During sexual stimulation, NO released from nerve ending and endothelium diffuses into the trabecular and arterial smooth-muscle cells to activate guanylyl cyclase, which catalyzes the formation of second messenger cyclic guanosine monophosphate (cGMP) (_{Trigo-Rocha et al, 1993}). cGMP in turn activates protein kinase G, which phosphorylates potassium and calcium channels, resulting in hyperpolarization and reduced intracytosolic calcium. The end result is dissociation of myosin head from actin and smooth-muscle relaxation. In addition to the NO-cGMP pathway, several neurotransmitters (eg, vasoactive intestinal polypeptide [VIP] and calcitonin gene related peptide [CGRP]) and drugs (eg, alprostadil) combine with membrane receptor and activate the cyclic adenosine monophosphate (cAMP) pathway, which also phosphorylates ion channels and causes smooth-muscle relaxation. On the other hand, norepinephrine, phenylephrine, and endothelin appear to activate phospholipase C, which leads to the formation of inositol triphosphate and diacylglycerol, which in turn increases cytoplasmic calcium and induces smooth-muscle contraction.

Detumescence occurs following degradation of cGMP and cAMP to GMP and AMP, respectively, by specific phosphodiesterases. Eleven classes of phosphodiesterases have been identified. The penis is rich in phosphodiesterase type V (GMP specific), and therefore specific type V phosphodiesterase inhibitors (sildenafil, vardenafil, and tadalafil) are able to improve penile erections in patients with ED.

Intercellular Communication

Gap junctions are aqueous intercellular channels that have been demonstrated to interconnect the cytoplasm of adjacent cells in many tissues. In the penis, smooth-muscle cells are sparsely innervated by the terminal branches of the cavernous nerves. Therefore, gap junctions play a vital role in the intercellular communication within the corpus cavernosum, which enables the penis to function as a unit (_{Melman and Christ, 2001}).