DOSE-DEPENDENT REDUCTION OF MYOCARDIAL INFARCT MASS IN RABBITS BY THENHE-1 INHIBITOR CARIPORIDE (HOE-642)

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 th e study, we tested the effect of cariporide in the rabbits when given prior to reperfusion. Rabbits (n=49) were randomized in 7 groups: sali ne vehicle, cariporide: 0.01, 0.03, 0.1 and 0.3 mg/kg, and subjected t o 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 m in before occlusion or 5 min before reperfusion. After reperfusion, my ocardial 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), 2 6 +/- 6% (-55 %, p<0.05), 11 +/- 4% (-81 %, p<0.05) respectively, wher eas area at risk did not differ in between the groups. The effect of t he lowest dose of 0.01 mg/kg did not reach significance. Plasma levels at different doses of cariporide were correlated to the respective in farct mass. After coronary occlusion left ventricular end-diastolic pr essure (LVEDP) significantly increased throughout occlusion and reperf usion. Cariporide in the doses of 0.3, 0.1 and 0.03 mg/kg normalized L VEDP when measured after 2 h reperfusion. In controls hemodynamic para meters such as mean arterial blood pressure (MAP), heart rate (HR), le ft 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 reperfusi on. Cariporide at doses of 0.1, 0.03 and 0.01 mg/kg did not significan tly 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.) adm inistered 5 min before reperfusion significantly reduced infarct mass by 31 %. Under these conditions the increase of LVEDP after coronary o cclusion was not influenced by cariporide. As in the pretreatment expe riments, the decrease of MAP and LVP was prevented when measured 2 h a fter reperfusion. The results show that pretreatment with the NHE-subt ype 1 inhibitor cariporide is cardioprotective by reducing infarct mas s in rabbits in a dose-dependent manner. While the cardioprotective ef fect of pretreatment could be demonstrated over a broad range of doses , the efficacy of the compound when given only on reperfusion was sign ificant but more limited.