Mechanisms of vasodilation by K^+ channel openers

K^通道开放剂的血管舒张机制

• 批准号: 02670076
• 负责人: YANAGISAWA Teruyuki
• 金额: $ 1.34万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1990
• 资助国家: 日本
• 起止时间: 1990 至 1991
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02670076/
• 关键词: K^+ channel openers; cromakalim; cytoplasmic Ca^<2+> concentration; fura-2; thromboxane A_2; Ca^<2+> channels; Ca^<2+> release; hyperpolarization; カルウムチャンネル開口薬; cromakalim; pinacidil; nicorandil; furaー2; agonist収縮; U46619

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 … More 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

为了研究K^+通道开放剂色满卡林、吡那地尔和尼可地尔的扩血管机制，我们使用Fura-2通过显微荧光法同时测量了细胞质Ca^2+浓度（[Ca^2+]i）的变化。克罗卡林是一种比吡那地尔和尼可地尔更具特异性的K^+通道开放剂，在本研究中，克罗卡林产生的血管舒张作用主要是由于超极化关闭电压依赖性Ca^<2 +>通道导致[Ca^<2+>]i降低的结果。相比之下，吡那地尔和尼可地尔的血管扩张作用涉及其他机制。其中之一与收缩蛋白对Ca^<2+>的敏感性降低有关。尼可地尔的后一种机制类似于硝酸甘油。这些K^+通道开放剂所开放的K^+通道可能是ATP敏感性通道，格列本脲可阻断这些通道。血栓素A2类似物U46619在犬中累积应用后可增加[Ca^<2+>]i和力 ...更多信息 冠状动脉20 mM KCl的去极化增强了U46619诱导的[Ca^<2+>]i和力的增加。Cromakalim和维拉帕米抑制这两种增加。cromakalim的抑制作用被20或25 mM KCl的去极化所抵消。在单剂量应用3 × 10 - 4 μ M的U46619后<-7>，[Ca^&lt;2+&gt;]i和力以阶段性和强直性方式增加，这几乎被cromakalim和Ki 4032消除。在缺乏细胞外Ca^&lt;2+&gt;的情况下，U46619诱导[Ca^&lt;2+]i短暂升高并伴有收缩。在cromakalim或Ki 4032存在下，[Ca^2+]i的增加被消除，这被K^+通道阻断剂四丁基铵（TBA）阻断，并被20 mM KCl的去极化所抵消。Cromakalim和Ki 4032不影响咖啡因诱导的Ca^&lt;2+&gt;释放。因此，U46619通过L-型Ca^2+通道产生Ca^2+内流，该L-型Ca ^2+通道被cromakalim和Ki 4032诱导的超极化灭活。K^+通道开放剂引起的质膜超极化可选择性地抑制IP_3诱导的与血栓素A^2受体激活相关的细胞内Ca^2+释放。少

项目成果

柳澤 輝行: "血管平滑筋のKチャンネルとそのモジュレ-タ-" 心臓. 24. 215-221 (1992)

Teruyuki Yanagisawa：“血管平滑肌 K 通道及其调节剂”《心脏》24. 215-221 (1992)

Yanagisawa, T., Yokoyama, H., Kurosawa, H., Ishii, K. & Taira, N.: "Selective stimulation of high-affinity beta1-receptors : Its implication in the treatment of mild heart failure." Recent Progress in Failing Heart Syndrome : from Molecular Biology to the

柳泽 T.、横山 H.、黑泽 H.、石井 K.

Mori, T., Yanagisawa, T. & Taira, N.: "Histamine increases vascular tone and intracellular calcium level using both intracellular and extracellular calcium in porcine coronary arteries." Japan. J. Pharmacol.52. 263-271 (1990)

森 T.、柳泽 T.

Satoh, E., Yanagisawa, T. & TAIRA, N.: "Specific antagonism by glibenclamide of negative inoropic effects of potassium channel openers in canine atrial muscle." Japan. J. Pharmacol.54. 133-141 (1990)

佐藤，E.，柳泽，T.

Teruyuki YANAGISAWA&Norio TAIRA: "Electrophysiology and lon Channels of Vascular Smooth Muscle Cells and Endothelial Cells.Nicholas Sperelakis&Hiroshi Kuriyma(ed.)" Elsevier, 12 (1991)

柳泽辉之