioning” prevents the brain from getting damaged by movement.
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Capillary endothelial cells are very tight connected to each other in the brain. Capillary endothelial cells are loosely connected in the choroid plexuses. 2 mechanisms for getting sodium into the interstitial space: -
sodium-proton mechanism, helps the sodium ions getting into the interstitial space, takes proton out of the cell.
Sodium-chloride co-transporter Splanchnic circulation Consists of organs of the GI tract, liver, pancreas and spleen. Represent the major circulatory unit. Receives ¼ of the cardiac output at rest. Blood flow can increase 7-8 times. Can decrease blood flow 3-4 times of cardiac output. There is different blood supply to various part of the splanchnic circulation. The mucosal blood flow is much higher compared to that of the muscular layers. Blood flow increases in the active part of the GI tract. Mechanisms: - vasodilation - vasocontriction vasoconstriction: - activation of splanchnic nerves vasodilatory: - local metabolite increase, partial pressure of CO, increase of local concentration of hydrogen ions, potassium ions. - VIP (vasointestinal peptide) is the major vasodilator in the splanchnic circulation. Liver have double blood supply - Hepatic artery (1/3 - 1/4) - Portal vein also contributes to the blood supply (2/3 - 3/4) Oxygen supply of liver: 38
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more than 50% (2/3) of oxygen needed by the liver comes from hepatic artery. Circulation of the skin
The metabolic needs decide the blood flow of certain organs; this is not the case of the skin. Here thermoregulation is the main regulator. in case of cold environment it is important for the body not to loose temperature vasoconstriction takes place, achieved by α1noradrenalin receptors in hot environment: vasodilation takes place, achieved by local metabolic factors, increase of partial pressure of C.O.... apical areas/regions ( nose, ears, fingers) where surface area/volume is high. Arteriovenous shunts make sure these areas get blood much faster than other places. Skeletal muscle represents 40-50% of total body weight. maximal cardiac output is 24L/min. During contraction the blood vessels are compressed. Any major increase of heart rate, decrease the duration of diastole! The Normal value is 530ms diastole and 270ms systole. Can change to 200ms for systole, less than 200ms for diastole. Neural, humoral, local metabolic can regulate blood flow, peripheral resistance and blood volume.
Physiolecture 12.10.07 Respiration Air: - oxygen 20.95%; nitrogen 78.08%; argon 0.93%; carbon dioxide 0.03%; other gases 0.01% 39
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internal respiration: - gas exchange between blood and tissues. Asphyxia - Impaired or absent exchange of oxygen and carbon dioxide on a ventilatory basis; combined hypercapnia and hypoxia or anoxia. Trachea : 2.5 cm2 surface Lungs: 70 m2 per lung Palpation: - 3rd finger put to the surface of the chest, between the ribs, tap with your other 3rd finger. Nasal cavity: - 16 cm2 surface cilia moves dust/particles upwards in the respiratory system at a speed of 1cm/min bronchoconstriction - Reduction in the caliber of a bronchus or bronchi, usually referring to a dynamic process as in asthma and emphysema, rather than a fixed constriction (the latter is a bronchial stenosis) Bronchodilatation - Increase in caliber of the bronchi and bronchioles in response to pharmacologically active substances or autonomic nervous activity. β2 receptor activity cause bronchodilatation. acetylcholin, vagal/parasympathetic or muscarine receptor activity results in bronchorestriction. VIP = vasointestinal-polypeptide activity result in vasodilatation asthma-treatment - give β2-stimulatory preparations. 40
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Excessive use would cause problems with the heart accelerating of heartrate. Gas exchange in the lungs start at the level of the respiratory bronchioles; the 17th division of the bronchial tree.
Physiolecture 15.10.07 Respiration Dipalmitoyl-phospatidylcholin is the main agent responsible for reducing the surface tension. It does this by not dissolving uniformly in the fluid lining the alveolar surface. anatomic dead space the volume of the conducting airways from the external environment (at the nose and mouth) down to the level at which inspired gas exchanges oxygen and carbon dioxide with pulmonary capillary blood; formerly presumed to extend down to the beginning of alveolar epithelium in the respiratory bronchioles, but more recent evidence indicates that effective gas exchange extends some distance up the thicker-walled conducting airways because of rapid longitudinal mixing. Type II pneumocyte is also called ”septal cell”. This type of cell is under vagal control. Early born children may have problems because of insufficient amount of surfactant. Air-blood barrier: - fluid surfactant - alveolar epithelium - alveolar epithelia basement membrane - interstitial space - capillary basement membrane - capillary endothelial cell eupnoea 41
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Normal respiration, with normal volume in rest. About 500ml air per inhalation. Up to 200l / min at full work
polypnoe, tachypnoe hyperpnoea - more respiration, bigger volume dyspnoe - respirate in a heavy condition - involves heavy muscular work apnoe - stop of respiration - same as asphyxia (closure somewhere in the respiratory tract) apneusis - respiration is stopped in an inspiratory situation hyperventilation - more respiration than needed hypoventilation - lower respiration than needed mechanics of respiration diaphragm moves downward, creates negative pressure diaphragm is innervated by the phrenic nerve, which originates from C4. Pleural suck Normal atmospherical pressure is 760 mmHg. Pressure in pleura is 756 mmHg; ”intrapleural pressure” contributes to the pleural suck ”negative pressure” Resting tidal volume = 500ml Resting tidal volume + inspiratory reserve volume = inspiratory capacity = 3600ml
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Vital capacity = inspiratory capacity + expiratory reserve volume = 5000ml Residual volume = about 1000ml, cannot be expired, always present in the lungs. Functional residual capacity = expiratory reserve volume + residual volume = 2400ml Vital capacity can be trained to be larger. Total lung capacity = vital capacity + residual volume = 6000ml Pulmonary metabolism of vasoactive substances: Activation Angiotensin I angiotensin II Inactivation Bradykinin Serotonin PGE, PGF Norepinephrine Histamine (probably) Total ventilation = 7500ml Anatomic dead space = 150ml Total alveolar gas = 3000ml Alveolar ventilation = 5250ml Pulmonary capillary blood = 70ml Pulmonary blood flow = 5000ml/min
Physiolecture 17.10.07 Pulmonary circulation Pressure decreases sharply at the arterioles in the circulatory circulation because of a sudden increase in surface area. 43
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In the pulmonary circulation this is not the case, since arterioles are not present. Net pressure from arteries to the pulmonary capillaries is 15 mmHg. Failure of the left side of the heart is the most common reason for pulmonary edema. The circulation is generally better in the lower part of the lung than in the upper part. gravity partial pressure of H2O in the respiratory gases, inside the body is 47 mmHg. Atmospheric pressure is 760 mmHg. Alveolar air - pO2 = 100 mmHg - pCO2 = 40 mmHg arterial blood - pO2 = 96 mmHg - pCO2 = 40 mmHg venous blood - pO2 = 40 mmHg - pCO2 = 46 mmHg
Physiolecture 18.10.07 Pulmonary circulation Myoglobin can only bind one molecule of oxygen, while hemoglobin can bind four molecules of oxygen. Myoglobin is a little bit easier saturated than hemoglobin. Weight of myoglobin vs. hemoglobin: 19000 Da vs. 68000 Da pH highly modifies the hemoglobin saturation curve. 44
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Low pH shifts curve to right, high pH shifts curve to left. Body temperature also modifies the curve. Higher temperature makes the curve shift to right, while lower temp makes the curve shift to left. Present CO2 concentration will also modify the curve. pH = 6.1 + log (HCO3-)/0,0301 PCO2 oxygen + hemoglobin = oxyhemoglobin 0-3% of oxygen is found dissolved in water, while the rest 97% is bound to hemoglobin. Hemoglobin Fe2+ Hemiglobin Fe3+ methaemoglobinaemia CO binds to hemoglobin 180 times stronger than CO2 and O2. Hamburger shift (chloride shift) - when CO2 enters the blood from the tissues, it passes into the red blood cell and is converted by carbonate dehydratase to bicarbonate (HCO3-); HCO3- ion passes out into the plasma while Cl- migrates into the red blood cell. Reverse changes occur in the lungs when CO2 is eliminated from the blood. The shift contributes to keep the pH constant, because CO2 is transported as HCO3-. CO2 travels in the body in 3 different ways Physically solved form 3% 70% HCO3- (hamburger shift) 30% carbaminoform (bound to NH2) - Carbon dioxide bound to hemoglobin by means of a reactive amino group on the latter, i.e., Hb–NHCOOH; approximately 30% of the total content of carbon dioxide in blood is combined with hemoglobin in this manner.
Physiolecture 19.10.07 Chemical control of respiration Pneumotaxic area inhibits respiration, located in the upper pons. 45
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Apneustic area stimulates respiration, located in the lower pons. After maximal hyperventilation for a certain time, respiration will stop. This is due to elevated values of CO2. (?) CO2 diffuses 20 times better than oxygen. Carotid bodies are found at the bifurcation of the carotid artery. These bodies are in close relation with the vagus nerve. They respond to changes of pO2, pCO2, and pH in arterial blood. Impulses travel to the CNS through Hering´s nerve (branch of CN IX). Aortic bodies are found near the aortic arch. These bodies are in close relation with the glossopharyngeal nerve.
