Huckstorf C, Bassenge E
Department of Applied Physiology, Freiburg, Germany.
J Cardiovasc Pharmacol. 1992;20 Suppl 3:S29-33. doi: 10.1097/00005344-199206203-00007.
Nicorandil acting as both nitrovasodilator and K(+)-channel opener was analyzed with regard to its dilator activity in large coronary arteries. In addition, it was tested for potential development of tolerance in six chronically instrumented conscious dogs that received a 5-day continuous i.v. infusion. Increasing dosages of nicorandil (3, 10, and 30 micrograms.kg-1.min-1) caused dose-dependent strong increases in left circumflex coronary artery diameter (1.3 +/- 0.4%, 5.3 +/- 2.2%, and 8.4 +/- 2.8% above control, respectively). However, 100 micrograms.kg-1.min-1 nicorandil produced substantial hypotension, reflex tachycardia, and reduction of the dilator response in large coronary arteries. During long-term nicorandil administration (10 micrograms.kg-1.min-1 i.v. for 5 days), the diameter of the left circumflex coronary artery was increased by 8.8 +/- 2.5%. This was accompanied by a decrease in mean arterial pressure of 13.3 +/- 6.4% and an increase in heart rate by 41.5 +/- 21.0% compared with controls. On the fifth day of continuous nicorandil infusion, dose-response relations for both nicorandil- and nitroglycerin-induced epicardial artery dilations were shifted to 3.5-fold higher doses. We conclude that nicorandil dilates large coronary arteries in dogs, long-term nicorandil administration does not cause a development of tolerance, long-term nicorandil administration is not associated with the development of cross-tolerance to nitroglycerin, and the small shift of the dose-response relations is considered to reflect a hemodynamic adaptation process due to long-term nicorandil exposure.
尼可地尔兼具硝基血管扩张剂和钾离子通道开放剂的作用，针对其在大冠状动脉中的扩张活性进行了分析。此外，对6只长期植入仪器的清醒犬进行了为期5天的静脉持续输注，以测试其耐受性的潜在发展情况。尼可地尔剂量增加（3、10和30微克·千克⁻¹·分钟⁻¹）导致左旋冠状动脉直径呈剂量依赖性显著增加（分别比对照高1.3±0.4%、5.3±2.2%和8.4±2.8%）。然而，100微克·千克⁻¹·分钟⁻¹的尼可地尔导致显著的低血压、反射性心动过速以及大冠状动脉扩张反应减弱。在长期给予尼可地尔（10微克·千克⁻¹·分钟⁻¹静脉输注5天）期间，左旋冠状动脉直径增加了8.8±2.5%。与对照组相比，这伴随着平均动脉压降低13.3±6.4%以及心率增加41.5±21.0%。在尼可地尔持续输注的第5天，尼可地尔和硝酸甘油诱导的心外膜动脉扩张的剂量反应关系均向高3.5倍的剂量偏移。我们得出结论，尼可地尔可扩张犬的大冠状动脉，长期给予尼可地尔不会导致耐受性的发展，长期给予尼可地尔与对硝酸甘油的交叉耐受性发展无关，剂量反应关系的小偏移被认为反映了由于长期暴露于尼可地尔而导致的血流动力学适应过程。
