Mechanism of Action of KRN2391, a Novel Vasodilator, in Canine Mesenteric Artery.

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概要

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• The present study was performed to clarify the mechanism of vasodilation of KRN2391 in canine mesenteric artery compared with those of nicorandil and cromakalim. We used the responses of isolated cranial mesenteric artery in vitro and changes in mesenteric blood flow in vivo as indicators reflecting the responses of a conductive artery and resistive arterioles, respectively. In isolated cranial mesenteric artery, KRN2391 (10<SUP>-8</SUP>-10<SUP>-5</SUP> M), nicorandil (10<SUP>-7</SUP>-10<SUP>-4</SUP> M)and cromakalim (10<SUP>-7</SUP>-10<SUP>-5</SUP> M)relaxed contractions caused by 25 mM KCl in a concentration-dependent manner. The concentration-relaxation curve for KRN2391 was shifted to the right by either methylene blue (10<SUP>-5</SUP>M)or glibenclamide (10<SUP>-6</SUP>M), but the inhibitory effect of methylene blue was more potent than that of glibenclamide. The concentration-relaxation curve for nicorandil was shifted to the right by methylene blue, but not by glibenclamide. In addition, the curve for cromakalim was shifted to the right by glibenclamide, but not by methylene blue. In in vivo experiments, the injections of KRN2391 (0.3-3 μg/kg), nicorandil (10-100 μg/kg)or cromakalim (1-10 μg/kg)into the mesenteric artery increased mesenteric blood flow in a dose-dependent manner. Glibenclamide (5 mg/kg, i.v.)attenuated the increase in mesenteric blood flow caused by KRN2391, nicorandil and cromakalim, but had no effect on that caused by nifedipine (1 μg/kg). The ED<SUB>20</SUB> value increased about 4.7-fold for KRN2391, 3.7-fold for nicorandil and 11.5-fold for cromakalim after administration of glibenclamide, as estimated from the % change to the absolute increase in mesenteric blood flow induced by nifedipine (1 μg/kg). These results suggest that KRN2391 shows nitrate and K channel opening actions in canine mesenteric artery, but the ratio of both actions appears to depend on the segment of mesenteric artery.

• 公益社団法人 日本薬理学会の論文

著者

• Miwa Atsushi

  Pharmaceutical Laboratory (takasaki Lab.) Kirin Brewery Co. Ltd.

• Fukushima Hideaki

  Pharmaceutical Research Laboratory Kirin Brewery Co. Ltd.

• Jinno Yasuhiro

  Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd.

• Fukata Yuzo

  Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd.

• Ogawa Nobuyuki

  Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd.

• Kaneta Soichiro

  Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd.

• Miwa Atsushi

  Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd.

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