Bush L R, Romson J L, Ash J L, Lucchesi B R
J Cardiovasc Pharmacol. 1982 Mar-Apr;4(2):285-96. doi: 10.1097/00005344-198203000-00018.
The calcium antagonist, diltiazem, was evaluated for its ability to reduce the extent of myocardial injury resulting from 90 min of left circumflex (LCX) coronary artery occlusion in anesthetized dogs. Administration of diltiazem (0.75 mg/kg over 10 min, followed by 600 microgram/kg/h for 4 h) was initiated 30 min prior to LCX occlusion. Regional myocardial blood flow (RMBF) was measured with radioactive microspheres 30 min after LCX occlusion, and at 45 min and 24 h after reperfusion. At 24 h, after obtaining hemodynamic and RMBF measurements, excised hearts were processed by perfusion staining to determine the percent of left ventricle (LV) perfused by LCX (area at risk) and infarct size, with triphenyltetrazolium chloride. Infarct size, expressed as a percentage of the area at risk, was significantly lower in the diltiazem-treated group compared to the control group (27 +/- 4 vs. 42 +/- 5%, respectively). The area at risk, expressed as a percentage of left ventricular mass, was similar in both groups [41 +/- 2 and 44 +/- 3% (area at risk-LV)]. In addition, the marked elevation of tissue Ca2+ content in noninfarcted and infarcted myocardium within the area at risk (18 +/- 2 and 42 +/- 8 mumol Ca2+/g) in control animals was attenuated by diltiazem (6 +/- 3 and 18 +/- 8 mumol Ca2+/g). Diltiazem did not increase blood flow to ischemic myocardium during LCX occlusion. However, reflow to the inner layers of formerly ischemic myocardium during reperfusion was significantly greater in diltiazem-treated dogs. Both arterial blood pressure and heart rate were significantly lower in the diltiazem -treated group. In addition, mortality (1 vs. 4) and occurrence of ventricular arrhythmias during reperfusion were lower in diltiazem-treated dogs. The data suggest that diltiazem reduces myocardial ischemic injury by lowering myocardial oxygen demands indirectly via favorable hemodynamic alterations, and directly by limiting transmembrane Ca2+ fluxes during ischemia and reperfusion.
评估了钙拮抗剂地尔硫䓬减少麻醉犬左旋冠状动脉（LCX）闭塞90分钟所致心肌损伤程度的能力。在LCX闭塞前30分钟开始给予地尔硫䓬（10分钟内给予0.75毫克/千克，随后以600微克/千克/小时的剂量持续4小时）。在LCX闭塞后30分钟、再灌注后45分钟和24小时，用放射性微球测量局部心肌血流量（RMBF）。在24小时时，在获得血流动力学和RMBF测量值后，用氯化三苯基四氮唑对切除的心脏进行灌注染色，以确定由LCX灌注的左心室（LV）百分比（危险区域）和梗死面积。与对照组相比，地尔硫䓬治疗组的梗死面积占危险区域的百分比显著降低（分别为27±4%和42±5%）。两组的危险区域占左心室质量的百分比相似[41±2%和44±3%（危险区域-LV）]。此外，地尔硫䓬可减轻对照组动物危险区域内心肌梗死和未梗死心肌中组织Ca2+含量的显著升高（分别为18±2和42±8微摩尔Ca2+/克）（分别为6±3和18±8微摩尔Ca2+/克）。在LCX闭塞期间，地尔硫䓬不会增加缺血心肌的血流量。然而，在再灌注期间，地尔硫䓬治疗的犬类中，以前缺血心肌内层的再灌注明显增加。地尔硫䓬治疗组的动脉血压和心率均显著降低。此外，地尔硫䓬治疗的犬类在再灌注期间的死亡率（1比4）和室性心律失常的发生率较低。数据表明，地尔硫䓬通过有利的血流动力学改变间接降低心肌需氧量，并通过限制缺血和再灌注期间的跨膜Ca2+通量直接减少心肌缺血损伤。
