Physiology and Pharmacology

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6.2.1 Physiology of Erection. The penis is composed of three bodies: a pair of corpora cavernosa on the dorsal side and a corpus spongiosum on the ventral side. The role of the corpus spongiosum is to protect and support the urethra, while the two corpora cavernosa are the parts that provide structure to the penis in the erect state. The cavernosal bodies consist of a network of vascular sinuses supplied by the terminal branches of the caver-nosal arteries. The vascular sinuses are supported by smooth muscles that are normally contracted when the penis is in the flaccid state. Factors that mediate cavernosal smooth muscle contraction, and therefore promote penile flaccidity, include the following (140):

endothelin, angiotensin, and thromboxane A,.

Erection occurs as a result of increased pressure in the corpora cavernosa, which translates into penile rigidity. The pressure increase is caused by three synergistic processes: (2) relaxation of the smooth muscles of the corpora cavernosa; (2)increase in arterial blood flow to the penis; and (3) restriction of the venous blood flow out of the penis. Both central and peripheral mechanisms contribute to the process of penile erection. At the central level, the psychological component of penile erection is controlled by the hypotha-lamic and limbic systems (140). At the peripheral level, both sympathetic and parasympa-thetic pathways as well as several mediators are involved. Psychogenic and local stimulation results in the release of neurotransmit-ters from the cavernosal nerve terminals and smooth muscle endothelium. Factors that mediate the corpus cavernosum relaxation include nitric oxide (NO), vasoactive intestinal peptide (VIP), calcitonin gene-related peptide and prostaglandin.

6.2.2 Role of Nitric Oxide. The NO pathway is the best understood and is believed to be the most important pathway for penile erection. NO is released from nonadrenergic noncholinergic (NANC) nerves in the corpus cavernosum and from the endothelium that lines the cavernosal vascular sinuses and blood vessels (140). Nitric oxide synthase catalyses NO formation from the precursors l-arginine and molecular oxygen (141). NO production in the vascular endothelium is stimulated by muscarinic acetylcholinergicre-ceptors. The released NO diffuses into smooth muscles and interacts with guanylate cyclase, which catalyses the formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. The resulting increase in cGMP activates several processes that lead to smooth muscle relaxation. The increased arterial inflow to the corpora cavernosa as a result of smooth muscle relaxation leads to an increase in intracavernosal pressure and volume and thus increased penis length and rigidity. The increase in intercav-ernosal pressure results in compression of the subtunical venules and hence reduction of the venous outflow, which further increases penile rigidity (140, 142). cGMP activity is terminated by hydrolysis by cGMP specific type-5 phosphodiesterase (PDE).

6.2.3 Other Mediators. It is believed that VIP-, CGRP-, and prostaglandin-mediated pathways contribute to smooth muscle relaxation by increasing intracellular cAMP concentration in the corpora cavernosa (140). Increased cAMP results in phosphorylation and dephosphorylation of the actin-smooth-mus-cle-myosin cascade that causes smooth muscle relaxation. Prostaglandin E (PGE) causes the elevation of cAMP through a G-protein-coupled mechanism and activation of adenylyl cyclase. In addition, PGE reduces the adreno-receptor mediated vasoconstriction by inhibiting norepinephrine release through prejunctional receptors on norepinephrine containing neurons.

6.2.4 Causes of Erectile Dysfunction. Erectile dysfunction can result from neurological, vascular, hormonal, or psychological factors, or from a combination of two or more of these factors. Neurological causes include spinal cord injury, multiple sclerosis, or any other condition that impedes the transmission of the neural signal generated by psychogenic stimulation. Vascular causes include arterial insufficiency, which results in low arterial pressure delivered to the penis, and venous insufficiency, in which excessive venous outflow occurs because of inadequate compression of the subtunical venules. Erectile dysfunction of hormonal origin results from inadequate androgenic stimulation of the sexual center in the anterior hypothalamus, which lowers libido and hence erection quality. In psychogenic erectile dysfunction, sexually inhibiting psychological issues can impede stimulatory signals to the penis, and anxiety can cause a sympathetic discharge, which favors flaccidity (142). It is usually difficult to distinguish primary psychogenic erectile dysfunction because many men with organic erectile dysfunction have a psychological response to their condition.

