Erectile dysfunction in men has long been the subject of research (by both amateur and professional scientists). Among the substances used in the past and generally discredited are “Spanish Fly” (a bladder and urethral irritant), yohimbine (an α2 antagonist; see Chapter 10), nutmeg, and mixtures containing lead, arsenic, or strychnine. Substances currently favored by practitioners of herbal medicine but of dubious value include ginseng and kava. Scientific studies of the process have shown that erection requires relaxation of the nonvascular smooth muscle of the corpora cavernosa. This relaxation permits inflow of blood at nearly arterial pressure into the sinuses of the cavernosa, and it is the pressure of the blood that causes erection. (With regard to other aspects of male sexual function, ejaculation requires intact sympathetic motor function, while orgasm involves independent superficial and deep sensory nerves.) Physiologic erection occurs in response to the release of nitric oxide from nonadrenergic-non-cholinergic nerves (see Chapter 6) associated with parasympa-thetic discharge. Thus, parasympathetic motor innervation must be intact and nitric oxide synthesis must be active. (It appears that a similar process occurs in female erectile tissues.) Certain other smooth muscle relaxants—eg, PGE1 analogs or α-adrenoceptor antagonists—if present in high enough concentration, can inde-pendently cause sufficient cavernosal relaxation to result in erec-tion. As noted in the text, nitric oxide activates guanylyl cyclase, which increases the concentration of cGMP, and the latter second messenger stimulates the dephosphorylation of myosin light chains (Figure 12–2) and relaxation of the smooth muscle. Thus, any drug that increases cGMP might be of value in erectile dys-function if normal innervation is present. Sildenafil (Viagra) acts to increase cGMP by inhibiting its breakdown by phosphodiester-ase isoform 5 (PDE-5). The drug has been very successful in the marketplace because it can be taken orally. However, sildenafil is of little or no value in men with loss of potency due to cord injury or other damage to innervation and in men lacking libido. Furthermore, sildenafil potentiates the action of nitrates used for angina, and severe hypotension and a few myocardial infarctions have been reported in men taking both drugs. It is recommended that at least 6 hours pass between use of a nitrate and the inges-tion of sildenafil. Sildenafil also has effects on color vision, caus-ing difficulty in blue-green discrimination. Three similar PDE-5 inhibitors, tadalafil, vardenafil, and avanafil, are available. It is important to be aware that numerous nonprescription mail-order products that contain sildenafil analogs such as hydroxythio-homosildenafil and sulfoaildenafil have been marketed as “male enhancement” agents. These products are not approved by the Food and Drug Administration (FDA) and incur the same risk of dangerous interactions with nitrates as the approved agents. PDE-5 inhibitors have also been studied for possible use in other conditions. Clinical studies show distinct benefit in some patients with pulmonary arterial hypertension but not in patients with advanced idiopathic pulmonary fibrosis. The drugs have possible benefit in systemic hypertension, cystic fibrosis, and benign prostatic hyperplasia. Both sildenafil and tadalafil are currently approved for pulmonary hypertension. Preclinical stud-ies suggest that sildenafil may be useful in preventing apoptosis and cardiac remodeling after ischemia and reperfusion. The drug most commonly used for erectile dysfunction in patients who do not respond to sildenafil is alprostadil, a PGE1 analog (see Chapter 18) that can be injected directly into the cav-ernosa or placed in the urethra as a minisuppository, from which it diffuses into the cavernosal tissue. Phentolamine can be used by injection into the cavernosa. These drugs will cause erection in most men who do not respond to sildenafil.