Background Phosphodiesterase type-5 (PDE-5) inhibition causes vasodilation and sympathetic activation. The contribution of each of these on resting vascular tone has not been studied. We tested the hypothesis that PDE5 inhibition contributes to increased sympathetically mediated vascular tone. Methods We studied 9 healthy males (44±2 years), randomized in a double-blind, crossover fashion to sildenafil 100 mg or placebo. Blood pressure and forearm vascular resistance (FVR) were determined at rest, after study drug administration and during intra-brachial infusion of norepinephrine (NE) 480 pmol/minute (to test alpha-receptors), adenosine (ADEN) 300 μg/minute (control), isoproterenol (ISO) 250 ng/minute (to test beta receptors) and phentolamine (PHEN) 120 μg/minute (to test sympathetically-mediated vascular tone). Norepinephrine was measured at baseline and 1 hour after study drug administration. Results Mean arterial blood pressure increased slightly after placebo (p=0.06) but was unchanged after sildenafil. FVR responses to NE, ADEN, ISO were similar (see Table; p=NS for all). FVR was reduced during PHEN following sildenafil compared to placebo(* p=0.002). Plasma norepinephrine increased by 84±31% and 30±12% following sildenafil and placebo (p=0.05). Conclusions PDE-5 inhibition significantly increased sympathetically mediated vascular tone compared to placebo in healthy, middle-aged men: this vasoconstriction offsets the vasodilatory effects of PDE-5 inhibition. Clinical Pharmacology & Therapeutics (2005) 77, P10–P10; doi: 10.1016/j.clpt.2004.11.042 Study Drug NE (% ΔFVR) ADEN (% ΔFVR) ISO (% ΔFVR) PHEN (% ΔFVR) Sildenafil 64 ± 15 −80 ± 2 −77 ± 3 −73 ± 3* Placebo 56 ± 14 −78 ± 2 −72 ± 3 −63 ± 3