title: Sildenafil increases sympathetically mediated vascular tone in humans.
abstract: BACKGROUND
  Sildenafil, a selective phosphodiesterase-type-5 (PDE-5) inhibitor, produces vasodilation that improves erectile dysfunction and pulmonary hypertension. Sildenafil could also cause baroreflex sympathetic activation that would enhance vascular tone and oppose direct vasodilation. We tested the hypothesis that sildenafil administration increases sympathetically mediated vascular tone in healthy middle-aged men.
  
  
  METHODS
  We randomized 9 healthy, middle-aged, male volunteers (mean age 45±2 years) in a double-blind, crossover fashion to receive a single oral dose of sildenafil 100mg or placebo on 2 separate study days. Hemodynamics and forearm blood flow responses were measured at baseline, at 30 and 45 minutes after study drug administration, and then during intra-arterial infusions of vasoactive drugs. After sildenafil and placebo administration, intrabrachial medications were infused to test forearm alpha receptor sensitivity (norepinephrine), cyclic-AMP-mediated vasodilation (isoproterenol), and sympathetically mediated vascular tone (phentolamine) (adenosine was a control vasodilator). Blood samples were taken before and 60 minutes after study drug administration and at the end of the intrabrachial infusions for measurement of plasma norepinephrine concentrations.
  
  
  RESULTS
  Forearm vascular responses to norepinephrine, isoproterenol, and adenosine were not different after placebo and sildenafil administration. Percentage reduction in forearm vascular resistance during phentolamine was significantly lower after sildenafil than placebo (-73% ± 3% vs -63% ± 3%; P = 0.0002). Sildenafil significantly increased plasma norepinephrine compared with placebo 60 minutes after study drug administration and at the end of the study session (P = 0.02).
  
  
  CONCLUSIONS
  Sildenafil increased sympathetically mediated vascular tone in middle-aged healthy men. Alpha-adrenergic-mediated vasoconstriction may offset vasodilation during PDE-5 inhibition and may explain the significant hypotension observed in patients taking alpha-blockers with sildenafil.
authors: Pharmacy Practice Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, USA. jmdopp@pharmacy.wisc.edu
authors: John M
authors: JM
authors: Dopp
authors: Alexei V
authors: AV
authors: Agapitov
authors: Christine A
authors: CA
authors: Sinkey
authors: William G
authors: WG
authors: Haynes
authors: Bradley G
authors: BG
authors: Phillips
mesh_terms: D001783:Blood Flow Velocity / Q000187:drug effects; D001916:Brachial Artery / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005500:Follow-Up Studies; D005542:Forearm / Q000098:blood supply; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage; D012016:Reference Values; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage*; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate
keywords: blood pressure; hypertension; norepinephrine; sildenafil; sympathetic nervous system; vascular tone; vasodilation.