Jpn. J. Pharmacol. 84 (3), 316-324 (2000)

Hypotensive Interaction of Sildenafil and Nicorandil in Rats Through the cGMP Pathway but Not by KATP Channel Activation

Nobuhiko Ishizuka, Keiji Saito, Michitaka Akima, Shuzo Matsubara and Motoo Saito

Chugai Pharmaceutical Co., Ltd., Product Research Laboratory, 3-41-8 Takada, Toshima-ku, Tokyo 171-8545, Japan
*Corresponding author.  FAX:+81-3-3985-7079

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 mg/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 mg/kg, i.v.) nor nicorandil (100 mg/kg, i.v.) were potentiated by sildenafil, however. Increases in femoral blood flow due to nitroglycerin (0.1-3 mg, i.a.) were potentiated significantly by sildenafil, but those due to nicorandil (1-30 mg, 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 augmentation of vasodilatation. Synergism of vasodilatation may be linked with NO action, but not with KATP channel-activation.

Keywords: Nicorandil, Sildenafil, cGMP, KATP channel

Copyright© The Japanese Pharmacological Society 2000

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