Erectile dysfunction is a common, multifactorial disorder that is associated with aging and a range of organic and psychogenic conditions, including
hypertension,
hypercholesterolemia,
diabetes mellitus,
cardiovascular disease, and depression. Penile erection is a complex process involving psychogenic and hormonal input, and a neurovascular nonadrenergic, noncholinergic mechanism.
Nitric oxide (NO) is believed to be the main vasoactive nonadrenergic, noncholinergic
neurotransmitter and chemical mediator of penile erection. Released by nerve and endothelial cells in the corpora cavernosa of the penis, NO activates
soluble guanylyl cyclase, which increases 3',5'-cyclic
guanosine monophosphate (cGMP) levels. Acting as a second messenger molecule, cGMP regulates the activity of
calcium channels as well as intracellular
contractile proteins that affect the relaxation of corpus cavernosum smooth muscle. Impaired NO bioactivity is a major pathogenic mechanism of
erectile dysfunction. Treatment of
erectile dysfunction often requires combinations of psychogenic and medical
therapies, many of which have been only moderately successful in the past. The advent of oral
phosphodiesterase type 5 (PDE-5) inhibitors, however, has greatly enhanced
erectile dysfunction treatment; patients have demonstrated high tolerability and success rates for improved erectile function. The efficacy of the
PDE-5 inhibitors also serves to illustrate the importance of the NO-cGMP pathway in erectile function since these agents counteract the degradation of NO-generated cGMP. Because not all patients respond to
PDE-5 inhibitors, additional
therapies are being investigated, such as
soluble guanylyl cyclase activators and NO donors, which act on NO-independent and NO-dependent pathways, respectively.