Giudicelli J F, la Rochelle C D, Berdeaux A
Département de Pharmacologie, Faculté de Médecine Paris-Sud, Le Kremlin-Bicetre, France.
J Pharmacol Exp Ther. 1990 Nov;255(2):836-42.
The effects of i.v. bolus administration of cromakalim (1-10 micrograms/kg) and pinacidil (3-100 micrograms/kg) on large (circumflex artery) and small coronary arteries and on systemic hemodynamics were investigated in chronically instrumented conscious dogs and compared to those of nitroglycerin (0.03-10 micrograms/kg). Nitroglycerin, up to 0.3 micrograms/kg, selectively increased circumflex artery diameter (CxAD) without simultaneously affecting any other cardiac or systemic hemodynamic parameter. In contrast, cromakalim and pinacidil at all doses and nitroglycerin at doses higher than 0.3 micrograms/kg simultaneously and dose-dependently increased CxAD, coronary blood flow and heart rate and decreased coronary vascular resistance and aortic pressure. Cromakalim was approximately 8- to 9.5-fold more potent than pinacidil in increasing CxAD. Vasodilation of large and small coronary vessels and hypotension induced by cromakalim and pinacidil were not affected by prior combined beta adrenergic and muscarinic receptors blockade but drug-induced tachycardia was abolished. When circumflex artery blood flow was maintained constant, the increases in CxAD induced by cromakalim (10 micrograms/kg), pinacidil (30 micrograms/kg) and nitroglycerin (10 micrograms/kg) were reduced by 68 +/- 7, 54 +/- 9 and 1 +/- 1%, respectively. Thus, whereas nitroglycerin preferentially and flow-independently dilates large coronary arteries, cromakalim and pinacidil dilate both large and small coronary arteries and this effect is not dependent upon the simultaneous beta adrenoceptors-mediated rise in myocardial metabolic demand. Finally, two mechanisms at least, direct vasodilation and flow dependency, are involved in the cromakalim- and pinacidil-induced increase in CxAD.
在慢性植入仪器的清醒犬中，研究了静脉推注克罗卡林（1 - 10微克/千克）和吡那地尔（3 - 100微克/千克）对大（回旋支动脉）、小冠状动脉及全身血流动力学的影响，并与硝酸甘油（0.03 - 10微克/千克）进行比较。高达0.3微克/千克的硝酸甘油可选择性增加回旋支动脉直径（CxAD），而不会同时影响任何其他心脏或全身血流动力学参数。相比之下，所有剂量的克罗卡林和吡那地尔以及高于0.3微克/千克剂量的硝酸甘油可同时且剂量依赖性地增加CxAD、冠状动脉血流量和心率，并降低冠状动脉血管阻力和主动脉压。克罗卡林在增加CxAD方面的效力比吡那地尔强约8至9.5倍。克罗卡林和吡那地尔引起的大、小冠状动脉血管舒张和低血压不受预先联合β肾上腺素能和毒蕈碱受体阻断的影响，但药物诱导的心动过速被消除。当回旋支动脉血流量保持恒定时，克罗卡林（10微克/千克）、吡那地尔（30微克/千克）和硝酸甘油（10微克/千克）引起的CxAD增加分别减少了68±7%、54±9%和1±1%。因此，硝酸甘油优先且不依赖血流地扩张大冠状动脉，而克罗卡林和吡那地尔则扩张大、小冠状动脉，且这种作用不依赖于同时由β肾上腺素能受体介导的心肌代谢需求增加。最后，至少有两种机制，即直接血管舒张和血流依赖性，参与了克罗卡林和吡那地尔引起的CxAD增加。
