Linz W, Albus U, Crause P, Jung W, Weichert A, Schölkens B A, Scholz W
Hoechst Marion Roussel, DG Cardiovascular Research, Frankfurt/Main, Germany.
Clin Exp Hypertens. 1998 Oct;20(7):733-49. doi: 10.3109/10641969809052116.
The aim of this study was to investigate the dose-dependent effect of pretreatment with the selective sodium-hydrogen exchange NHE-subtype 1 inhibitor cariporide on myocardial infarct mass in a rabbit model of coronary ligation and reperfusion. Furthermore, in a second part of the study, we tested the effect of cariporide in the rabbits when given prior to reperfusion. Rabbits (n=49) were randomized in 7 groups: saline vehicle, cariporide: 0.01, 0.03, 0.1 and 0.3 mg/kg, and subjected to a 30 min occlusion of a branch of the left coronary artery followed by 2 h reperfusion. Cariporide was given as a bolus intravenously 10 min before occlusion or 5 min before reperfusion. After reperfusion, myocardial infarct mass was determined by triphenyl tetrazolium chloride staining and expressed as a percent of area at risk. Cariporide given intravenously 10 min before occlusion in doses of 0.01, 0.03, 0.1, 0.3 mg/kg, led to a dose-dependent reduction in infarct mass from 58+/-6% in controls to 48+/-4% (-17%, NS), 36+/-5% (-38%, p<0.05), 26+/-6% (-55%, p<0.05), 11+/-4% (-81%, p<0.05) respectively, whereas area at risk did not differ in between the groups. The effect of the lowest dose of 0.01 mg/kg did not reach significance. Plasma levels at different doses of cariporide were correlated to the respective infarct mass. After coronary occlusion left ventricular end-diastolic pressure (LVEDP) significantly increased throughout occlusion and reperfusion. Cariporide in the doses of 0.3, 0.1 and 0.03 mg/kg normalized LVEDP when measured after 2 h reperfusion. In controls hemodynamic parameters such as mean arterial blood pressure (MAP), heart rate (HR), left ventricular pressure (LVP) and LV dP/dt(max) were not significantly changed by ischemia/reperfusion with the exception of MAP, LVP and LV dP/dt(max) which were significantly decreased after 120 min reperfusion. Cariporide at doses of 0.1, 0.03 and 0.01 mg/kg did not significantly influence these parameters, whereas the highest dose of 0.3 mg/kg prevented the decrease of MAP and LVP. Cariporide (0.3 mg/kg i.v.) administered 5 min before reperfusion significantly reduced infarct mass by 31%. Under these conditions the increase of LVEDP after coronary occlusion was not influenced by cariporide. As in the pretreatment experiments, the decrease of MAP and LVP was prevented when measured 2 h after reperfusion. The results show that pretreatment with the NHE-subtype 1 inhibitor cariporide is cardioprotective by reducing infarct mass in rabbits in a dose-dependent manner. While the cardioprotective effect of pretreatment could be demonstrated over a broad range of doses, the efficacy of the compound when given only on reperfusion was significant but more limited.
本研究的目的是在冠状动脉结扎和再灌注的兔模型中，研究选择性钠氢交换NHE-1亚型抑制剂卡里波罗预处理对心肌梗死面积的剂量依赖性影响。此外，在研究的第二部分，我们测试了卡里波罗在再灌注前给予兔子时的效果。将49只兔子随机分为7组：生理盐水载体组、卡里波罗组：0.01、0.03、0.1和0.3mg/kg，对左冠状动脉分支进行30分钟闭塞，随后进行2小时再灌注。卡里波罗在闭塞前10分钟或再灌注前5分钟静脉推注。再灌注后，通过氯化三苯基四氮唑染色测定心肌梗死面积，并表示为危险区域面积的百分比。在闭塞前10分钟静脉给予剂量为0.01、0.03、0.1、0.3mg/kg的卡里波罗，导致梗死面积呈剂量依赖性降低，从对照组的58±6%分别降至48±4%（-17%，无统计学意义）、36±5%（-38%，p<0.05）、26±6%（-55%，p<0.05）、11±4%（-81%，p<0.05），而各组间危险区域无差异。最低剂量0.01mg/kg的效果未达到统计学意义。不同剂量卡里波罗的血浆水平与各自的梗死面积相关。冠状动脉闭塞后，左心室舒张末期压力（LVEDP）在整个闭塞和再灌注过程中显著升高。再灌注2小时后测量时，0.3、0.1和0.03mg/kg剂量的卡里波罗使LVEDP恢复正常。在对照组中，除再灌注120分钟后平均动脉血压（MAP）、左心室压力（LVP）和左心室dp/dt（max）显著降低外，缺血/再灌注对血流动力学参数如平均动脉压（MAP）、心率（HR）、左心室压力（LVP）和左心室dp/dt（max）无显著影响。0.1、0.03和0.01mg/kg剂量的卡里波罗对这些参数无显著影响，而最高剂量0.3mg/kg可防止MAP和LVP降低。再灌注前5分钟静脉注射卡里波罗（0.3mg/kg）可使梗死面积显著减少31%。在这些条件下，冠状动脉闭塞后LVEDP的升高不受卡里波罗影响。与预处理实验一样，再灌注2小时后测量时，MAP和LVP的降低得到了预防。结果表明，NHE-1亚型抑制剂卡里波罗预处理通过以剂量依赖性方式减少兔梗死面积而具有心脏保护作用。虽然预处理的心脏保护作用在广泛的剂量范围内都能得到证实，但仅在再灌注时给予该化合物的疗效显著但更有限。
