Hypotensive interaction of sildenafil and nicorandil in rats through the cGMP pathway but not by K(ATP) channel activation
Abstract
The possibility that sildenafil citrate can potentiate nicorandil-induced hypotension by increasing cGMP levels of vascular smooth muscle cells was examined using anesthetized rats and isolated aortas. In pentobarbital-anesthetized rats, more than 0.3 mg/kg of sildenafil (i.v.) potentiated intra-aortic (i.Ao.) administration of nitroglycerin-induced hypotension. Hypotension due to nicorandil (100 microg/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 nitroglycerin (3 microg/kg, i.v.) nor nicorandil (100 microg/kg, i.v.) were potentiated by sildenafil, however. Increases in femoral blood flow due to nitroglycerin (0.1-3 microg, i.a.) were potentiated significantly by sildenafil, but those due to nicorandil (1-30 microg, i.a.) were not. Isolated rat aortas precontracted with phenylephrine were dilated dose-dependently using nicorandil, nitroglycerin, pinacidil or sildenafil. The relaxant effect due to nicorandil and nitroglycerin was reinforced significantly by pretreatment with an ineffective concentration of sildenafil (10(-8) M), but pinacidil was not. After ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) completely blocked relaxation by nicorandil, sildenafil did not increase relaxation. These findings suggest that combination of sildenafil with nicorandil, as well as with nitroglycerin, potentiates the hypotensive response by…
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