Physiolecture 20.10.07 Neural regulatory mechanisms of respiration High-pressure pure oxygen is used for artificial respiration: used for children born into incubators can destroy certain parts of the retina, which will eventually result in blindness. High-pressure pure oxygen used in adults: CO2 being produced in the tissue cannot be transported into the erythrocytes because the hemoglobin is still oxygenated at the venous side. tissue hypercapnia In acute hypoxia pure oxygen must be used. Reflexes of the lung Inflation of the lung artificially would evoke deflation Hering-Breuer reflex - the effects of afferent impulses from the pulmonary vagi in the control of respiration; e.g., inflation of the lungs arrests inspiration with expiration then ensuing, whereas deflation of the lungs brings on inspiration. 46
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Anoxia - Absence or almost complete absence of oxygen from inspired gases, arterial blood, or tissues; to be differentiated from hypoxia. Hypoxia: - pO2 is very low, can be acute, chronic Anemic hypoxia: - not enough Hb in your body, or not enough red blood cells. Stagnating hypoxia - circulation failure, venous blood is more (?), stasis in the circulation. Perfusion in not good enough. Diffusion hypoxia - problem with diffusion of oxygen towards the tissue cytotoxic hypoxia - due to tissue poisoning; will lead to death air embolia injection of air through a syringe daily secretion of intestinal juices see book for details parotid gland is a serous gland (produce α-amylase (ptyalin) sublingual gland is mucinuous (produce mucin) submaxillary is a mixed gland primary secretion in the secretory part, concentration of secretory product changes in the duct. Saliva is a little bit acidic. Function of saliva: Moistening: mucous membrane (speech) Dissolving - diluting function: solid materials (dust, powder, sand; dilution of acids and alkaline materials). Taste-receptors - dilution, washing out 47
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Lubrication: mixed saliva (mucin) coats bites of food Digestion: α-amylase (1-4 glycoside bounds) Cleaning teeth: cleaning mouth and teeth (prevents caries) Bacteriostatic effects Secretory effects: heavy meal salts, rhodanide Mouth drying (loss of water/ions): thirst Via the mouth infection with saliva: (poliomyelitis, rabies, etc.)
Physiolecture 24.10.07 The gastrointestinal tract Swallowing - purpose: guide food into the esophagus o voluntary stage o pharyngeal stage food is directed correctly into esophagus relaxation of pharyngoesophageal sphincter o esophageal stage peristalsis propels food toward stomach relaxation of gastroesophageal sphincter (cardia) oropharyngeal phase: 1 sec, from the mouth to the esophagus bolus is prevented from: - reentering the mouth (tongue) - entering the nasal passage (soft palate, uvula) - entering the trachea (vocal folds, epiglottis, inhibition of respiratory control) 1. Tongue pushes bolus against soft palate and back of mouth, triggering swallowing reflex. 2. Upper esophageal sphincter relaxes while epiglottis closes to keep swallowed material out of the airways. 48
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esophageal phase 5-9 sec primary peristaltic wave (vagus) secondary peristaltic wave (intrinsic nerve plexuses) 3. Food moves downward into the esophagus, propelled by peristaltic waves and aided by gravity. Esophagus - primary function is to conduct food from pharynx to stomach - during the esophageal phase of swallowing, primary peristalsis, initiated by distension of the pharynx, pushes the food toward the GastroEsphagealSphincter. - Any food that remains after primary peristalsis stimulates secondary peristalsis. - GES (a physiologic sphincter) relaxes Peristalsis: - produced by a series of localized reflexes in response to distention of wall by bolus wave-like muscular contraction: - circular smooth muscle contract behind, relaxes in front of the bolus. - Followed by longitudinal contraction (shortening) of smooth muscle. o Rate of 2-4 cm/sec - after food passes into stomach, LES (lower esophageal sphincter) constricts Stomach - most distensible part of the GI tract. o Empties into the duodenum - functions of the stomach: o stores food o initiates digestion of proteins o kills bacteria (because of e.g. HCl) o moves food (chyme) into intestine. Electrical activity - smooth muscle of the GI tract is subject to continuous, slow electrical activity - slow waves o ”background” 49
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o not action potentials spike potentials o action potentials that result in contraction
Regulation of the motility intrinsic nervous control - Enteric nervous system o submucosal and myenteric plexuses extrinsic nervous control o parasympathetic nervous system o sympathetic nervous system hormonal control o paracrine secretion o endocrine o neurocrine
Physiolecture 25.10.07 The stomach. Gastric secretion Gastric motility 1. gastric filling (50ml 1000ml) - plasticity - receptive relaxation 2. gastric storage - in the body of the stomach (weak muscle weak peristaltic waves) 3. gastric mixing - in the antrum (strong muscle) gastric emptying: - antral peristaltic waves provide the force for gastric emptying -
stimulate gastric emptying: amount of chyme increases in stomach (via vagus, gastrin) 50
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inhibit gastric emptying: accumulation of non-processed chyme in the duodenum, e.g. i. accumulation of fat (most potent) ii. accumulation of acid iii. accumulation of osmotically active compounds (hypertonically) iv. distension of the duodenum
these factors inhibit gastric emptying via: - neural reflexes - hormonal pathways (secretin, cholecystokinin (CCK), GIP - gastric inhibitory peptide) secreted by the duodenum Gastric glands - secrete gastric juice i. goblet cells: mucus ii. parietal cells: HCl and intrinsic factor iii. chief cells: pepsinogen iv. enterochromaffin-like cells (ECL): histamine and serotonin v. G cells: gastrin vi. D (delta cell of pancreas) cells: somatostatin vii. Stomach: ghrelin -
gastric mucosa has gastric pits in the folds cells that line the folds deeper in the mucosa, are gastric glands.
Gastric secretion - oxyntic (gastric) glands i. mucous neck cells 1. mainly mucus but some pepsinogen ii. parietal (oxyntic) cells 1. HCl, intrinsic factor iii. peptic (chief) cells 1. pepsinogen - pyloric glands i. few peptic cells and almost no parietal cells ii. mostly mucous cells iii. G cells secrete gastrin 51
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Oxyntic = acid forming HCl production - parietal cells secrete H+ into gastric lumen by primary active transport, through H+/K+ ATPase pump. - Parietal cell’s basolateral membrane takes in Cl- against its electrochemical gradient, by coupling its transport with HCO3-. -
HCl production is stimulated
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i. Indirectly by gastrin ii. Indirectly by acetylcholine Acetylcholine and gastrin stimulate release of histamine i. Histamine 1. Stimulates gastric secretion
Acid secretion - HCl in stomach serves to kill bacteria, activate pepsinogen, and promote binding of B12 to intrinsic factor - Achieved by active transport i. Allows for generation of pH as low as 0.8 HCl function - makes gastric juice very acidic i. denatures ingested proteins (alter tertiary structure) to become more digestible - activates pepsinogen to pepsin i. pepsin is more active at pH of 2.0 pepsinogen secretion - secreted by chief cells, transformed to pepsin endocrine function - gastrin: by the G cells in the pylori gland area - somatostatin: by D cells other secretory function - intrinsic factor: by parietal cells
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Physiolecture 27.10.07 Gastrin Source: - antral G cells in the stomach (90%) - duodenum (10%) effects - gastric acid secretion ↑ o local histamine release H2 receptors o direct effect on parietal cells -
pepsinogen ↑ (due to HCl (↑) ?) gastric mucosal blood flow ↑ gastric and intestinal motility ↑ trophic effects on gastric mucosa, pancreas and intestines
digestion and absorption in the stomach CH digestion: in the corpus (by salivary amylase) Protein digestion: in the antrum (where chyme is well mixed) Absorption: ethanol and weak acids (aspirin)
Regulation of gastric function - gastric motility and secretion are automatic - waves of contraction are initiated spontaneously by pacesetter cells. - Extrinsic control of gastric function is divided into 3 phases o Cephalic phase o Gastric phase o Intestinal phase
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Cephalic phase - stimulated by sight, smell, and taste of food. - Activation of vagus o Stimulates chief cells to secrete pepsinogen o Directly stimulates G cells to secrete gastrin. o Directly stimulates ECL cells to secrete histamine o Indirectly stimulates parietal cells to secrete HCl - continues into the 1st 30 minutes of a meal gastric phase - arrival of food in stomach stimulates the gastric phase - gastric secretion is stimulated by o distension o chemical nature of chyme (amino acids and short polypeptides) stimulates G cells to secrete gastrin stimulates chief cells to secrete pepsinogen stimulates ECL cells to secrete histamine • histamine stimulates secretion of HCl - positive feedback effect 54
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o As more HCl and pepsinogen are secreted, more polypeptides and amino acids are released. Intestinal phase - inhibits gastric activity when chyme enters the small intestine - arrival of chyme increases osmolality and distension. o Activates sensory neurons of vagus and produces an inhibitory neural reflex Inhibits gastric motility and secretion In the presence of fat, enterogastrone inhibits gastric motility and secretion - hormone secretion o inhibit gastric activity somatostatin, CCK and GLP-1 (glucagonlike peptide) GLP-1 - a gut hormone that slows gastric emptying and stimulates insulin secretion. It may become useful in the future in the treatment of noninsulin-dependent diabetes mellitus, perhaps administered by patch, inhaler, or buccal pellet formulation. If the barrier is damaged: peptic ulcer develops - heliobacter pylori - chemicals (alcohol) - stress (vasoconstriction) o histamine ↑↑ hemorrhage • perforation intestinal contraction and motility - 2 major types of contraction occur in the small intestine o peristalsis slow movement pressure at the pyloric end of small intestine is greater than at the distal end. - segmentation o major contractile activity of the small intestine o contraction of circular smooth muscle mix chyme
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absence of food in GI tract intermittent GI motor activity (migration motility complex) intestinal reflexes - intrinsic and extrinsic regulation controlled by intrinsic, sympathetic, parasympathetic and paracrine regulators (gastrin, CCK, secretin, GIP) - gastroileal reflex o increased gastric activity causes increased motility of ileum and movement of chyme through ileocecal sphincter. o Vagovagal reflex - ileogastric reflex o distension of ileum, decreases gastric motility - intestino-intestinal reflex o overdistension in 1 segment, causes relaxation throughout the rest of intestine.
