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 μM). 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 μM). Preincubation with sildenafil (0.1 μM) 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 μM). 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.