| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1991: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1990: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
To investigate the vasodilator mechanisms of the K^+ channel openers, cromakalim, pinacidil and nicorandil, we measured changes in cytoplasmic Ca^<2+> concentration ([Ca^<2+>]i) simultaneously with force by a microfluorimetric method using fura-2. Cromakalim is a more specific K^+ channel opener than pinacidil and nicorandil and that vasodilation produced by cromakalim in this study is predominantly a result of a reduction of[Ca^<2+>]i due to the closure of voltage-dependent Ca^<2+> channels by hyperpolarization. In contrast, additional mechanisms are involved in the vasodilator actions of pinacidil and nicorandil. One of these is related to a reduction in the sensitivity of contractile proteins to Ca^<2+>. The latter mechanism of nicorandil is akin to that of nitroglycerin. K^+ channels opened by these K^+ channel openers may be ATP-sensitive ones which are blocked by glibenclamide. A thromboxane A2 analogue U46619 increased [Ca^<2+>]i and force, upon cumulative application in canine
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coronary arteries. Depolarization by 20 mM KCI potentiated the increases in [Ca^<2+>]i and force induced by U46619. Cromakalim and verapamil inhibited both increases. The inhibitory effect of cromakalim was counteracted by depolarization by 20 or 25 mM KCI. Upon single dose applications of U46619 at 3x10^<-7> M, [Ca^<2+>]i and force increased in phasic and tonic manners, which were almost abolished by cromakalim and Ki4032. In the absence of extracellular Ca^<2+>, U46619 induced a transient increase in [Ca^<2+>]i with a contraction. In the presence of cromakalim or Ki4032, the increase in[Ca^<2+>]i was abolished, which was blocked by the K^+ channel blocker tetrabutylammonium(TBA)and counteracted by the depolarization by 20 mM KCI. Cromakalim and Ki4032 did not affect caffeine-induced Ca^<2+> release. Thus, U46619 produces Ca^<2+> influx through L-type Ca^<2+> channels, which are deactivated by hyperpolarization induced by cromakalim and Ki4032. The IP_3-induced Ca^<2+> release from intracellular stores related to stimulation of the thromboxane A^2 receptor is selectively inhibited by hyperpolarization of plasma membrane by K^+ channel openers. Less
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