Relaxant effect of sildenafil in the rabbit basilar artery

We hypothesized that sildenafil, inhibitor of phosphodiesterase-5 (PDE-5), interacts with the nitric oxide (NO)-cGMP pathway in the cerebral arteries and shows vasoactive effects. To prove it in the isolated rabbit basilar artery, we compared the effects of sildenafil with other PDE-5 inhibitors, assessed the endothelial dependence of the vasoactive responses, and used modulators of the cGMP and cAMP signaling processes. Sildenafil (10 nM-0.1 mM) induced concentration-dependent relaxations of endothelin-1 (10 nM)-precontracted basilar artery, which were partially inhibited both in endothelium-denuded arteries and in arteries precontracted by depolarization with KCl (50 mM). Endothelin-1 (1 pM-30 nM) induced concentration-dependent contractions that were inhibited by sildenafil (0.1-100 mu M). Zaprinast(10 nM-0.1 mM) and MBCQ (1 nM-0.1 mM), PDE-5 inhibitors, induced concentration-dependent relaxations with lower and higher potency than sildenafil, respectively. Sildenafil-induced relaxation was inhibited in arteries preincubated with the NO synthase inhibitor L-NAME (0.1 mM) or the soluble guanylyl cyclase inhibitor ODQ (10 mu M). Preincubation with sildenafil (0.1 mu M) enhanced the relaxations induced by acetylcholine (0.1 nM-0.1 mM)and the NO donor sodium nitroprusside (0.1 nM-0.1 mM), but not those induced by the cell-permeable cGMP analogue 8-Br-cGMP (1 nM-0.1 mM) and the adenylyl cyclase activator forskolin (0.1 nM-10 mu M). These results show that sildenafil has vasoactive effects in isolated cerebral arteries. By enhancing the NO-cGMP signaling pathway in the cerebrovascular wall, sildenafil induces vasodilation, prevents vasoconstriction, and potentiates the effect of other NO-dependent vasodilators. (C) 2005 Elsevier Inc. All rights reserved.