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Physiolecture 29.10.07 Secretion and absorption in the small intestine
Small intestine - regions o duodenum o jejunum o ileum o facilitate the major events of digestion and absorption -
provides high surface area for maximum reabsorption
pancreas - exocrine o acini secrete pancreatic juice 57
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endocrine o islets of Langerhans secrete insulin and glucagon
pancreatic juice - pancreatic juice (alkaline, HCO3-) is secreted into the duodenum (1-1.5 liters per day) - contains o pancreatic amylase - breaks down polysaccharides into disaccharides o trypsin - polypeptides into dipeptides o pancreatic lipase - major fat digesting enzyme o Pancreatic juice is alkaline due to a high content of bicarbonate ions and thus helps to neutralize the acidic gastric contents entering the duodenum. Trypsin is secreted in the form of trypsinogen, converted into trypsin by the action of enterokinase. Trypsin in turn acts as an activator of : Trypsinogentrypsin Chymotrypsinogenchymotrypsin Proelastaseelastase Procarboxypeptidasecarboxypeptidase Pancreatic secretion - secretion in 3 phases: cephalic phase - only 10-15% of total secretion o activation of vagal efferents stimulates enzyme release gastric phase - only present in some species o NOT SIGNIFICANT IN HUMANS Intestinal phase - majority of secretion o combination of hormones CCK and secretin results in maximal enzyme and bicarbonate release
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Gall bladder - the gallbladder stores and concentrates bile - the gall bladder does not make bile - bile flows into the gall bladder when the sphincter of the hepatopancreatic ampulla (sphincter of Oddi) is closed. Bile and gallbladder - hepatocytes secrete about 1 liter of bile per day. - Bile is an alkaline solution consisting of water, bile salts, cholesterol and bile pigments. - Bile is both an excretory product and a digestive secretion o Bile salts - emulsify fats (breakdown large lipid globules into smaller fat droplets Bile salts also make cholesterol soluble (avoid gall stones) - bile pigment - bilirubin (old red cells) - cholesterol Excess bilirubin is associated with jaundice. - a medical condition with yellowing of the skin or whites of the eyes, arising from excess of the pigment bilirubin and typically caused by obstruction of the bile duct, by liver disease, or by excessive breakdown of red blood cells. Bile production and secretion - bile acids are derivatives of cholesterol o major pathway of cholesterol breakdown in the body - principal bile acids are o cholic acids o chenodeoxycholic acids combine with glycine or taurine to form bile salts • bile salts aggregate as micelles. - 95% of bile acids are absorbed by ileum. Digestion - fat in duodenum stimulates CCK release from I cells gall bladder contraction sphincter of Oddi relaxes mixing of bile salts and large lipid droplets form micelles 59
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Hormones released during the intestinal phase - when acidic chyme arrives, hormones are released by the duodenum. - Secretin o Stimulates pancreas to secrete bicarbonate ions that neutralize stomach acid o Inhibits gastric secretion and motility of stomach o The entire molecule is needed for physiological activity o S cells in the duodenum and proximal jejunum secretes it o Duodenal acidification (below pH 4) stimulates release
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Effect: 1. pancreatic bicarbonate and water secretion↑ (CCK potentiates this effect) 2. gastric acid secretion↓ (by stimulating the local release of somatostatin from the gastric mucosal D cells) clinical use: to evaluate pancreatic function Cholecystokinin (CCK) - stimulates production / release of pancreatic enzymes - stimulates bile release from gallbladder - inhibits gastric secretion and motility of stomach old name: pancreozymin source: - upper small intestine - endocrine cells as well as enteric nerves receptors - CCK-A and CCK-B - Second messenger: IP3/DAG effects 1. contraction of gallbladder 2. enzyme-rich pancreatic secretion↑ 3. increases the effects of secretin on bicarbonate-rich pancreatic secretion 4. inhibits gastric emptying stimulated by - intraduodenal fat and protein gastric inhibitory peptide (GIP) - a.k.a. glucose-dependant insulinotropic polypeptide source - jejunum (some in duodenum and ileum) K cells stimuli - 4x increase 1h after a meal 61
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- glucose and triglycerides effects 1. insulin release ↑ in response to glucose 2. gastrin release↓ 3. gastric motility↓ 4. fluid and electrolyte secretion by ileum ↑ chemical digestion in the small intestine - pancreatic juice and bile enters the duodenum; - fat droplets emulsified by bile - carbohydrates, proteins and fats chemically digested by pancreatic enzymes - bicarbonate ions in pancreatic juice neutralize stomach acid small nutrient molecules are absorbed by mucosal epithelial cells where further chemical digestion occurs intestinal juice - yellowish, alkaline fluid - enzymes to convert disaccharides to monosaccharides o maltase, sucrase, lactase (decreased in lactose intolerant) - intestinal juice also contains proteases to break dipeptides into amino acids - most of the enzymatic digestion occurs in the epithelial cells rather than the lumen emptying at the ileocecal valve - pressure and chemical irritation relax sphincter and excite peristalsis. (in ileum) - fluidity of contents promotes emptying. (in ileum) - pressure or chemical irritation inhibits peristalsis of ileum and excites sphincter. Large intestine - cecum - colon o ascending, transverse, descending, sigmoid o taeniae coli (longitudinal muscle) o haustra (created by the taeniae coli) 62
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- rectum - anal canal o internal and external sphincters little absorptive function - absorbs H2O, electrolytes, several vitamin B complexes, K and folic acid o intestinal microbiota produce significant amounts of folic acid and vitamin K o bacteria ferment indigestible molecules to produce shortchain fatty acids does not contain villi - secrets H2O, via active transport of NaCl into intestinal lumen. The large intestine function - essentially a drying and storing organ - each day the large intestine receives about 500ml of residual intestine contents - the large intestine absorbs about 350ml of fluid as well as some salt and vitamins (bacterial action produces vitamins K and B5) - about 150g of feces passes out by defecation each day.
Physiolecture 31.10.07 Large intestine motility, fecal formation, carbohydrates, lipids -
essentially a drying and storing organ each day the large intestine receives about 500ml of residual intestine contents.
Large intestine motility - large intestine muscle inactive most of the time & muscle contraction sluggish & short-lived. 1. -
haustral contractions similar to segmentation occur every 30 min (approx) individual haustra contract / food propelled into next haustra aids water absorption 63
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2. -
mass movements long, slow powerful contractile waves occur over large areas of the colon 3-4 times daily forces food residues towards rectum typically occur just after eating - gastrocolic reflex
Feces formation - bilirubin decomposition produces characteristic fecal color - H2O is absorbed in conjunction with the movement of absorbed substances - Haustral churning and peristalsis drive colonic contents into the rectum Defecation - food in stomach stimulates mass peristalsis - food moves through intestine - rectal pressoreceptors respond to distention - release of internal anal sphincter gives a conscious awareness of distension - conscious release of external sphincter - diaphragm and intercostals contract - defecation occurs digestion and absorption of carbohydrates - salivary amylase o begins starch digestion - pancreatic amylase o digests starch to oligosaccharides o oligosaccharides hydrolyzed by brush border enzymes - glucose is transported by secondary active transport with Na+ into the capillaries. Glucose short oligosaccharides, maltriose and maltose (with the help of the enzyme amylase. -
digestion begins in the stomach when pepsin digests proteins to form polypeptides in the duodenum and jejunum: o endopeptidases cleave peptide binds in the interior of the polypeptide trypsin 64
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chymotrypsin elastase o exopeptidases cleave peptide bonds from the ends of the polypeptide carboxypeptidase aminopeptidase all protein digestive enzymes are born in an inactive form, to prevent from self-digestion. -
Free amino acids absorbed by co-transport with Na+ Dipeptides and tripeptides transported by secondary active transport using a H+ gradient to transport them into the cytoplasm Hydrolyzed into free amino acids and then secreted into the blood.
Digestion and absorption of lipids - arrival of lipids in the duodenum serves as a stimulus for secretion of bile. - Emulsification o Bile salt micelles are secreted into duodenum to break up fat droplets. - Pancreatic lipase and co-lipase hydrolyze triglycerides to free fatty acids and mono-glycerides o Co-lipase coats the emulsification droplets and anchors the lipase enzyme to them o Form micelles and move to the brush border. - free fatty acids, monoglycerides, and lysolecithin leave micelles and enter into epithelial cells o resynthesize triglycerides and phospholipids within cell combine with a protein to form chylomicrons - secreted into central lacteals
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Physiolecture 05.11.07 Function of the kidneys Normal amount of urine produced/day is about 1500ml Polyuria: 2.5 l/day Olyguria: 0.5 l/day Anuria: 0.1 l/day Haematuria: blood in the urine Proteinuria: proteins in the urine, inflammation of the kidney, nephritis and/or malfunction of the kidney; nephrosis. Glucose should not be found in the urine if so; diabetes 66
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Sometimes fructose can be found in the urine, this is due to excess intake of fruits. 120 ml/min primary urine 119 ml/min reabsorbed 180 l/day produced by the glomeruli 1.5 l/day urine pH of the urine varies between 4.5-7.8, but will normally be around 5.8-6.5. comparison of blood flows in the kidney, brain and skeletal muscle: kidney 350ml/min/100g brain 65ml/min/100g skeletal muscle 25-115ml/min/100g plasma ultra filtration is made within the glomeruli. only plasma passes through. afferent arterioles reach the glomeruli, efferent arterioles go out of it, and reach the vasa recta system. Double capillarization is found in the kidneys; in the bowman capsule and vasa recta system. Juxtamedullary glomerulus: ”next to”-medullary glomerulus Podocytes are believed to play a role in the ultrafiltration of blood. - These cells are attached to the outer surface of the glomerular capillary basement membrane by cytoplasmic foot processes (pedicels)
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Physiolecture 05.11.07 Liver functions The liver weights about 1.5 kg in an adult. -
Largest gland; largest organ Covered by visceral peritoneum and a layer of dense irregular connective tissue deep to the peritoneum 2 main lobules, right and left (divided by the falciform ligament) lobes of the liver are made of functional units called lobules
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Kupffer cells destroy red cells, white cells, and bacteria from blood draining from the GI tract.
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Hepatocytes will also extract nutrients and toxins from the blood in the sinusoids
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The nutrients are stored or made into other substances
The liver in unusual in that it receives blood from two sources: 68
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1. the major portion (approx 75%) is supplied by the portal vein that drains the blood from the intestinal system (including the pancreas and the spleen) and is rich in nutrients that have been absorbed in the intestine, but is poor in oxygen 2. oxygenated blood is supplied by the hepatic artery the blood exiting the liver drains into the hepatic vein that connects to the IVC enterohepatic circulation - compounds that re-circulate between liver and intestine o many compounds can be absorbed through small intestine and enter hepatic portal blood o variety of exogenous compounds are secreted by the liver into the bile ducts - can excrete these compounds into the intestine with the bile hepatic portal system - products of digestion that are absorbed are delivered to the liver - capillaries drain into the hepatic portal vein, which carries blood to liver o 75% of blood is deoxygenated o hepatic vein drains liver Liver functions 1. formation and secretion of bile 2. detoxification of chemicals 3. metabolic processing of nutrients 4. synthesis of plasma proteins 5. storage of glycogen, fats, iron, copper and vitamins 6. production of hormones, activation of vitamin D 7. removal of worn out red blood cells bile production and secretion - the liver produces and secretes 250-1500 ml of bile per day - bile pigment (bilirubin) is produced in the spleen, bone marrow, and liver o derivative of the heme groups (without iron) from hemoglobin - free bilirubin combines with glucuronic acid and forms conjugated bilirubin o secreted into bile 69
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converted by bacteria in intestine to urobilinogen o urobilinogen is absorbed by intestine and enters the hepatic vein. Recycled, or filtered by kidneys and excreted in urine.
