From an anatomic standpoint, the penis is highly vascular, invested with a rich supply of smooth muscle erectile tissue, and harbors numerous sinusoids, all of which render it well suited to accommodate the enhanced perfusion of the penis underlying physiologic erection.

Within the penis, erection begins with vasodilatation of the cavernous artery and helicine arterioles in association with relaxation of the trabecular erectile tissue. These actions cause engorgement of blood in the sinusoidal spaces of the corpora cavernosa and spongiosum, and penile erection results. The expansion of penile blood volume leads to compression of subtunical venules by the resistant fibrous outer covering, the tunica albuginea, with occlusion of venous outflow and physiologic erection.

Voluntary or reflexogenic contraction of the ischiocavernous and bulbocavernous musculature contributes to the increase in intracavernosal pressure, which may reach or exceed mean arterial pressure.^[49,50]

Penile erection is initiated by sexual stimuli, including auditory, visual, and olfactory stimuli, and erotic cognitions. Spinal cord sexual arousal occurs as a result of tactile stimulation of the penis. The neurotransmitter mediating these sexual signals is nitric oxide (NO), initially termed endothelium-derived relaxing factor.^[51] NO is produced by the endothelium in the absence of cholinergic or adrenergic influences.^[52,53]

NO stimulates smooth muscle guanylate cyclase, upregulating synthesis of cyclic guanine monophosphate (cGMP), which plays a pivotal role in penile arteriolar vasodilatation and relaxation of penile corporeal smooth muscle. Oxygen levels are important in NO-mediated responses, which vary widely from penile flaccidity to erection. Decreasing oxygen tension levels progressively inhibit NO responses, and elevation of oxygen to normal levels restores NO-dependent activities.^[54]

Both cholinergic and adrenergic influences are significant in penile erection and detumescence. Parasympathetic fibers and acetylcholine, the release of which may be stimulated by tactile sensory stimuli to the penis, enhance penile blood flow and smooth muscle relaxation.^[55] Sympathetic (adrenergic) fibers and norepinephrine neurotransmission help to maintain the penis in its flaccid state.^[56]

Detumescence is mediated by adrenergic nerve terminals whose neurotransmitter, norepinephrine, activates alpha-adrenergic receptors (found chiefly in the thoracolumbar region of the spinal cord). Activation of these receptors produces vasoconstriction of the penile vasculature and decompression of penile venules, which result in detumescence. Incomplete corporeal smooth muscle relaxation resulting from impairment of the NO-induced relaxing mechanism or from augmented alpha-adrenergic activity has been proposed as a mechanism of ED.^[57]

Prostaglandin E₁ (PGE₁) is produced during erection by the penile musculature and activates adenylate cyclase, which alters ion-channel permeability and results in calcium release by the smooth muscle cells. (Although the PGE₁ pathway is not thought to play a major intrinsic proerectile role, it is considered to be important as a therapeutic approach.)

These smooth muscle cells then relax, allowing increased blood flow.^[58] Dynamic vascular studies have demonstrated that venous outflow obstruction and the resultant entrapment of arterial blood in the penis are essential in the initiation and maintenance of a rigid erection.^[59]

Failure of these vascular phenomena, as seen with venous leakage, can result in ED.^[60] Venous leakage may be of traumatic origin, resulting in abnormal venous communication between the corpora cavernosa and the glans penis. Leakage may also result from the failure of emissary veins to close, as in Peyronie's disease.^[59] An unusual cause of ED is a traumatic or congenital arteriovenous fistula between the pudendal artery and a pelvic vein. An elevated penile content of corporeal connective tissue, possibly related to a decrease in oxygen, has been proposed as a mechanism for defective veno-occlusion.^[61]

Phosphodiesterases are essential in regulating intracellular cGMP activity through enzymatic hydrolysis (to 5'-GMP), thus terminating its second-messenger function.^[2] Multiple PDEs exist throughout the body; their isoforms vary depending on the specific function that they perform. In cGMP penile activity, the PDE5 isoform terminates the vasodilator and smooth muscle-relaxing effects of cGMP. Inhibition of this process by PDE5 inhibitors forms the basis for recent developments in the oral therapy of ED.

Recent advances in elucidating the physiology of penile erection and possible mechanisms of ED have spawned the development of new pharmacologic agents. These agents exploit or potentiate normal physiologic mechanisms producing penile erection or modify the pathophysiologic factors leading to ED.

The physiologic response produced by sexual arousal is potentiated -- not engendered --by PDE5 inhibitors. These agents selectively and competitively inhibit hydrolysis of cGMP, the second messenger responsible for NO-induced penile smooth muscle relaxation and increased penile blood flow. Indeed, although approximately 30% to 40% of sildenafil users reported improvements in relationships with partners and/or QOL,^[62] PDE5 inhibitors are without benefit in the absence of sexual arousal. This is a critical concept for the patient and his sexual partner to understand.

Because adrenergic stimulation, primarily of alpha-2 receptors, is responsible for penile detumescence and maintenance of flaccidity, agents such as phentolamine, which block alpha-adrenergic stimulation, have been used in the treatment of ED. These agents have been most effective when applied topically to the urethra and may also be useful with ICIT or as oral therapy (in Mexico and other non-US markets), although the latter is of questionable efficacy.

Several vasoactive agents, including synthetic PGE₁, have been administered by ICIT either alone or in combination with other agents. They enhance penile blood flow and erection by promoting smooth muscle relaxation and penile arteriolar dilatation. The latter processes occur either by direct action on the smooth muscle of the corpora and penile arterioles or by increased intracellular levels of cGMP through stimulation of NO release.^[63,64]