6.2.5 Mechanisms of Action. Most erectile dysfunction pharmacotherapies act by either inhibiting the contractile system (e.g., a-adre-noreceptor antagonists), or by stimulating or enhancing the vasodilatory system (e.g., prostaglandin El9 NO donors, PDE inhibitors). These mechanisms can work regardless of the origin of the disorder.

6.2.5.1 Sildenafil. Sildenafil is a selective PDE5 inhibitor. PDE5 is the cGMP-specific PDE and is the predominant form of the isoenzyme in the corpora cavernosa. By inhibiting the hydrolysis of cGMP that is generated through the NO pathway, sildenafil enhances the cavernosal smooth muscle relaxation. For sildenafil to exert its effect, it requires intact NO-relaxing nerve fibers and an intact cavernosal epithelium. Sildenafil is not effective in patients with vascular disease where NO production is impaired, and has no effect in the absence of sexual stimulation.

Sildenafil has high selectivity for PDE5. It has 80- to more than 8500-fold selectivity to PDE5 versus PDE1, PDE2, PDE3, and PDE4 (125). PDE6, the isoenzyme found in the retina, is closely related to PDE5. The selectivity of sildenafil to PDE6 is one-tenth of that to PDE5 (143). This explains the visual abnormalities observed with higher plasma levels of sildenafil. In addition to the cavernosal tissue, PDE5 is also found in lower concentrations in other human tissues including platelets, vascular smooth muscles, and skeletal muscles. The inhibition of PDE5 in these tissues is believed to be responsible for the vascular side effects of sildenafil.

6.2.5.2 Alprostadil. Alprostadil is chemically identical to the naturally occurring form of prostaglandin Ex and acts similar to the endogenous PGE. It induces erection by relaxation of the cavernosal smooth muscle and dilation of cavernosal arteries, which leads to increased arterial inflow and decreased venous outflow. Alprostadil has various systemic effects including vasodilatation, inhibition of platelet aggregation, and stimulation of intestinal and uterine smooth muscles.

6.2.5.3 Yohimbine. Yohimbine is an a-ad-renoreceptor antagonist, with high selectivity to the presynaptic a2-adrenergic receptors. It is generally believed that yohimbine exerts its erectogenic effect by antagonizing the adrenergic inhibitory tone that suppresses erection. The mechanism of action of yohimbine on some sexual functions seems to be central, i.e., by inhibiting the presynaptic a2 receptors in the brain (129). Published data from animal experiments support the postulation that yo-

effects on sexual arousal and ejaculation occur through a central mechanism, because the drug can induce arousal even after genital anesthesia (144) and it reverses clonidine-induced inhibition of ejaculation (145,146). However, the mechanism of action of yohimbine on erectile function was not fully understood and its site of action was not conclusively identified until it was demonstrated few years ago that functional a2 receptors are expressed in the human corpus cavernosum (147). It is now believed that yohimbine exerts its erectogenic action by blocking post-synap-tic a2 receptors in the corpus cavernosum and thus inhibits the contractility of the caver-nosal tissue (128). In addition to its a-adren-ergic effects, yohimbine exerts a stimulatory action on the mood and may increase anxiety. This effect is at least partially attributed to yohimbine's central serotonergic activity although it has not been adequately studied.

6.2.5.4 Other Agents. Phentolamine is a nonselective al- and a2-adrenoreceptor antagonist. It is a weak erectogenic agent when used alone as an intracavernosal injection. Phentolamine is usually used in combination with alprostadil and/or papaverine.

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