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bile acids are derivatives of cholesterol o major pathway of cholesterol breakdown in the body principal bile acids are o cholic acid o chenodeoxycholic acid combine with glycine or taurine to form bile salts • bile salts aggregate as micelles o 95% of bile salts are absorbed by ileum
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detoxification of the blood - liver can remove hormones, drugs, and other biologically active molecules from the blood by o excretion into the bile o phagocytosis by Kupffer cells o chemical alteration of the molecules ammonia is produced by de-amination of amino acids in the liver liver converts it into urea • excreted in urine o inactivation of steroid hormones and drugs conjugation of steroid hormones and xenobiotics make them anionic • can be transported into bile by multispecific organic anion transport carriers. Steroid and xenobiotic receptors stimulate production of cytochrome p450 enzymes. (xenobiotics: substances foreign to the body, including drugs and some food additives) processing and storage of nutrients and minerals - a large portion of the blood that drains into the portal vein comes from the mesenteric vein - these drain the capillary network of the intestine to which the digested and absorbed nutrients have been delivered. - The portal vein blood is thus rich in nutrients 70
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Role of the liver in glucose metabolism - the liver plays a unique role in the control of glucose metabolism - it stores glucose in the form of glycogen after a meal and releases glucose under fasting conditions - it thus maintains glucose concentrations in the blood stream in the normal range and function as a ”glucostat” - a constant supply of glucose is crucial for brain function since the brain can only use glucose as fuel after a meal, when the sinusodal blood glucose concentration is high, glucose is taken up by the hepatocytes, converted into glycogen and stored in glycogen granules -
under fasting conditions the stored glycogen is metabolized (glycogenolysis) and glucose is released into the sinusoidal blood from where it is transported into the circulation via the central veins and hepatic vein.
secretion of glucose, triglycerides and ketones - liver helps regulate blood glucose concentration by o glycogenesis and lipogenesis role of the liver in lipid metabolism -
the liver plays a central role in lipid metabolism with the: 1. production of the bile acids 2. metabolism and excretion of cholesterol 3. clearance of chylomicron remnants 4. uptake of fatty acids 5. de novo synthesis of fatty acids 6. synthesis and storage of triglycerides 7. production of apolipoproteins 8. assembly of very low density lipoproteins (VLDL)
production of plasma proteins - albumin and most of the plasma globulins (except immunoglobulins) are produced by the liver o albumin constitutes 70% of the total plasma protein 71
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contributes to most to the colloidosmotic pressure in the blood o globulins transport cholesterol and hormones inhibit trypsin produce blood clotting factors I, II, V, VII, IX, X, XI participation in iron metabolism - approximately 20-30% of the iron in the body is stored in hepatocytes, predominantly in ferritin, an intracellular iron storage protein - inappropriately high absorption of iron leads to iron overload in parenchymal cells in various tissues, including the liver storage of vitamin A - this function is performed by the Ito cells that are located in the space of Disse - Ito cells are characterized by an abundance of fat droplets in the cytoplasm and the presence of well-branched cytoplasmic processes - Ito cells store 80% of the whole body retinoids in the lipid droplets and they regulate the levels of retinoids in the bloodstream. Production of hormones - the liver also produces the following hormones that are released into the circulation - angiotensinogen: precursor to pressor peptide angiotensin II - insulin-like growth factor I: mediator of anabolic effects of growth hormone - these hormones are also produced locally in many different tissues, where they exert autocrine and paracrine effects. Phagocytosis of debris and bacteria - this function is performed by the Kupffer cells - the Kupffer cells are macrophages that are permanent residents within the lumen of the sinusoids - they function in the filtration of the portal blood and phagocytose old red blood cells and bacteria. They play an important part in innate immune defense - they also secrete growth factors and are active in remodeling of the ECM. 72
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Introduction to vitamins - vitamins are assigned letters in orders of discovery, but may also be more commonly known by other chemical names - human body needs adequate supply of 13 vitamins - 4 of these are fat soluble, 9 are water-soluble -
vitamins often act as coenzyme
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may have antioxidant function by neutralizing effect of free radicals
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vitamins are an indispensable, essential, non-caloric, organic nutrient needed in tiny amounts o do not produce energy o often act as coenzyme in energy producing reactions
Physiolecture 07.11.07 Renal circulation Inuline clearance - for determination of glomerular filtration rate o result: 120ml/min
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the filtrate is produced from the blood being circulated through the glomeruli
RPFarterial (renal plasma flow) RPFvenous + V + RLF RPF • Pa = RPF • Pv + UV RPF (Pa - Pv) = UV RPF = UV / (Pa - Pv) E = (Pa - Pv) / Pv = 0 1 UV = urine volume E = excretion RPF = C / E = C RBF = 1200 ml / min CPAH = 600ml /min FF = filtration fraction GFR = glomerural filtration rate FF = GFR /RPFeff = 120 / 600 = 0.2 (in normal conditions, 20% of the plasma will be filtrated) 74
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Filtration fraction increases in case of efferent arteriolar constriction and afferent dilation.
Physiolecture 08.11.07 The renin-angiotensin system 1. Automatic regulation a. Afferent vessels constricts when Pg increases, by myogeneric reflex (smooth muscle stretched contracts) b. By this decreasing the GFR 2. Sympathetic regulation a. Afferent > efferent, so RBF decreases b. Norepinephrine - ADRENERIC - on alpha-receptors vasoconstriction... more receptors! c. But in higher doses bound to B receptors 3. Angiotensin II B receptors not in vessels but in macula densa ! (?)
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Preprorenin prorenin renin (renin is an activator of angiotensinogen) α2-globulin & angiotensinogen angiotensin Iangiotensin II Angiotensin II - vasoconstrictor (7x more effective than norepinephrine) - sick kidney: ↑renin renal hypertension
Physiolecture 14.11.07 Angiotension II acts as a vasoconstrictor of both afferent and efferent vessels in the kidney decrease filtration rate 1.012 is the specific gravity of normal urine 1.035 is the specific gravity of high/dense urine 1.003 is the specific gravity of diluted urine drink 1.5liters of water, within 3 hours it is excreted (?)
Physiolecture 15.11.07 76
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ADH facilitates water reabsorbtion and the sensation of thirst increases. ADH is secreted by the posterior pituitary gland.
Physiolecture 19.11.07 Acid-base regulation
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innervation of the urinary bladder consists of both parasympathetic and sympathetic nerve fibers. - sympathetic fibers controls contraction of the bladder via βreceptors, and at the same time relaxation of the sphincter via α-receptors. However, this mechanism is voluntary, and must be learned, usually by the age of 1-2. Hypertrophy (cancer) of the prostate could easily lead to incontinence.
