Hypotensive interaction of sildenafil and nicorandil in rats through the cGMP pathway but not by K-ATP channel activation

The possibility that sildenafil citrate can potentiate nicorandil-induced h ypotension by increasing cGMP levels of vascular smooth muscle cells was ex amined using anesthetized rats and isolated aortas. In pentobarbital-anesth etized rats, more than 0.3 mg/kg of sildenafil (i.v.) potentiated intra-aor tic (i.Ao.) administration of nitroglycerin-induced hypotension. Hypotensio n due to nicorandil (100 mug/kg, i.Ao.) was potentiated by sildenafil (1 mg /kg, i.v.), even after glibenclamide treatment, although pinacidil-induced hypotension was not reinforced. Hypotensive responses to neither nitroglyce rin (3 mug/kg, i.v.) nor nicorandil (100 mug/kg, i.v.) were potentiated by sildenafil, however. Increases in femoral blood flow due to nitroglycerin ( 0.1 - 3 mug, i.a.) were potentiated significantly by sildenafil, but those due to nicorandil (1 - 30 mug, i.a.) were not. isolated rat aortas precontr acted with phenylephrine were dilated dose-dependently using nicorandil, ni troglycerin, pinacidil or sildenafil. The relaxant effect due to nicorandil and nitroglycerin was reinforced significantly by pretreatment with an ine ffective concentration of sildenafil (10(-8) M), but pinacidil was not. Aft er ODQ (1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one) completely blocked re laxation by nicorandil, sildenafil did not increase relaxation. These findi ngs suggest that combination of sildenafil with nicorandil, as well as with nitroglycerin, potentiates the hypotensive response by augmentation of vas odilatation. Synergism of vasodilatation may be linked with NO action, but not with K-ATP channel-activation.