Gralinski M R, Black S C, Kilgore K S, Chou A Y, McCormack J G, Lucchesi B R
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0626.
Cardiovasc Res. 1994 Aug;28(8):1231-7. doi: 10.1093/cvr/28.8.1231.
The aim was to examine the putative cardioprotective effects of the novel antianginal agent, ranolazine, using an isolated rabbit heart model of ischaemia and reperfusion.
Hearts from male New Zealand White rabbits were perfused in the Langendorff mode with a recirculating Krebs buffer at a constant flow of 20-25 ml.min-1. After equilibration, hearts were treated with ranolazine (10 or 20 microM) or vehicle control for 10 min before exposure to a 30 min period of global ischaemia and 60 min reperfusion; a normoxic control group was also studied. Haemodynamic variables (left ventricular pressure), myocardial creatine kinase, and potassium release were measured at baseline (preischaemic) and at selected points during reperfusion; tissue calcium and ATP content were also measured and electron microscopy was performed.
Left ventricular developed pressure during reperfusion was improved (p < 0.05) in a concentration dependent manner by 10 and 20 microM ranolazine (the baseline value was unaffected) with the latter dose resulting in a return to preischaemic values. The release of creatine kinase and potassium was reduced in the ranolazine groups (p < 0.05). A 2.5-fold increase in tissue calcium content in vehicle treated hearts at the end of reperfusion (compared to normoxic time control) was reduced by 10 microM ranolazine (p < 0.05) and completely prevented by 20 microM ranolazine. Similarly, the decrease in tissue ATP was largely inhibited by ranolazine in a concentration dependent manner. Electron microscopy showed that 20 microM ranolazine prevented the occurrence of many indications of reperfusion injury observed in vehicle treated control hearts, for example, blurring of myofibrillar Z bands, derangement of myofibrillar architecture, disruption of mitochondrial cristae and matrices, and the appearance of electron-dense bodies within them. The deposition of lanthanum chloride, a marker of blood vessel integrity, is also modified in the ranolazine treated hearts.
Ranolazine has impressive cardioprotective properties in an isolated rabbit heart model of ischaemia and reperfusion, suggesting that the drug warrants further research into its precise mechanism of action.
使用离体兔心脏缺血再灌注模型，研究新型抗心绞痛药物雷诺嗪假定的心脏保护作用。
雄性新西兰白兔的心脏在Langendorff模式下，用循环的Krebs缓冲液以20 - 25 ml·min⁻¹的恒定流速灌注。平衡后，在经历30分钟全心缺血和60分钟再灌注之前，心脏用雷诺嗪（10或20 μM）或溶剂对照组处理10分钟；还研究了一个常氧对照组。在基线（缺血前）和再灌注期间的选定时间点测量血流动力学变量（左心室压力）、心肌肌酸激酶和钾释放；还测量了组织钙和ATP含量，并进行了电子显微镜检查。
10 μM和20 μM雷诺嗪使再灌注期间的左心室舒张末压以浓度依赖性方式得到改善（p < 0.05）（基线值未受影响），后一剂量使其恢复到缺血前值。雷诺嗪组中肌酸激酶和钾的释放减少（p < 0.05）。再灌注结束时，溶剂处理心脏的组织钙含量增加2.5倍（与常氧时间对照组相比），10 μM雷诺嗪使其降低（p < 0.05），20 μM雷诺嗪完全阻止了这种增加。同样，雷诺嗪以浓度依赖性方式在很大程度上抑制了组织ATP的减少。电子显微镜显示，20 μM雷诺嗪可防止在溶剂处理的对照心脏中观察到的许多再灌注损伤迹象出现，例如肌原纤维Z带模糊、肌原纤维结构紊乱、线粒体嵴和基质破坏以及其中出现电子致密体。在雷诺嗪处理的心脏中，血管完整性标志物氯化镧的沉积也发生了改变。
在离体兔心脏缺血再灌注模型中，雷诺嗪具有显著的心脏保护特性，表明该药物值得进一步研究其确切作用机制。
