Effects of the Na+/H+ exchange inhibitor cariporide (HOE 642) on cardiac function and cardiomyocyte cell death in rat ischaemic-reperfused heart

1. Na+/H+ exchange has been implicated in the mechanism of reperfusion inju ry. We examined the effects of the cardiac-specific Na+/H+ exchange Inhibit or cariporide (HOE 642) on postischaemic recovery of cardiac function and c ardiomyocyte cell death (i.e. necrosis and apoptosis), 2. Rat isolated and buffer-perfused hearts were subjected to 25 min normoth ermic global ischaemia followed by 120 min reperfusion. Cariporide (10 mu m ol/L) or its vehicle (0.01 % dimethylsulphoxide) was administered for 15 mi n before Ischaemia and for the first 30 min after reperfusion, 3. Cariporide significantly improved the recovery of isovolumic left ventri cular function (heart rate, left ventricular developed pressure and left ve ntricular end-diastolic pressure) and coronary flow throughout reperfusion, Creatine kinase release during reperfusion was significantly less in the c ariporide-treated heart. In situ terminal deoxynucteotidyl transferase-medi ated dUTP nick-end labelling (TUNEL)-positive cardiomyocytes were also sign ificantly less in the cariporide-treated heart after 120 min reperfusion. E lectron microscopy showed necrotic changes without typical apoptotic featur es in cardiomyocytes after reperfusion. Such necrotic changes,were mitigate d by cariporide. Simultaneous detection of necrotic and apoptotic cardiomyo cytes using propidium iodide (PI) and Annexin V revealed that cardiomyocyte s in the infarct area were stained with only PI or both PI and Annexin V, C ariporide did not alter the pattern of cardiomyocyte staining with PI and A nnexin V, although the number of cardiomyocytes stained with P1 or PI plus Annexin V was less than that in vehicle-treated hearts. 4. These results suggest that apoptosis is not a major manifestation of car diomyocyte cell death in the ischaemic-reperfused myocardium and a caripori de-sensitive mechanism of reperfusion injury promotes both necrotic and apo ptotic processes of cell death.