TIME-DELAY OF CELL-DEATH BY NA+ H+-EXCHANGE INHIBITION IN REGIONALLY ISCHEMIC, REPERFUSED PORCINE HEARTS/

Studies in different preparations have suggested that Na+/H+ exchange is one mechanism causally involved in cell death in myocardial ischemi a and reperfusion. The time delay of cell death by pretreatment with t he Na+/H+-exchange inhibitor HOE642, cariporide (4-isopropyl-3-methyls ulphonylbenzoyl-guanidine methanesulphonate), was investigated in regi onally ischemic, reperfused porcine hearts. HOE642 (1 mg/kg) was injec ted intravenously in 14 thoracotomized pigs 10 min before occlusion of the left anterior descending coronary artery (45 min of ischemia, six pigs; 70 min of ischemia, six pigs; 90 min of ischemia, two pigs). Is chemia was followed by 24 h of reperfusion. Six animals (45 min of isc hemia) served as controls. Infarct size was determined as a ratio of i nfarcted (tetrazolium stain, histology) to ischemic myocardium (dye te chnique), and regional myocardial function was assessed by sonomicrome try. HOE642 did not affect global hemodynamic parameters. In the pretr eated group with 45 min of ischemia, HOE642 significantly decreased hi stochemical infarct size from 51.2 +/- 12.6% (control group) to 13.2 /- 12% (p < 0.005) and histologic infarct size from 44.5 +/- 9% to 17. 1 +/- 7% (p < 0.005). Recovery of regional systolic shortening after 2 4 h of reperfusion was improved from 2 +/- 6% (control-group) to 12 +/ - 7% (p = 0.02). In addition, myocardial contracture and increase in h eart rate during early reperfusion were attenuated. When ischemia was prolonged to 70 min after pretreatment with HOE642, infarct size, reco very of systolic shortening, myocardial contracture, and increase in h eart rate did not differ from those of the control group. Pretreatment with HOE642 increased the tolerance to ischemia/reperfusion by simila r to 20-25 min. Inhibition of Na+/H+ exchange appears to be very promi sing in the clinical treatment of acute myocardial ischemia and reperf usion.