Physiolecture 19.11.07 Energy metabolism 78
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Energy expenditure - is characteristic of every living cell, energy rich nutrient are taken in - chemically converted - metabolic end products are eliminated from the cell. Metabolism is the basis of all physiologic processes Metabolism is the sum transformation of both material and energy that occurs in the living cell. Metabolism refers to all the chemical reactions that take place within the cells of the body Reactions may be: - anabolic (synthesis of larger molecules) - catabolic (breakdown of larger molecules) catabolism - oxidation of carbohydrates, fats and proteins - liberates CO2, H2O and energy - energy liberated appears as external work heat or is stored for later use anabolism - synthesis of glycogen, protein or fat - energy required to convert carbohydrates into glycogen - energy required to convert amino acids into proteins - energy required to convert lipids into fat forms of energy - chemical - electrical - mechanical - osmotic - thermal - energy can not be created or destroyed. - forms of energy can only be interchanged. Food chemical energy metabolic pool chemical energy metabolic pool chemical energycellular chemical energy 79
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cellular chemical energy leads to thermal energy chemical work mechanical work osmotic work electrical work the last 4 is work energy, which leads back to thermal energy efficiency of the human body - 70-80% of all chemical energy converted by the body is lost as heat - the other 20-30% of energy is used for processes such as growth and repair of tissues, active transport of chemicals across cell membranes and force generation in muscle cells but even during these processes energy is lost as heat. Energy input should equal energy output to maintain body mass. Losing weight: - if the energy expenditure is more than energy input then mass is lost. The same will happen if the energy input is limited. Gaining weight - if the energy input is more than energy expenditure, mass is gained. metabolism means simply all the chemical reactions in all the cells of the body the rate at which the chemical energy is expended by the body is known as the metabolic rate metabolic rate is normally expressed in terms of the rate of heat liberation during the chemical reactions. The biologic unit of energy is the kilocalorie (kcal) which is the amount of heat required to raise the temperature of 1 kilogram of water 1 Celsius 80
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The SI unit of energy is the joule (J) which is the energy used when 1 kg is moved a distance of 1 meter (m) by a force of 1 Newton (N) 1kcal = 4,182 kJ 1kJ = 0.239 kcal caloric values: - the amount of heat produced by the oxidation of o 1 gram of carbohydrate (17kJ) o 1 gram of fat (39kJ) or o 1 gram of protein (22kJ) when they are burned in a bomb calorimeter. Biologic caloric values: The amount of heat produced by the oxidation of 1 gram of carbohydrate, fat or protein in the body Similar values are obtained - for carbohydrate: 17kJ and - for fat: 39kJ, but - for protein: 17kJ, because the oxidation of protein is incomplete respiratory quotient (RQ) - the ratio of the volume of CO2 produced to the volume of O2 consumed - RQ = moles CO2/moles O2 - RQ for CHO = 1 - RQ for fat = 0.7 - RQ for protein = 0.8 - Mixed diet RQ = 0.85 - To determine the proportions of carbohydrates, proteins and fats being metabolized Factors affecting the RQ - the kinds of foodstuffs metabolized - interconversion of foodstuffs o carbohydrates converted to fats - (force-feeding) because fat contains less O2 than do carbohydrates a corresponding amount of O2 is released, so the amount of O2 uptake through the lungs falls and the RQ becomes larger than 1 (1.38-1.58) o fasting and diabetes RQ = 0.6 81
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Cause: increased conversion rate of fats and proteins that accompanies diminished glucose metabolism Energy equivalent of O2: - the energy expended per liter of O2 consumed is very similar for all three major nutrients, so if the mixture of nutrients being oxidized is close to the mixture of nutrients in a normal diet, a value of 20 kJ/liter of O2 consumed is a good approximation of the energy expenditure carbohydrate: 21,2 kJ fat: 19.7kJ protein: 19.2kJ caloric content of alcohol: 30kJ summary: 1. since energy can neither be created nor destroyed, the amount of energy put into the body must equal that put out by the body 2. energy input is in the form of the chemical energy of food 3. energy output is in the form of work, heat, and stored chemical energy 4. if energy intake exceeds energy output as heat plus work, body chemical energy-stores will increase, inducing a gain in weight. If energy intake is less than energy output as heat plus work, a weight loss is inevitable. energy expenditure - energy expenditure = basal metabolism + energy used for activity o a small amount of energy is used to digest and absorb food o most is used for basal metabolism o a variable amount is used for physical activity the rate at which the chemical energy is expended by the body in known as the metabolic rate
Physiolecture 21.11.07 82
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Energy metabolism Factors that affect the metabolic rate 1. exercise↑ for several minutes : 20 times normal 2. energy requirements for daily activities - resting O2 consumption is 250ml/min - 300kJ/h, 7200kJ/day 3. light work: O2 consumption: < 500 ml/min, 600kJ/h 4. moderate work: O2 consumption: 0.5 - 1L/min, 600-1200kJ/h 5. heavy work: O2 consumption: 1-2L/min, 1200-2400kJ/h -
when an average man of 70kg lies in bed all day he utilizes 300kJ/h = 7200kJ/day the process of eating increase the amount of energy utilized each day by an additional 800kJ. Together 8000kJ/day if he sits in a chair all day, total energy is 8400-9400kJ/day the daily energy requirement simply for existing is about 8400kJ + the daily energy requirement of the type of work 11200 18000kJ/day
7. thyroid hormone 100%↑, 50-60% ↓ 8. sympathetic stimulation - NE and E↑ o direct effect on muscle and liver o brown fat 9. male sex hormone - 10-15%↑ 10. growth hormone - 15-20%↑ o direct stimulation of cellular metabolism 11. pregnancy - 20-25%↑ o due to accelerated tissue growth o increased work of the heart, lung 12. lactation - 60%↑ 13. fever - increases metabolic rate↑ van hoffs rule: metabolic rate increases exponentially with increasing temp - for every 10C in temp, oxygen consumption rates (e.g. metabolism) double 14. climate 15. sleep ↓ - decreased tone of the skeletal muscle - decreased activity of the sympathetic nervous system 83
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16. malnutrition - 20-30% ↓ - lack of necessary food substances basal metabolic rate (BMR) - a method for comparing metabolic rates between individuals - BMR - the rate of energy utilization during absolute rest but while the person is awake - The metabolic rate is measured under so-called basal conditions BMR is the lowest rate of energy use that can sustain life - measured after 12 hours of fasting - measured after an overnight sleep - in reclining position (lie down) - optimal conditions of quiet, rest and relaxation - no physical work before the measurement - emotional factors must be eliminated - indifferent temperature (thermoneutral temp.) = 28C if naked = 20-22C if in normal street clothes -
indirectly measured using oxygen consumption
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O2 consumption: 1.5 liter / 6 min, 15L/h
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Energy equivalent of O2 = 20 kJ / liter
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15x20 = 300kJ/hour expressed for body surface area (DuBois): o m2 = 0.007184 x W(kg)0.425 x H(cm) 0.725
nomogram - 300 : 15 = 200kJ/h/m2 normality is determined by comparing the measured value to standards and it is given in terms of percentage deviation from the standards -
these standards have been obtained from the average BMR of a large population of normal persons of the same sex, body size and age
normal value: 20 years old man = 160kJ/h/m2 200 -160 = 40kJ 84
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BMR: +25% Normal person BMR = 0 +/- 15% Factors that affect BMR: - age - height - growth - body composition (gender) - fever: ↑ - stresses: - environmental temp: ↑ - fasting/starvation - malnutrition: - hormones (gender) - smoking - caffeine - sleep
nutrition -
essential nutrient: one that must be provided in the diet in order to insure adequate growth and maintenance nutrient categories: macro and micro macronutrients: protein, lipid, carbohydrates, etc micronutrients: trace metals, vitamins important: molecular weight
necessary elements of diet - nutrient classes o carbohydrate o protein o lipid o vitamins o minerals o water calculation of energy requirement - BMR: 7200kJ/day - Energy requirement for 8 h (leisure activity) o 8 x 200 = 1600kJ o 7200 + 1600 = 8800kJ/day - energy requirement for 8 h (type of work) 85
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total energy req : 11200-18000kJ/day
RUBNER - isodynamic law: o the different types of food are interchangeable with regard to their energy content - BUT o Not only the quantity but the quality of the food also must be sufficient to supply the metabolic needs of the body! Protein: 12-15% Fat: 20-30% Carbohydrate: 50% Proteins - dietary sources: o egg, milk, meat, fish, bread, potatoes, vegetables (beans, peas), nuts - function: o synthesis of cellular components o formation of new tissues o in regulating the acid-base balance - plasma proteins: o body’s fluid balance, transport, colloid osmotic pressure, defense mechanisms, blood clotting protein requirements: - absolute protein minimum: 20g - physiologic protein minimum: 40g - functional or optimal protein minimum: 80g o WHO: 1g/kg body weight.
Physiolecture 22.11.07 Proteins Distribution of body proteins - skin: 10% - bone 20% - muscle 50% - other 20% 86
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protein NOT stored for future use; use it or loose it - dietary protein body proteins - too much protein, no obvious benefit - too little start to loose muscle problem with excess protein - associated with high intakes of kcals & saturated fat - associated with increased risk of CardioVascularDiseases - often converted to fat (or fat stored while protein used for energy) - increases urinary calcium losses - in infancy, can stress kidney & liver protein/amino acid quality - amino acids are basically divided into two nutritional categories o essential - 10 o non-essential -
complete protein (high quality)- all essential amino acids & in balance o animal sources - eggs, meats
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incomplete protein (lower quality)
protein deficiency - kwashiorkor -- symptoms - apathy; reduced brain development - decreased growth (stunting) - GI problems - mal-absorption; diarrhea - Edema - Increased infection; anemia - Loss pigmentation in skin, hair - Decreased ability to use fat for energy Kwashiorkor - protein deficiency, with adequate calorie intake ”sickness of older child when new baby is born” - characteristic edema protein malnutrition - famine edema o cause: inadequate synthesis of plasma proteins, especially albumin, so that fluid escapes into tissues 87
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marasmus: also known as protein-energy malnutrition, protein-calorie deficiency. -
Lipids
dietary sources. Saturated fatty acids: in animal products o Beef, lamb, pork, chicken, egg yolk, cream, milk, butter, cheese Unsaturated fatty acids: in plant sources: o Seeds
Functions: - energy source and reserve - protection and insulation - vitamin carrier - hunger depressor - components of hormones and precursors or prostaglandin synthesis Fat provide energy; 1 gram provides 37kJ (9kcal). Foods that contain a lot of fat provide a lot of energy -
fat is made up of different types of fatty acids. A high intake of saturates can have an adverse effect of health fat provides essential fatty acids. It is a carrier of fat-soluble vitamins and is necessary for their absorption fat is needed for health but only in small amounts. No more than about one third of our energy intake should come from fat
essential fatty acids - linoleic - found mostly in plant oils - linolenic - found mostly in cold-water fish and some plant oils (canola oil, nuts seeds) - deficiency leads to poor growth, liver problems, diarrhea hidden fats - nuts, seeds (75% but high in monos) - peanut butter (75%) - avocado (80%) - cheese (75%), whole milk (50%) - fried foods & most fast foods - baked goods 88
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chocolate; tofu carbohydrates
dietary sources o most of it is in the form of plant starch fruit, green vegetables, potatoes (also include cellulose)
functions: - energy source - 1 gram of carbohydrate provides 17kJ (4kcal) - protein sparer o if the diet is low in carbohydrates, a greater % of dietary protein is used to provide glucose, which means less is available for the growth and repair of body tissues - metabolic primer o for fat metabolism: certain derivatives from the breakdown of carbohydrates must be present to facilitate the breakdown of fat - fuel for the CNS - antiketogenic effect - maintenance of a suitable intestinal flora (vitamin synthesis) - fibers (cellulose) - peristalsis fibers - dietary fiber o nondigestible carbohydrates and lignin that are present naturally in plants - functional fibers o nondigestible carbohydrates isolated from natural sources or synthesized in a lab and added to a food or supplement sources of fiber - all plant foods contain fiber, but processing can remove it - good sourced of fiber o fruits (especially while, unpeeled fruits) o vegetable o legumes o oars o whole grains and wheat function - foods high in fiber stay in gut longer, leaving a feeling of fullness and satisfaction 89
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high intake of fiber evens out blood glucose levels may reduce chances of colon cancer lowers cholesterol level by 20% or more promotes GI tract functions
average and desirable proportion of energy from different metabolic fuels average: - protein 15% - alcohol 3% - carbohydrates 42% - Fat 40% desirable - protein 15% - alcohol 0% - fat 30% - carbohydrates 55% -
Reduction in fat should be by reducing saturated fat from 17% to 10% of energy increase in carbohydrates should be by increasing starch and decreasing sugar Vitamins
fat soluble vitamins - a, d, e, k water-soluble vitamins - thiamin - riboflavin - niacin - b6 - b12 - folic acid - biotin - vitamin c fat soluble vitamins: - usually occur together in foods 90
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absorbed with fat, require bile for absorption once absorbed, not easily excreted - stored in tissue generally toxic at high doses, but do not reach those levels with food intakes
water soluble - B-complex, vitamin C o Can be leached out in cooking and storage o Stored in limited amounts in tissue o Stores lost with cell turnover o less likely to reach toxic levels o need to consume daily VIT A - main functions o essential for vision and dim light o necessary for maintenance of mucous membrane, skin and growth - main sources o as retinol in milk, fortified margarine, butter, cheese, egg, liver and fatty fish o as carotenes in milk, carrots, tomatoes, dark green vegetables - deficiency o reduced night vision, loss of sight through gradual damage to the cornea o lowered resistance to infection - excess o stored in liver, since fat-soluble o excess can be toxic VIT D - main functions o promotes calcium and phosphate absorption from food and is thus essential for bones and teeth - main sources o sunshine o fortified margarine o oily fish o egg yolk o fortified breakfast cereals - deficiency 91
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o failure of bones to grow and calcium leading to rickets in children and osteomalacia in adults excess o can be toxic
VIT E - function o protects cells membranes from damage by oxidation - main source o vegetable oils o vegetable o nuts o cereals - deficiency o may occur in premature infants or due to mal-absorption - excess o not known VIT K - function o essential in the formation of blood clotting proteins - sources o synthesis by bacteria in the gut o dark green leafy vegetables - deficiency o increase clotting time - excess o not known
Physiolecture 23.11.07 Water-soluble vitamins Vitamin C Main function - Involved in the production of collagen. Used in the structure of connective tissue and bone. - Also aids wound healing and iron absorption. Sources 92
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fresh fruits especially citrus fruits and green vegetables and potatoes
deficiency - scurvy o results from prolonged deficiency - poor wound healing and bleeding gums excess - may lead to kidney stone -
the use of high doses of vitamin c has not been shown to provide any medical benefit the use of high doses of vitamin c has been shown to cause nausea, diarrhea, and lead to the formation of oxalate kidney stones.
