Petersson J, Ryman T, Högestätt E D
Department of Clinical Pharmacology, Institute of Laboratory Medicine, Lund University Hospital, Sweden.
Naunyn Schmiedebergs Arch Pharmacol. 2000 Jul;362(1):68-73. doi: 10.1007/s002100000270.
The vasodilator action of KRN2391 (10 nM-10 microM), a combined ATP-sensitive potassium channel (KATP) opener and organic nitrate, was investigated in human pial and omental arteries. Previous animal studies have suggested that opening of KATP and activation of guanylate cyclase may contribute to varying extents to the vasodilator action of KRN2391, depending on the origin and size of the vascular preparation. Vasodilator responses were studied in isolated vascular segments (diameter 0.4-0.8 mm) pre-contracted with endothelin-1 in the presence or absence of glibenclamide (inhibitor of KATP), LY83583 (inhibitor of guanylate cyclase), zaprinast (inhibitor of cyclic GMP phosphodiesterase V) and NG-nitro-L-arginine (inhibitor of nitric oxide synthase). KRN2391 induced concentration-dependent vasodilator responses of similar potency in arteries from the two vascular regions. While glibenclamide (1 microM) had no effect in omental arteries, this compound produced a tenfold rightwards shift of the concentration-response curve for KRN2391 in pial arteries without affecting the maximal response (Emax). LY83583 (10 microM), zaprinast (10 microM) and NG-nitro-L-arginine (0.1 mM) all failed to affect the vasodilator responses to KRN2391 significantly in either artery. However, in ring segments of rat aorta LY83583 displaced the concentration-response curve for the nitric oxide donor 3-morpholino-sydnonimin (10 nM-0.1 mM) to the right, while zaprinast produced a leftwards shift. The prototype KATP opener levcromakalim (0.01-10 microM) elicited a larger relaxation in pial (Emax 80+/-6%) than in omental (Emax 47+/-13%) arteries, whereas 3-morpholino-sydnonimin produced a smaller relaxation in pial (Emax 50+/-18%) than in omental (Emax 90+/-4%) arteries. These results suggest that the vasodilator response to KRN2391 is mediated by KATP in human cerebral arteries, but dependent on neither KATP nor guanylate cyclase in human omental arteries. The results with levcromakalim and 3-morpholino-sydnonimin indicate that opening of KATP may be a more effective mechanism of vasodilatation in pial than in omental arteries from man, whereas the reverse appears to be true for guanylate cyclase activation.
研究了KRN2391（10 nM - 10 microM）的血管舒张作用，它是一种ATP敏感性钾通道（KATP）开放剂与有机硝酸盐的组合，在人软脑膜动脉和网膜动脉中进行了研究。先前的动物研究表明，KATP的开放和鸟苷酸环化酶的激活可能在不同程度上促成KRN2391的血管舒张作用，这取决于血管标本的来源和大小。在存在或不存在格列本脲（KATP抑制剂）、LY83583（鸟苷酸环化酶抑制剂）、扎普司特（环磷酸鸟苷磷酸二酯酶V抑制剂）和NG - 硝基 - L - 精氨酸（一氧化氮合酶抑制剂）的情况下，研究了用内皮素 - 1预收缩的离体血管段（直径0.4 - 0.8 mm）中的血管舒张反应。KRN2391在来自两个血管区域的动脉中诱导出类似效力的浓度依赖性血管舒张反应。虽然格列本脲（1 microM）对网膜动脉无作用，但该化合物使软脑膜动脉中KRN2391的浓度 - 反应曲线向右移动了10倍，而不影响最大反应（Emax）。LY83583（10 microM）、扎普司特（10 microM）和NG - 硝基 - L - 精氨酸（0.1 mM）在两种动脉中均未显著影响对KRN2391的血管舒张反应。然而，在大鼠主动脉环段中，LY83583使一氧化氮供体3 - 吗啉代 - 西多硝胺（10 nM - 0.1 mM）的浓度 - 反应曲线向右移动，而扎普司特使其向左移动。原型KATP开放剂左卡尼汀（0.01 - 10 microM）在软脑膜动脉（Emax 80±6%）中引起的舒张比在网膜动脉（Emax 47±13%）中更大，而3 - 吗啉代 - 西多硝胺在软脑膜动脉（Emax 50±18%）中引起的舒张比在网膜动脉（Emax 90±4%）中更小。这些结果表明，在人脑中动脉中，对KRN2391的血管舒张反应由KATP介导，但在人网膜动脉中既不依赖于KATP也不依赖于鸟苷酸环化酶。左卡尼汀和3 - 吗啉代 - 西多硝胺的结果表明，在人中，KATP的开放可能是软脑膜动脉中比网膜动脉更有效的血管舒张机制，而对于鸟苷酸环化酶激活，情况似乎相反。
