Sildenafil citrate, a selective phosphodiesterase type 5 inhibitor: Research and clinical implications in erectile dysfunction

Under normal physiological conditions, following sexual stimulation, releas e of nitric oxide (NO) from penile non-adrenergic, non-cholinergic nerves a nd the endothelium activates guanylyl cyclase and induces intracellular cGM P synthesis in erectile tissue trabecular smooth muscle cells. Increased cG MP levels reduce intracellular Ca2+ concentrations, inhibiting smooth muscl e contractility and thereby initiating the er erectile response. Phosphodie sterase type 5 (PDE type 5) is the predominant enzyme responsible for cGMP hydrolysis in trabecular smooth muscle. Activation of PDE type 5 terminates NO-induced, cGMP-mediated smooth muscle relaxation, resulting ultimately i n restoration of basal smooth muscle contractility and penile flaccidity. S ildenafil citrate is a potent PDE type 5 reversible and selective inhibitor that blocks cGMP hydrolysis effectively (K-i similar to 3 nM). Under condi tions of excessive adrenergic tone or impaired neurovascular status, follow ing sexual stimulation, sildenafil acts to enhance NO-mediated smooth muscl e relaxation, resulting in improved penile erection in men with erectile dy sfunction. In this review, we summarize the current state of knowledge of t he physiology of penile erection and the pharmacology, metabolism and clini cal experience with sildenafil citrate in the management of erectile dysfun ction.