Blocking Na+–H+Exchange by Cariporide Reduces Na+-overload in Ischemia and is Cardioprotective

In myocardial ischemia, rapid inactivation of Na+–K+-ATPase and continuing influx of sodium induce Na+-overload which is the basis of Ca2+-overload and irreversible tissue injury following reperfusion. The Na+–H+-exchanger of subtype 1 (NHE-1) is assumed to play a major role in this process, but previously available inhibitors were non-specific and did not allow to verify this hypothesis. Cariporide (HOE 642) is a recently synthesized NHE-1 inhibitor. We have investigated its effects on Na+homeostasis (23Na NMR spectroscopy), cardiac function and energy metabolism (31P NMR) in ischemia and reperfusion. In the well-oxygenated, isolated guinea-pig heart, cariporide (10 μ m) had no effect on intracellular Na+, pH or cardiac function. NHE-1 inhibition by cariporide was demonstrated using the NH4Cl prepulse technique. When hearts were subjected to 15 min of ischemia, cariporide markedly inhibited intracellular Na+-accumulation (1.3±0.1 vs 2.1±0.1-fold rise) but had no effect on the decline in pHi. In reperfusion, NHE-1-blockade significantly delayed pH recovery. With longer periods of ischemia (36 min), cariporide delayed the onset of contracture, reduced ATP depletion, Na+-overload and again had no effect on pH. In reperfusion, hearts treated with cariporide showed an improved recovery of left ventricular pressure (60±1 vs 16±8 mmHg); end-diastolic pressure was normalized and phosphocreatine fully recovered, while there was only a partial recovery in controls. The data demonstrate that Na+–H+-exchange is an important port of Na+-entry in ischemia and contributes to H+-extrusion in reperfusion. By reducing Na+-overload in ischemia and prolonging acidosis in reperfusion, NHE-blockade represents a promising cardioprotective principle.