Molecular mechanisms for the regulation of penile smooth muscle contractility

Abstract

Relaxation of penile smooth muscle (arterial and trabecular) initiates and maintains penile erection. Relaxation of smooth muscle is viewed as a ‘resetting’ of contractile machinery by resumption of a precontractile state accomplished by lowering cytosolic Ca⁺² and/or by a decrease in sensitivity of the contractile machinery to Ca⁺². There are various mechanisms whereby cytosolic Ca⁺² can be reduced and relaxation achieved, but in general, all pathways depend on the accumulation of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) or activation of K channels with hyperpolarization. Another mechanism, activation of Na⁺/K⁺ adenosine triphosphatase (ATPase) by nitric oxide, has been shown to be involved in relaxation of trabecular smooth muscle. Since Na⁺/K⁺ ATPase is electrogenic, its stimulation would cause hyperpolarization. Hyperpolarization will prevent the opening of voltage-dependent calcium channels. Guanylate cyclase, which catalyzes the conversion of guanosine triphosphate to cGMP, is activated by nitric oxide. cGMP activates protein kinase G, which through multiple phosphorylations facilitates calcium sequestration and reduces the entry of calcium into the cell. Other muscle relaxants act by way of a cAMP-dependent mechanism such as prostaglandin E, vasoactive intestinal polypeptide, and catecholamines (via β-receptors). These substances react with membrane receptors coupled to a GS-type protein that stimulates adenylate cyclase, which catalyzes the accumulation of cAMP.