Vitamin B1 (thiamin) Main functions - involved in the release of energy from carbohydrates - it is important for the brain and nerves which use glucose for their energy needs. Sources - cereals - nuts and pulses are rich sources - green vegetables - pork - fruits - fortified cereals contain thiamin deficiency - leads to beriberi - alcoholics sometimes develop deficiency excess - the body excretes excess thiamin RDA (recommended daily intake) = 1.5mg
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BERIBERI - thiamin deficiency - dry beriberi wernicke-korsakoff syndrome and affects the nervous system Vitamin B2 (riboflavin) Function - involved in energy release especially from fat and protein sources - liver - milk, cheese, yoghurt - eggs - green vegetables - yeast extract - fortified cereals deficiency - include changes to the mucous membrane and skin around the mouth and nose excess - the body excretes excess riboflavin
Vitamin B3 function - involved in the release of energy sources - liver - beef - fish - most breakfast cereals are fortified - some is made in the body deficiency - leads to pellagra excess 94
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high doses cause dilation of arteries and reduction of blood lipids excess can cause kidney damage
Vit B6 (pyridoxin) Function - synthesis and catabolism of amino acids - cofactor in production of heme precursor - coenzyme metabolism of CHO, fat and particularly proteins sources - eggs, milk - fish - meat - yeast - beans - banana - whole grain deficiency - rare - microcytic hypochromic anemia - symptoms o irritability o insomnia o weakness o nervousness excess - toxicity notes since 1983 - progressive numbness and tingling Vit B12 Function - is necessary for the erythropoesis and nerve fibers sources - rich source is meat - eggs and milk also contain B12 - almost no plant foods contain B12 - fortified breakfast cereals are a useful source 95
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deficiency - leads to pernicious anemia excess - no toxic effects are known Folate - function o involved in the formation of blood cells o reduces the risk of NTDs in babies -
sources o liver, orange juice, dark green vegetables o nuts, wholemeal bread and fortified breakfast cereals are fair sources
MINERALS
What are minerals? - minerals are inorganic substances required by the body for a variety of functions such as : formation of bones and teeth; essential constituents of body fluid major minerals Calcium - function o formation and maintenance of bones and teeth o blood clotting and nerve function - deficiency o bone weakening; rickets and osteomalacia o this is due to failure to absorb calcium owing to vitamin D deficiency - excess o no known issues Sodium - function o regulation of body water content o nerve function 96
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deficiency o fatigue o nausea o cramps o thirst is experienced excess o excess sodium has been linked to hypertension
Potassium - function o constituent of body fluids -
deficiency o weakness, mental confusion and if extreme: heart failure
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excess o excess is dangerous especially if the kidneys are not functioning properly
magnesium - function o involved in energy transfer in the cell, in enzyme activity and muscle functioning -
deficiency o depression, irritability
Iron - function o formation of Hb in RBC -
deficiency o iron deficiency anemia
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excess o excessive absorption may be due to a rare genetic disorder
Zinc 97
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Function o essential for growth, and sexual maturation o involved in enzyme activity and taste perception
Iodine - function o formation of thyroid hormones -
deficiency o goiter and cretinism
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excess o excess iodine is not absorbed
Fluoride - function o Increases the resistance of teeth to decay -
Deficiency o tooth decay more likely
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excess o fluorosis
Selenium - function o As an antioxidant it protects cell membranes against oxidation -
deficiency o keshan disease (a type of heart disease)
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excess o excess selenium is toxic WATER
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carries nutrients transport nutrients and wastes 98
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serves as a solvent participates in chemical reactions acts as a lubricant around joints serves as a shock absorber in the eyes, spinal cord, joints and amniotic sac aids in body temperature maintenance
water input should equal water output
Physiolecture 26.11.07 Endocrinology Endocrine - any material which is released to the blood stream and travels via the blood to the target. Endocrine glands: - pineal gland - pituitary gland - thyroid gland - parathyroid glands - thymus gland - adrenal glands - pancreas: islets of Langerhans - ovaries / testis 3 levels of hormonal regulation: - CNS - pituitary gland - peripheral glands
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Physiolecture 26.11.07 Temperature regulation 1. core temperature 2. surface temp when measuring body temperature, the most precise result would be found: rectal > oral > axillary factors influencing body temperature - it shows diurnal (circadian) rhythm - 24 hour cycle during which body temp fluctuates around the normal temp - most women show body temp changes related to the menstrual cycle (increases around 1°C at ovulation) - the temperature increases under the following conditions o after a meal o emotional stress o exercise o high ambient temp o febrile diseases o nonfebrile diseases (hyperthyroidism) - the body temperature decreases o in cold weather o sleep o metabolic disorders (hypothyroidism) o in the case of peripheral circulatory obstruction - age o children have higher temp - other factors, such as the seasons, amount of hair, clothing influence body temperature the major mechanisms of heat exchange between the skin and the environment are: - radiation o heat transfer by electromagnetic waves - conduction o heat exchange between two objects - convection o by movement of molecules of a gas or liquid 103
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evaporation o insensible perspiration sensible perspiration - sweating
sweating is the only regulation of heat loss. Heat balance - rate of heat production = rate of heat loss - when the two are out of equilibrium, the body temp will increase or decrease - the ambient temp at which the activities of the heat producing and heat loss mechanisms are at minimum o lightly dressed : 20-22C o naked: 27-28C
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Physiological thermoregulation - maintain body temp by: o vasomotor responses (23-30 ambient) o evaporative responses (above 30 ambient) o metabolic responses (below 23 ambient) In cold environment heat balance can be maintained: - by decreasing non-evaporative heat loss (e.g. putting on clothes) - by increasing metabolic heat production o metabolic activity can be increased basal heat production by hormonal means (thyroxine) by mechanical means (muscle activity, shivering) by thermal means In warm environment - non-evaporative heat loss mechanisms become heat sources to prevent body temp from rising - sweating is initiated (sympathetic cholinergic nerves) at comfortable temperature o vasomotor regulation (sympathetic nervous system) 105
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Heat production mechanisms - shivering thermogenesis o metabolic heat production by muscle contraction -
non-shivering thermogenesis
shivering thermogenesis - hypothalamus o the shivering center is located in the post hypothalamus near the third ventricle o the non-rhythmic signals do not cause muscle shaking. Instead muscle tone rises, and shivering is the result of feedback oscillation of the muscle spindle stretch reflex. o Hear production can increase 5-fold Non-shivering thermogenesis - sympathetic activity ↑ o brown fat some animals and all human infants have brown fat with large amounts of mitochondria. Circulating catecholamines released during cold exposure increase metabolic rate in all cells, but especially in brown fat. Thyroid hormone secretion increases heat production ↑
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venous flow may be shifted from superficial vessels to deep venous plexuses. central integration: receptors - central thermoreceptors o large numbers of temp sensitive neurons are located in the anterior hypothalamic pre optic area. Information arising from the ant hypothalamic pre optic area are transmitted to the post hypothalamus - cutaneous thermoreceptors o these receptors stimulate the post hypothalamus bilaterally: there are many more cold sensitive receptors in the skin than warm receptors thermoreceptors and thermosensors - cutaneous thermoreceptors - CNS thermosensors - Core thermosensors
Central integration: effectors - heat production mechanisms o vasoconstriction stimulated by the posterior hypothalamic sympathetic center o piloerection sympathetic stimulation causes erector pili muscles to contract 107
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o shivering hypothalamic stimulation by cold receptors from the skin o sympathetic activity
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Physiolecture 28.11.07 The endocrine system Major regulatory systems - endocrine system: sustained, slow responses - nervous system: rapid, precise responses - immune system Endocrine vs nervous system - major communication system in the body - integrate stumuli and responses to changes in external and internal environment - both are crucial to coordinated functions of highly differentiated cells, tissues and organs - unlike the nervous system, the endocrine system is anatomically discontinuous Nervous system - the nervous system exerts point-to-point control through nerves, similar to sending messages by conventional telephone. Nervous control is electrical in nature and fast Hormones travel via the bloodstream to target cells - the endocrine system broadcasts its hormonal messages to essentially all cells by secretion into blood and extracellular fluid - like a radio broadcast, it requires a receiver to get the message - in the case of endocrine messages, cells must bear a receptor for the hormone being broadcasted in order to respond. the function of the endocrine, nervous and immune system is intertwined: - they regulate each other’s function - neurons in the nervous system and cells of the immune system produce ”classic hormones” - neurons and ”classic endocrine organs” produce immunemediators. HORMONES - any substance released by a cell which acts on another cell (to regulate its function) - the means of intercellular communication 109
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Endocrine system (classic definition) - ductless glands - secretes hormones into the blood - acts on distant targets - regulates a pre-existing cellular activity; coordinates the activities of various tissues to maintain ”systemic homeostasis” - minimal overlap of biological activities ( deficiencies cause marked abnormalities) Paracrine - Hormones works on nearby cells Autocrine - hormones influences the secreting cell itself Hormone transport - non-steroid hormone (transported in blood, often unbound) - steroid hormone (transported in blood, bound to carrier protein. o Released when they reach target organ
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Free concentration of hormone in blood plasma depends on: - rate of secretion from endocrine tissue - rate of inactivation - rate of uptake by other tissues - rate of excretion by kidneys - extent of binding to plasma proteins Plasma half-life of a hormone - the time taken for the plasma hormone concentration to fall by 50% - adrenaline - 2 min - cortisol - 90 min - thyroxine - 7 days - this largely depends on the extent of binding to plasma proteins (e.g. adrenaline is not bound at all, whereas thyroxine is 99.9% bound) Classification of hormones - site of the production - site of the action - chemical structure site of production - endocrine glands 111
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isolated endocrine cells extracellular fluid (plasma) pituitary pineal glands thyroid parathyroid adrenals ovaries testes pancreas thymus hypothalamus kidney liver intestines heart adipose tissues placenta blood
The ”master” glands - the pituitary has been called the ”master” gland in the body - this is because most of the pituitary hormones control other endocrine glands The hypothalamus and the pituitary gland -- master endocrine glands! The hypothalamus: - located in the brain, this region controls most endocrine secretions - mainly regulatory hormones are released here. Most control the pituitary gland The pituitary gland - descending from the hypothalamus, this gland has two halves, anterior and posterior - the anterior half secretes mainly regulatory hormones - the posterior half secretes hormones, but manufactures none Hypothalamus and pituitary: control of hormones - there are both neurons and blood vessels that run through the infundibulum site of the action: - tropic hormones 112
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o primary function: regulation of hormones secretion by another endocrine gland, e.g. hypothalamic trophic hormones, TSH, ACTH, etc. - nontrophic hormones o primary function: modulate the function of nonendocrine target tissues, e.g. T4, mineralocorticoids, glucocorticoids, insulin, etc. endocrine hierarchies: - hypothalamus pituitary peripheral endocrine gland (eg adrenal gland; ”HPA axis”) - amplification!
