Abstract P130: Effect of Calpain Inhibition on Myocardial Infarction Following Local Ischemia and Reperfusion
This study was performed to test the protective effectiveness of a novel water-soluble and cell-permeable calpain inhibitor when administered before or after local ischemia. Isolated rabbit hearts were perfused in an open working Langendorff heart system at constant pressure (80 mmHg) and temperature (37°C) with Krebs-Henseleit buffer solution. After a steady state period of 20 min, the ramus interventricularis of the left coronary artery was blocked just below the origin of the first diagonal branch by means of a Tourniquet for 60 min, and subsequently reperfused for 120 min. The calpain inhibitor A-705253 (Ki = 27 ± 2.5 nM) from Abbott/Ludwigshafen/Germany was added to the perfusion fluid in various final concentrations in one series (A) of experiments before the closure and in an other series (B) after the reopening of the coronary vessel. Hearts without inhibitor or with the administration of the Na+/H+− exchange inhibitor cariporide® served as controls. Hemodynamic monitoring and biochemical analysis of perfusion fluid from the coronary outflow were performed. Myocardial infarct size was determined by microscopic evaluation of left ventricular slices after a special staining procedure. The area of necrosis/infarction was 77.9 ± 2.3% of the area at risk in controls without calpain inhibition of series A (n=12), respectively 72.7 ± 4.0% of series B (n=8). Preischemic administration of A-705253 (n=8) reduced the area of infarction most effectively (p<0.001) to 49.3 ± 3.9% (n=8) with an inhibitor concentration of 10−8 mol/l. Even with postischemic inhibitor application (n=8) area of infarction could be reduced significantly (p<0.01) to 48.3 ± 2.3% using an inhibitor concentration of 10−6 mol/l. Administration of cariporide® (n=8; 10−6 mol/l) resulted in a comparable reduction (p<0.01) to 50.2 ± 3.4% of the area at risk. The protective effect of calpain inhibition on myocardial infarction was dose dependant in relation to the time point of administration. The experiments imply a major role of calpains in myocardial ischemia and reperfusion injury which can be attenuated as well by preischemic as by postischemic calpain inhibition. The protective effect of Na+/H+-exchange inhibition seems to be mediated by the inhibition of calpain activation.