Grover G J, Dzwonczyk S, Parham C S, Sleph P G
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, NJ 08543-4000.
Cardiovasc Drugs Ther. 1990 Apr;4(2):465-74. doi: 10.1007/BF01857755.
The direct myocardial protective effects of intracoronary infusions of cromakalim and pinacidil were determined in an anesthetized canine model of coronary occlusion and reperfusion. The left circumflex coronary artery was occluded for 90 minutes and reperfused for 5 hours, at which time the infarct size was determined. Cromakalim (0.1 micrograms/kg/min) or pinacidil (0.09 micrograms/kg/min) were infused into the left circumflex coronary artery starting 10 minutes preischemia. Cromakalim significantly reduced infarct size as a percent of the left ventricular area at risk (25 +/- 5%) compared with vehicle controls (55 +/- 7%). Pinacidil did not reduce infarct size at an equimolar dose, but at the higher dose also significantly reduced infarct size. Collateral blood flow was not significantly altered by either drug, though reperfusion flow was significantly higher in cromakalim-treated animals, particularly in the subepicardial region. When the same dose of cromakalim was given starting 2 minutes before the initiation of reperfusion, no significant beneficial effect of cromakalim was observed. In another study, isolated buffer-perfused rat hearts were subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. These hearts were treated with 7 microM cromakalim, either starting 10 minutes before ischemia or only during reperfusion, and its effect on reperfusion function and LDH release were determined. Cromakalim pretreatment (both when given throughout the experiment and when not present in the reperfusion buffer) resulted in significant improvements in the reperfusion function. Reperfusion contracture and LDH were also significantly reduced with this treatment. When given only during reperfusion, cromakalim did not reduce the severity of ischemia when compared with vehicle controls. Thus, both cromakalim and pinacidil reduce ischemic/reperfusion injury, though the timing of treatment may be important.
在麻醉犬冠状动脉闭塞和再灌注模型中，测定了冠脉内输注克罗卡林和吡那地尔的直接心肌保护作用。左旋冠状动脉闭塞90分钟，再灌注5小时，此时测定梗死面积。在缺血前10分钟开始向左旋冠状动脉内输注克罗卡林（0.1微克/千克/分钟）或吡那地尔（0.09微克/千克/分钟）。与赋形剂对照组（55±7%）相比，克罗卡林显著降低了梗死面积占左心室危险区面积的百分比（25±5%）。吡那地尔在等摩尔剂量时未降低梗死面积，但在较高剂量时也显著降低了梗死面积。两种药物均未显著改变侧支血流，尽管在克罗卡林治疗的动物中再灌注血流显著更高，尤其是在心外膜下区域。当在再灌注开始前2分钟给予相同剂量的克罗卡林时，未观察到克罗卡林的显著有益作用。在另一项研究中，对离体缓冲液灌注的大鼠心脏进行25分钟的全心缺血和30分钟的再灌注。这些心脏用7微摩尔克罗卡林处理，要么在缺血前10分钟开始，要么仅在再灌注期间进行，并测定其对再灌注功能和乳酸脱氢酶释放的影响。克罗卡林预处理（无论是在整个实验过程中给予还是在再灌注缓冲液中不存在时）均导致再灌注功能显著改善。这种治疗还显著降低了再灌注挛缩和乳酸脱氢酶水平。当仅在再灌注期间给予时，与赋形剂对照组相比，克罗卡林并未降低缺血的严重程度。因此，克罗卡林和吡那地尔均可减轻缺血/再灌注损伤，尽管治疗时机可能很重要。
