29th SIU Congress Sep 2–6, 2007 Paris

Approaches to Improve on the Long-Term Effectiveness of PDE5 Inhibitor Therapy Khaled L. Dabees, MD, PHD President of African Gulf Society of Sexual Medicine (AGSSM) Egypt

29th SIU Congress, Sep 2–6, 2007, Paris

NO Formation

29th SIU Congress, Sep 2–6, 2007, Paris

Activation of eNOS

Sexual Arousal Activation of penile nNOS

PDE5i AKT/eNOS-P

Nitric Oxide sGC

Sheer stress AKT-P

Vasodilation

PKG

cGMP PDE5

-

PDE5I

Ca2+ sensitisation

RhoA/ Rho kinase Adrenoceptor Activation (α1)

Tumescence Penile Erection

+

Detumescence Flaccid Penile

Vasoconstriction IP3/Ca2+

Noradrenaline Sympathetic NS Activation. 29th SIU Congress, Sep 2–6, 2007, Paris

Oxidative stress and Endothelial dysfunction • Oxidative Stress leads to ED • Endothelial dysfunction is mainly due to reduced bioavailability and bioactivity of Nitric Oxide (NO) • It is also a physiological process • Takes place gradually by age and menopause.

Vascular Endothelial Mediators Include the following • Nitric oxide (NO) • Cycloxygenase (CxO) • Endothelin-1 (ET-1) • Endothelium Depolarisation Factor (EDF) • And many others - thus • It is the largest endocrine gland

ED and NO ↓ NO deficiency in the vessel wall promotes • Inflammation • Oxidation of lipoproteins • Smooth muscle proliferation • Accumulation of lipid rich material • Platelet activation and thrombus formation Finally results in atherosclerosis.

Regulatory Functions of the Endothelium Normal

Dysfunction

Vasodilation NO, PGI2, EDHF, BK, C-NP

Vasoconstriction ROS, ET-1, TxA2, A-II, PGH2

Thrombolysis

Thrombosis

tPA, Protein C, TF-I, vWF

PAI-1, TF-α, Tx-A2

Platelet Disaggregation

Adhesion Molecules

NO, PGI2

CAMs, P,E Selectins

Antiproliferation

Growth Factors

NO, PGI2, TGF-β, Hep

ET-1, A-II, PDGF, ILGF, ILs

Lipolysis

Inflammation

LPL

ROS, NF-κB

Vogel R

Erectile Dysfunction Vascular Causes

Structural Changes Atherosclerosis

Hypertension Hypercholesterolemia

Functional Changes Impairment of endothelium-dependent relaxations

Diabetes Impairment of neurogenic relaxations

Arteries Arterial stenosis

Arterial insufficiency

Arteries

Impaired vasodilatation

Reduced inflow Trabeculae

Excessive outflow

Trabeculae

Smooth muscle atrophy and fibrosis

Corporo-venoocclusive disease

Impaired relaxation

Adapted from Tejada I et al. In: Erectile Dysfunction. Plymbridge Distributors; 2000:65 29th SIU Congress, Sep 2–6, 2007, Paris

Clinical Sequelae

Oxidative Stress: Endothelial Dysfunction and CAD/Renal Risk Factors Hypertension

Diabetes

Smoking

LDL

Homocysteine

Estrogen deficiency

× O2 Endothelial Cells and × H2O2 Vascular Smooth Muscle

Endothelial Dysfunction Apoptosis Leukocyte adhesion

Lipid deposition Vasoconstriction

VSMC growth

Thrombosis

Prevalence of Comorbidities in Men With and Without ED: MALES Phase I Study* 40

36†

35 29†

30

25†

25 Prevalence of Comorbidities (%)

20

19

17†

16

15 10

0

13

7 4

5 Men without ED Men with ED

14†

HTN

CVD

Dyslipidemia

Diabetes

N=27,839 men aged 25-70 years. *Self-reported. †P