Type 5 phosphodiesterase inhibitors in the treatment of erectile dysfunction and cardiovascular disease.
Since the discovery of sildenafil in 1989 as a highly selective inhibitor of the phosphodiesterase type-5 (PDE-5) receptor, 2 additional PDE-5 inhibitors, tadalafil and vardenafil, have emerged as safe and effective treatments of erectile dysfunction (ED). Enzymes in the PDE family catalyze the hydrolysis of the intracellular signaling molecules cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which is the second messenger of nitric oxide (NO) and a principal mediator of smooth muscle relaxation and vasodilation. Sildenafil was initially introduced for clinical use as the result of extensive research on chemical agents targeting PDE-5 that might potentially be useful in the treatment of coronary heart disease. Erection is largely a hemodynamic event, which is regulated by vascular tone and blood flow balance in the penis. Endothelial dysfunction, an early component of atherosclerosis, may inhibit a vascular event such as erection and is rarely confined to the arteries supplying blood to the penis, but more likely occurs throughout the vascular bed. In addition to the effects of the NO-cGMP signaling pathway on cavernosal smooth muscle, clinical findings have suggested that vascular tone in the pulmonary, coronary, and other vascular tissues expressed by PDE-5 is also influenced by this signal transduction mechanism. This has led to the emergence of novel therapeutic indications for sildenafil over a range of cardiovascular conditions that are either well-established risk factors or comorbidities with ED. Recently, the U.S. Food and Drug Administration approved sildenafil as an orally active therapy for the treatment of primary pulmonary hypertension. The drug will be marketed under the trade name of Revatio, not Viagra, the name used for the ED indication. The approved dose for primary pulmonary hypertension is 20 mg 3 times daily.
Ravipati
Gautham
G
Division of General Internal Medicine, New York Medical College/Westchester Medical Center, Valhalla, New York 10595, USA.
McClung
John A
JA
Aronow
Wilbert S
WS
Peterson
Stephen J
SJ
Frishman
William H
WH
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002243:Carbolines / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000150:complications / Q000188:drug therapy*; D003326:Coronary Circulation / Q000187:drug effects; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004347:Drug Interactions; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D007093:Imidazoles / Q000627:therapeutic use; D018783:Impotence, Vasculogenic / Q000150:complications / Q000188:drug therapy*; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use; D011652:Pulmonary Circulation / Q000187:drug effects; D011687:Purines / Q000627:therapeutic use; D018570:Risk Assessment / Q000379:methods; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use; D000068581:Tadalafil; D016896:Treatment Outcome; D014227:Triazines / Q000627:therapeutic use; D000069058:Vardenafil Dihydrochloride
D000959:Antihypertensive Agents; D002243:Carbolines; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human