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.ﾊﾊFAX:+81-3-3985-7079
E-mail: ishizukanbh@chugai-pharm.co.jp
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ﾊmg/kg of sildenafil (i.v.)
potentiated intra-aortic (i.Ao.) administration of nitroglycerin-induced
hypotension. Hypotension due to nicorandil (100ﾊmg/kg,
i.Ao.) was potentiated by sildenafil (1ﾊmg/kg, i.v.), even after glibenclamide
treatment, although pinacidil-induced hypotension was not reinforced. Hypotensive
responses to neither nitroglycerin (3ﾊmg/kg,
i.v.) nor nicorandil (100ﾊmg/kg, i.v.) were potentiated
by sildenafil, however. Increases in femoral blood flow due to nitroglycerin
(0.1-3ﾊmg, i.a.) were potentiated significantly
by sildenafil, but those due to nicorandil (1-30ﾊ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ﾊ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ｩ The Japanese Pharmacological Society 2000
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