title: The effect of sildenafil on nitric oxide-mediated vasodilation in healthy men.
abstract: 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 guanosine monophosphate breakdown. Since PDE 5 is widely expressed in the vasculature, 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 the 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-fold 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 induced by phenylephrine from 81% +/- 3% to 74% +/- 3% (P =.025). Sildenafil did not significantly affect the maximal venodilatory response to acetylcholine (35% +/- 7% after placebo versus 32% +/- 8% after sildenafil) (P =.7). In the arterial vasculature, flow-mediated dilation before (2.4% +/- 1%) and after (2.8% +/- 1.4%) sildenafil (P =.8) and postischemic reactive hyperemia 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 dinitrate, an endothelium-independent vasodilator, caused a significant increase in resting brachial artery diameter from 0.53 +/- 0.01 cm to 0.56 +/- 0.02 cm (P =.005), without altering flow-mediated dilation.
  
  
  CONCLUSIONS
  In healthy men sildenafil increased sensitivity to nitroglycerin, an exogenous NO donor, approximately 4-fold but did not affect endothelium-dependent, NO-mediated responses in either the hand vein or forearm vasculature. Differential vascular responses to sildenafil may localize its enhancement of endogenous NO-mediated vasodilation to vascular beds such as the corpus cavernosum.
authors.affiliation: Division of Clinical Pharmacology and General Clinical Research Center, Department of Biomedical Engineering, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
authors.forename: V
authors.initials: V
authors.lastname: Dishy
authors.forename: G
authors.initials: G
authors.lastname: Sofowora
authors.forename: P A
authors.initials: PA
authors.lastname: Harris
authors.forename: M
authors.initials: M
authors.lastname: Kandcer
authors.forename: F
authors.initials: F
authors.lastname: Zhan
authors.forename: A J
authors.initials: AJ
authors.lastname: Wood
authors.forename: C M
authors.initials: CM
authors.lastname: Stein
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D001916:Brachial Artery / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006225:Hand / Q000098:blood supply; D006801:Humans; D006940:Hyperemia / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D010991:Plethysmography; D011687:Purines; D012039:Regional Blood Flow / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones; D014664:Vasodilation / Q000187:drug effects*; D014680:Veins / Q000187:drug effects
chemical_list: D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D000109:Acetylcholine