The effect of sildenafil on nitric oxide-mediated vasodilation in healthy men

Background: Sildenafil, a treatment for erectile dysfunction, is a specific phosphodiesterase type 5 (PDE 5) inhibitor that enhances nitric oxide (NO) -mediated vasodilation in the corpus cavernosum by inhibiting cyclic guanos ine monophosphate breakdown. Since PDE 5 is widely expressed in the vascula ture, we examined the hypothesis that sildenafil could enhance NO-mediated vasodilation in other vascular beds and improve endothelial function. Methods: NO-mediated responses to acetylcholine (endothelium-dependent) and nitroglycerin (endothelium-independent) were measured in healthy men in th e dorsal hand vein (n = 13), after the administration of either sildenafil 50 mg or placebo. Flow-mediated dilation of the brachial artery and forearm postischemic reactive hyperemia were measured before and after sildenafil 50 mg, isosorbide dinitrate 5 mg, and placebo in a double-blind, randomized , crossover study (n = 11). Results: In the hand vein, sildenafil administration increased sensitivity to local nitroglycerin. The 50% effective dose decreased approximately 4-fo ld from 13.5 ng/min (range, 6.9-26.6 ng/min) to 2.7 ng/min (range, 1.1-6.4 ng/min) (P = .025). Sildenafil decreased the maximum venoconstriction induc ed by phenylephrine from 81% +/- 3% to 74% +/- 3% (P = .025). Sildenafil di d not significantly affect the maximal venodilatory response to acetylcholi ne (35% +/- 7% after placebo versus 32% +/- 8% after sildenafil) (P = .7). In the arterial vasculature, flow-mediated dilation before (2.4% +/- 1%) an d after (2.8% +/- 1.4%) sildenafil (P = .8) and postischemic reactive hyper emia area under the curve before (1807 +/- 393 mL (.) min (.) s/100 mL) and after (1467 +/- 257 mL (.) min (.) s/100 mL) sildenafil were not different (P = .8). Resting heart rate, blood pressure, and resting brachial artery diameter were unchanged after sildenafil administration. Isosorbide dinitra te, an endothelium-independent vasodilator, caused a significant increase i n resting brachial artery diameter from 0.53 +/- 0.01 cm to 0.56 +/- 0.02 c m (P = .005), without altering flow-mediated dilation. Conclusions: In healthy men sildenafil increased sensitivity to nitroglycer in, an exogenous NO donor, approximately 4-fold but did not affect endothel ium-dependent, NO-mediated responses in either the hand vein or forearm vas culature. Differential vascular responses to sildenafil may localize its en hancement of endogenous NO-mediated vasodilation to vascular beds such as t he corpus cavernosum.