Section: II: Basic science update: PDE5 inhibition and endothelial dysfunction A unifying model of peripheral and coronary vascular disease Content Points: The slide summarizes current thinking on the pathobiology of atherosclerosis, which is that risk factors lead to an environment in which the three principal oxidative systems in the vascular wall are activated.11 Excessive production of reactive oxygen species (ROS) overwhelms endogenous antioxidant mechanisms, leading to oxidation of lipoproteins, nucleic acids, carbohydrates, and proteins. The principal target of this oxidative stress is the vascular endothelium, although data suggest that there may be other targets, such as mononuclear cells. The specific functional alterations induced by ROS are impairment of endothelium-dependent vasorelaxation (secondary to a decline in nitric oxide [NO] bioavailability) and development of a procoagulant surface. Ultimately, plaque growth, vascular wall remodeling, and other structural alterations occur, leading to the well known clinical sequelae of death, MI, stroke, ischemia, and congestive heart failure (CHF).

Evolution of atherosclerotic plaque Content Points: This timeline illustrates, from left to right, some of the events that occur during atherosclerosis.12 An early step is monocyte adhesion. Selectins slow the passage of leukocytes over the endothelium (leukocyte rolling) and permit establishment of stronger interactions. Adhesion molecules are involved in the arrest of leukocyte rolling to permit migration between endothelial cells. Monocyte arrest is followed by migration into the arterial intima. Monocyte chemoattractant protein-1 (MCP-1) plays an important role in monocyte recruitment into the vascular wall. However, other mediators are also involved. Local migration of monocytes is accompanied by smooth muscle cell migration from the arterial media. Monocyte-derived macrophages take up oxidized low-density lipoprotein cholesterol (LDL-C) and become foam cells. These accumulate along with T cells to form fatty streaks, which are the initial raised lesions of atherosclerosis. Advanced atherosclerosis is characterized by the development of plaques with a cellular fibrous cap of smooth muscle cells, calcium, and proteoglycans, and a lipid core. These plaques may rupture and lead to thrombotic complications or undergo further growth and cause flow-limiting stenoses.

Erectile dysfunction = endothelial dysfunction Content Points: Levine and Kloner wrote, “The same vascular/endothelial injuries that occur in the coronary arteries are likely to occur in the cavernosal arteries, the primary arteries supplying penile erectile tissue.”13 Examining the condition of erectile tissue may yield insights into clinically unseen but nevertheless present coronary, peripheral, or cerebrovascular disease and, likewise, undiagnosed hypertension, diabetes, or other endocrine diseases.

Role of PDE5 in penile erection Content Points: Sexual arousal induces neural stimuli, which promote release of NO from cavernous nonadrenergic, noncholinergic nerve terminals, endothelial cells, and smooth muscle cells in corporeal erectile tissue.14 NO diffuses into the cytoplasm, where it binds with and activates soluble guanylate cyclase (sGC). Activated sGC converts guanosine 5'-triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), starting a cascade of biochemical events leading to relaxation of cavernosal smooth muscle. Phosphodiesterase type 5 (PDE5) degrades cGMP, regulating penile smooth muscle contractile tone. Inhibition of PDE5 increases cGMP, and thus enhances NO-mediated smooth muscle relaxation and consequently penile erection.

Anatomy of penile erection Content Points: During an erection, the trabecular smooth muscle relaxes and the arterioles undergo vasodilatation, causing blood flow to increase severalfold. The sinusoidal spaces expand, lengthening and enlarging the penis.4 Sinusoidal expansion also compresses the subtunical venular plexus against the tunica albuginea; this stretching of the tunica compresses emissary veins. The overall result is almost complete stoppage of blood outflow from the penis, trapping the blood within the corpora cavernosa. The penis assumes an erect position, with full erection yielding an intracavernous pressure ~100 mm Hg.

Hemodynamics of penile erection Content Points: Arterial blood flows into the sinusoidal spaces of the corpus cavernosum and corpus spongiosum, and flows out through the postcavernous venules.15 Both the arteries supplying the sinusoids and the sinusoids themselves have a smooth muscle cell layer in their walls. When these smooth muscle cells relax, blood flow resistance into the penis is reduced and blood flows into the sinusoids, thereby increasing their volume and causing penile tumescence. Sexual stimulation, which provides the incitement for erection, causes increased NO release from noncholinergic, nonadrenergic parasympathetic nerve endings in the arterial walls and sinusoids of the penile corpora cavernosa.

Strategies for improving NO bioavailability and endothelial function Content Points: The following modalities have been shown to improve NO bioavailability and endothelial function. - Exercise training,16 L-arginine supplementation,17 and tetrahydrobiopterin17 - Risk factor modification, such as cholesterol level reduction, antihypertensive treatment, estrogen replacement,17 and treatment with an insulin sensitizer or thiazolidinediones18 - Antioxidants17 - Aspirin19 - Renin-angiotensin system (RAS) manipulation via angiotensin-converting enzyme (ACE) inhibition, which reduces angiotensin II formation and enhances bradykinin activity17 As this slide kit demonstrates, inhibition of PDE5 provides a strategy for improving NO availability and endothelial function.