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chemical structure: - peptides / proteins - steroids (adrenal cortex, gonads, vitamin D) - amines (thyroid hormones, adrenal medulla) Peptide hormones - structure: o structure: chains of amino acids o amino-terminal and carboxy-terminal end - solubility: hydrophilic - synthesis: rER, packaged in golgi complex - storage: secretory granules - secretion: exocytosis - transport: mostly as a free hormone - receptor site: surface of target cell - action: channel changes or second messenger system rule: - all peptide hormones are synthesizes as inactive ”pre-pro” precursors - A signal peptide must be cleaved off to activate the mature form of the hormone Amines - catecholamines (dopamine, epinephrine and norepinephrine) - structure: tyrosine derivatives - solubility: hydrophilic - synthesis: cytosol - storage: secretory granules - secretion: exocytosis - transport: as a free hormone and bound to plasma proteins - receptor site: surface of the target cell - action: second messenger system thyroid hormones - structure: iodinated tyrosine derivatives - solubility: lipophilic - synthesis: extracellular colloid - storage: extracellular colloid - secretion: endocytosis of colloid - transport: mostly bound to plasma proteins - receptor site: inside of target cells - action: direct effects on genes production of new proteins 114
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steroids (mineralocorticoids, glucocorticoids, sex hormones, vitamin D) structure: cholesterol derivatives solubility: lipophilic synthesis: stepwise modification of cholesterol molecule in various intracellular compartments (in the endocrine gland and also in the blood and target tissues) storage: hormones not stored, only precursor (cholesterol) stored secretion: diffusion transport: mostly bound to plasma proteins receptor: inside of target cell action: direct effects on genes production of new proteins Control of hormonal action 1. regulation of plasma concentration of free, biologically active hormones 2. regulation of target cell responsiveness regulation of plasma concentration of free, biologically active hormone - principles: o plasma hormone levels are regulated around a set point o the set point changes according to the needs of the organism (or for no apparent reason) - hormone levels are maintained at set point by the regulation of : o hormone formation o hormone secretion o hormone transport/plasma levels of free hormone o hormone elimination regulation of target cell responsiveness - changes in the concentration of a hormone may sensitize or desensitize target tissues to the effects of that hormone: Homeostatic response of the target tissues a: change in receptor number o receptor upregulation o receptor downregulation b: change in receptor affinity o positive cooperativity o negative cooperativity
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Target cell adaptation - fast: o negative cooperativity -- diminished receptor affinity for effector o receptor inactivation – e.g. by phosphorylation - slow o reduction in receptor number o changes in downstream molecules
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Physiolecture 29.11.07 117
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The endocrine system
2. by other hormones: a. thyroid stimulating hormone, released from the pituitary gland, stimulates the release of thyroxine from the thyroid gland 3. by the concentration of a blood constituent: a. a high blood glucose concentration stimulates the betacells of the pancreas to secrete insulin 4. by negative feedback a. level of thyroxine in blood controls its own rate of secretion regulation of the endocrine system - feedback mechanism o negative feedback system produces a response that reduces the initiating stimulus o positive feedback system the initial stimulus is reinforces and is intensified not common in the human system because it leads to instability • ex: in childbirth oxytocin stimulates contraction of the uterus, which stimulates a further increase of contraction.
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Neuroendocrine reflexes: the nervous system regulates the secretion (set point) of certain hormones, (e.g. epinephrine and prolactin) Capable of eliciting quick responses in hormone secretion to specific stimuli NB. The secretion of not all hormones is subjected to neuroendocrine reflexes (e.g. insulin) 119
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Higher brain function and pituitary secretion - hypothalamus receives input from higher brain centers - psychological stress affects o circadian rhythms o menstrual cycle hypophysis adenohypophysis (=anterior lobe = anterior pituitary) - function: produces and releases hormones - regulation: by hypophysiotropic hormones neurohypophysis (posterior lobe = posterior pituitary = neural lobe = pars nervosa) - function: stores and releases hormones that are produces by the hypothalamus - regulation: by neural inputs (action potentials) intermediate lobe - well developed in the fetus, almost non-existent in adults pituitary-hypothalamic relationships: - anterior lobe: o the anterior lobe of the pituitary is an outpocketing of the oral mucosa o there is no direct neural contact with the hypothalamus
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Too low plasma hormone levels a. hyposecretion of the hormone a. primary b. secondary b. increased removal of the hormone from the blood Therapy: - hormone replacement Too high plasma hormone levels a. hyposecretion of the hormone a. tumors b. stimulatory autoantibodies b. reduced plasma protein binding c. decreased removal of the hormone from the plasma d. substance abuse therapy: - tumor removal - blocking hormone synthesis - blocking hormone secretion - inhibiting hormone receptors Abnormal target cell responsiveness - e.g. - leptin receptor defect obesity - testicular feminization syndrome: lack of testosterone receptors diseases of the adenohypophysis ↑function : hyperpituitarism ↓function: hypopituitarism - nonfunctional adenoma - inflammatory lesions - ischemic injury - mass effects o enlargement of sella turcica o visual field defects (classically bitemporal hemianopsia) o increased intracranial pressure headache, blurring of vision nausea and vomiting
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Physiolecture 30.11.07 The endocrine system
pituitary growth hormone the effects of growth hormone (GH) - growth-promoting effects on bones - growth promoting effects on soft tissues - metabolic effects - stimulatory effects on insulin-like growth factor secretion - feedback effects on hypothalamic hormones
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Scheme of endochondral ossification and the role of hGH and IGF-1 - IGF (insulinlike growthfactor) is a somatomedin
Growth in thickness: - periosteal osteoblasts deposit new layers of bone - osteoclasts dissolve bone central cavity enlarge growth-promoting effects on soft tissues - hyperplasia (cell division↑ and apoptosis↓) - hyperthropy effects of growth hormone - metabolic actions: conserves glucose for glucose-dependant tissues (brain) and increases lean body mass o mobilizes fat stores as a major energy source: triglycerides breakdown↑ plasma FFA (unesterified Free Fatty Acids)↑ o suppresses glucose uptake by muscles (muscle will utilize FFA for energy) and stimulates glucose secretion by liver plasma glucose↑ o stimulates protein synthesis (cell a.a. uptake↑) plasma amino acids↓ and suppresses protein degradation
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GH as a trophic hormone: the significance of insulin-like growth factors
regulation of GH secretion
Negative feedback - GH and IGF-1 stimulate SST and inhibit GHRH (Growth Hormone-Releasing Hormone)
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Factors that stimulate GH secretion - circadian factors - hypoglycemia - plasma amino acids↑ - plasma FFA↓ - exercise - stress The pathology of GH secretion - somatic growth defects o absence of GH action results in short stature hypopituitary short stature (pituitary dwarfism): pituitary failure of GH production, and consequent proportional reduction in body size Laron syndrome: unresponsiveness of liver to GH with failure to stimulate somatomedin (IGF-1) production o excess GH results in overgrowth a common cause is eosinophilic adenoma (tumor of pituitary somatotrophs) gigantism: GH excess during early postnatal life acromegaly: GH excess during adult life o impaired ability to form bone from cartilage achondroplasia
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endocrine regulation of growth
different phases of growth
Other hormones requires for normal growth - thyroid hormone - GH secretion is reduced in absence of TH (exerts a permissive role) - cortisol - stimulates GH gene expression 131
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insulin - promotes protein synthesis and binds weakly to IGH receptors androgen - terminates growth of long bones in males after puberty; DHEA enhances pubertal growth spurt in females estrogen - terminates growth of long bones in females after puberty
growth - normal growth also requires thyroid hormones, androgens, estrogen, glucocorticoids and insulin. - It is also affected by genetic and external factors. in humans there are 2 periods of rapid growth, the first in infancy and the second in late puberty.
