Mechanism of Penile Erection

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The main mediator of penile erection is nitric oxide (NO). NO is synthesized by two enzymes: endothelial NO synthase (eNOS; NOS3) and neuronal NO synthase (nNOS; NOS1). nNOS-containing (nitrergic) nerve fibers course from the major pelvic ganglia (MPG) and terminate in the penis. eNOS localizes to the vascular and sinusoidal endothelium in the penis [4].

Sensory reflexogenic and psychogenic sexual stimulation activates nNOS, which initiates the erectile response. Sexual stimulation also neuronally releases acetyl-choline, which stimulates eNOS in the endothelium. The resulting increase in blood flow activates eNOS and causes sustained endothelial NO release, accounting for the achievement and maintenance of full erection [1]. Upon its synthesis and release from nerve terminals and endothelial cells, NO diffuses to neighboring vascular and trabecular smooth muscle cells in the penis where it activates soluble guanylate cyclase to produce cyclic guanosine monophosphate (cGMP). NO/cGMP activates downstream targets such as ion channels, leading to the relaxation of the cavernosal

Shear Stress Erection

Fig. 28.1 NO-mediated penile erection. NO is the main mediator of penile erection. NO is synthesized from its precursor l-arginine by nNOS in nitrergic nerve terminals in response to a sexual stimulus, and by eNOS in endothelium in response to acetylcholine and shear stress elicited by increased blood flow in the corporeal sinusoids. NO diffuses to adjacent smooth muscle cells where it activates soluble guanylyl cyclase (sGC) and increases the production of 3' ,5'-cyclic guanosine monophosphate (cGMP) from 5'-guanosine triphosphate (GTP). Subsequent activation of cGMP-specific protein kinase I (PKG) reduces contractile activity and promotes relaxation of smooth muscle cells and erection. cGMP in the penis is hydrolyzed primarily by type 5 phosphodiesterase (PDE5) to inactive 5 ' -GMP, which terminates NO signaling and returns the penis to the flaccid state

Fig. 28.1 NO-mediated penile erection. NO is the main mediator of penile erection. NO is synthesized from its precursor l-arginine by nNOS in nitrergic nerve terminals in response to a sexual stimulus, and by eNOS in endothelium in response to acetylcholine and shear stress elicited by increased blood flow in the corporeal sinusoids. NO diffuses to adjacent smooth muscle cells where it activates soluble guanylyl cyclase (sGC) and increases the production of 3' ,5'-cyclic guanosine monophosphate (cGMP) from 5'-guanosine triphosphate (GTP). Subsequent activation of cGMP-specific protein kinase I (PKG) reduces contractile activity and promotes relaxation of smooth muscle cells and erection. cGMP in the penis is hydrolyzed primarily by type 5 phosphodiesterase (PDE5) to inactive 5 ' -GMP, which terminates NO signaling and returns the penis to the flaccid state smooth muscle and vasodilation of blood vessels [5]. It also inhibits contractile regulatory pathways (see below).

cGMP is hydrolyzed by the phosphodiesterases, predominantly type 5 (PDE5), to inactive 5 '-GMP, terminating penile erection [6]. PDE5 inhibitors such as sildenafil, vardenafil, and tadalafil inhibit PDE5, thereby augmenting cGMP levels and penile erection (see Fig. 28.1).

28.2.3 Contractile Pathways in the Penis

While activation of the NO pathway leads to penile erection, vasoconstrictive mechanisms maintain the penis in its flaccid state. Vasoconstriction is evoked by several mediators, such as norepinephrine, endothelins, angiotensins, and thromboxane A2 [7]. Contraction of smooth muscles is mediated by calcium-dependent and calcium-independent pathways. The calcium-dependent pathway involves activation of receptors and/or opening of calcium channels on smooth muscle cells resulting in increase in intracellular levels of calcium. Once the cytosolic calcium returns to the basal levels, the calcium-sensitizing pathway takes over. This pathway causes contraction by increasing calcium sensitivity without changes in cytosolic calcium levels. This pathway involves RhoA, a small protein, which activates Rho-kinase (ROCK [8-10]). Tonic activity of RhoA/ROCK plays a key role in the control of erectile function and maintenance of penile flaccidity.

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