Prolactin (PRL) - in females, stimulates milk production by the breasts - triggered by the hypothalamic prolactin-releasing hormone (PRH) - inhibited by prolactin-inhibiting hormone (PIH) 132
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blood levels rise toward the end of pregnancy suckling stimulates PRH release and encourages continued milk production
Thyroid stimulating hormone (thyrotropin) - tropic hormone that stimulate the normal development and secretory activity of the thyroid gland - triggered by hypothalamic peptide thyrotropin-releasing hormone (TRH) - rising blood levels of thyroid hormones act on the pituitary and hypothalamus to block the release of TSH adrenocorticotropic hormone (corticotropin) - stimulates the adrenal cortex to release corticosteroids - triggered by hypothalamic corticotropin-releasing hormone (CRH) in a daily rhythm - internal and external factors such as fever, hypoglycemia, and stressors can trigger the release of CRH gonadotropins - FSH and LH - Regulate the function of the ovaries and testes - FSH stimulates gamete (egg or sperm) production - Absent from the blood in prepubertal boys and girls
Physiolecture 03.12.07 Hormonal regulation of male sexual functions
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hypothalamus releases GnRH, which stimulates the anterior pituitary to release FSH and LH.
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The red line is formed by epithelium blood-testis barrier: - an occluding barrier formed by Sertoli cells in the seminiferous tubules of the testis, which separates the more mature cells of spermatogenesis in the adlumenal compartment of the tubule from blood-derived products in the basal compartment. FSH increases the number of testosterone receptors.
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37°C is too high for spermatozooa production, the testis require 3-4°C lower temperature for normal production. FSH and testosterone are necessary for a normal spermatogenesis A large dose of testosterone stops the spermatogenesis via negative feedback.
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Testosterone stimulates anabolism directly, (e.g. that’s why male have more muscle mass)
Physiolecture 10.11.07 Regulation of the ovarian cycle
GnRH is secreted every 90 minute. 138
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Granulosa cells have FSH-receptors. Theca cells have LH-receptors.
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Midcycle lasts only 1 to 2 days Concentration of estrogen reach threshold level to give positive feedback on hypothalamus - GnRH
LH maintains corpus luteum, in pregnancy: hCG (human chorionic gonadotropin)
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Menstrual cycle Layers of the uterus wall - endometrium - myometrium - perimetrium Estrogens - endometrium proliferation↑ - progesterone receptors↑ - myometrium tone↑ (by channel proteins) - important in case of no fertilization Progesterone: - endometrium transformation - myometrium contractility↓ (important for fetal development) Proliferative phase: - regeneration of endometrial lining in response to estrogens: o endometrium regenerates o uterine glands enlarge length↑ become coiled o blood vessels grow arterioles become coiled blood supply↑ o progesterone receptors synthesized Secretory phase - in response to estrogens and (mainly) progesterone o progestational changes in the endometrium to prepare for possible implantation of the blastocyst o endometrium: further increases in vascularization o glands become more coiled, secretory activity↑↑ large amounts of nutrients secreted (glycogen↑↑) Contraceptive methods - contraceptive pill o synthetic estrogen combined with synthetic progesterone pills are taken once each day for 3 weeks after the last day of menstruation o Pill taken constant ”high” level of estrogen will prevent an surge of LH/FSH by ↓GnRH released by 140
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hypothalamus. By this no selection and development of follicles NO ovulation... o ”Endocrinesterilization” negative feedback inhibits ovulation o placebo pill taken the 4th week permits menstruation rhythm method o women measure oral basal body temperature upon awakening daily on the day of LH surge, there is a slight drop in basal body temperature
Pregnancy: the role of the placenta Placenta function - site for exchange of gases and other molecules between maternal and fetal blood - gas exchangeo O2 and CO2 - nutrient exchange - waste exchange - synthesis of proteins and enzymes
1. human chorionic gonadotropin (hCG) - LH is inhibited (due to the high levels of estrogens and progesterone, hCG takes over the roe of LH 141
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maintains corpus luteum ( maintains estrogen and progesterone secretion) stimulates androgen secretion in male fetus peaks at 60 days and declines around week 10 pregnancy tests
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progesterone suppresses uterus contractility stimulates the formation of cervical mucus plug prepares mammary glands for lactation in the 1-6th week, corpus luteum is crucial for production
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estrogens cause myometrium hypertrophy prepare mammary glands for lactation endometrial growth inhibition of prolactin secretion growth of mammary ducts enlargement of mothers uterus estriol is the most potent estrogen o Fetoplacental unit: DHEA estrogen
4. human chorionic somatomammotropin - prepares mammary glands for lactation 5. relaxin - softens cervix - loosens connective tissue between pelvic bones 2 peptide hormones - hCG & relaxin 2 steroid hormones - estrogen & progesterone Placental hormones Fetal-placental unit: - placenta must cooperate with the adrenal cortex in the fetus to produce estrogen. - Estrogen/estriol stimulates o Endometrial growth o Inhibition of prolactin secretion o Growth of mammary ducts o Enlargement of mothers uterus 142
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The placenta requires androgen precursors from the maternal and fetal adrenal glands. DHEA-S from fetal and maternal adrenals is converted to estradiol and estrone by the placenta. The fetal liver 16hydroxylates DHEA-S, and the placenta converts this substance to estriol.
in case of liver damage of the fetus, the 16-OH DHEA-S hormone will not be produced, since this is the only place for production HPL : 143
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human placental lactogen = human chorionic somatomammotropin pregnancy: the hormonal control of labor parturition - estrogen in late pregnancy o stimulates production of oxytocin receptors in myometrium o produces receptors for prostaglandins o produces gap junctions between myometrium cells in uterus - factors responsible for initiation of labor are incompletely understood - fetal adrenal cortex o chain of events may be set in motion through CRH production o fetal adrenal zone secretes DHEA-S, which travel from fetus and placenta - uterine contractions o oxytocin o prostaglandins -
dilation of the cervix o prostaglandins and relaxin
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contractions of the myometrium o oxytocin
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Physiolecture 12.12.07 Hormonal regulation of female sexual functions mammary gland histology
hormonal control of mammary growth and lactation
Lactation - hypothalamus releases PRH (prolactin releasing hormone) - anterior pituitary releases prolactin o stimulates milk production - prolactin secretion primarily controlled by PIH 145
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oxytocin needed for ”milk letdown”
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when not lactating, PRH is tonically inhibited.
This reflex is a neuroendocrine reflex: stimulus is afferent, response is efferent. 146
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”MILK” - nearly complete food (↓ iron) - apocrine process - liquid phases o Fat vitamins steroids carotenoids FAAs etc o Aqueous Lactose (milk sugars) Minerals (Ca2+, etc) (Proteins in colloidal suspension) • Caseins • Whey
Thyroid gland Thyroid hormones - thyroid gland is located just below the larynx - thyroid is the largest of the pure endocrine glands - follicular cells secrete thyroxine - parafollicular cells secrete calcitonin - endocrine gland with 2nd most problems, after pancreas.
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thyrosine is a common amino acid, while thyronine is a protein.
Physiolecture 13.12.07 Thyroid hormone Thyroid hormone (TH) synthesis
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iodine deficiency in drinking water compromises the production of thyroid hormone. This is especially evident in underdeveloped countries.
in some diseases, the negative feedback mechanism of TH-production is not working, which leads to hyperthyroidism. Function of TH - primary function o stimulates enzymes linked to glucose oxidation 149
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basal metabolic rate body heat production secondary function - nutrient metabolism - neural development & function - heart function (rate, blood pressure) - muscle development & function - skeletal growth & development - gastrointestinal function (motility, secretion) - reproductive function - skin hydration & secretory functions diarrhea is often common in hypothyroid (?) persons because of excess secretion of the GI The effect of TH - every tissue is affected - slow onset and long lasting effects
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Enhancement /inhibition - pregnancy, prolonged cold: o stimulate TRH release o overcomes negative feedback o increases metabolism, heat production - TSH inhibited by o GH inhibiting hormone (somatostatin) o Glucocorticoids o Estrogen & testosterone The pathology of TH secretion - grave´s disease 151
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o follicular cell hyperfunction eyes are protruding out of the eye socket cretinism o follicular cell hypofunction tongue usually hangs out of the patients mouth skeletal muscle doesn’t develop properly
iodine deficiency - requirement sources o 150 micrograms/day in adolescent and adults o seafood, soil, milk products o iodized salt, 60% of world’s salt is iodized but not targeted to those at risk - prevalence o 1 billion at risk o 655 million with goiter o 11 million with cretinism o high mountainous areas; away from sea Goiter Symptoms - low metabolic rate - chilled feeling - edema (abnormal swelling) - lethargy - mental sluggishness (NOT retardation)
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Endemic goiter - diffuse enlargement of thyroid o 10% population, in endemic areas, need iodine moderate iodine deficiency is associated with an average reduction on IQ of 13 points - mechanism: thyroxine production requires iodine, underproduction stimulates hyperplasia via TSH o protein calorie malnutrition also giotrogenic
Physiolecture 14.12.07 The posterior pituitary -
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From hypothalamus to posterior pituitary by neural secretion Oxytocin - contraction by smooth muscle (uterus, myoepithelial cells of lactating ducts) Oxytocin is found in males as well, but in smaller concentrations ADH - vasopressin ADH and oxytocin differ only by two amino acids 3 different hormone mechanisms Receptor In nucleus A mix of the two other - calcitonin Osmoreceptors in hypothalamus o If much water swell o If little water shrink o Baroreceptors and cardiopulmonary receptors would trigger the supraoptic nucleus to produce more ADH into circulation increase the permeability of tubes in kidney make aquaporins o Decrease in excretion
Oxytocin - stimulates contractions to pregnant uterus. Stimulates milk ejection from breasts after childbirth
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synthesized in hypothalamus and released from neurohypophysis. Action potentials located in hypothalamic secretory neurons. Target area o Smooth muscle, especially uterus of pregnant women; mammary glands (breasts)
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Atrial natriuretic factor = ANF permissive effect - when aldosterone will only be secreted when angiotensin II is present. - Even with CRH present
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