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  • Title: Blocking Na(+)-H+ exchange by cariporide reduces Na(+)-overload in ischemia and is cardioprotective.
    Author: Hartmann M, Decking UK.
    Journal: J Mol Cell Cardiol; 1999 Nov; 31(11):1985-95. PubMed ID: 10591025.
    Abstract:
    In myocardial ischemia, rapid inactivation of Na(+)-K(+)-ATPase and continuing influx of sodium induce Na(+)-overload which is the basis of Ca(2+)-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 microM) 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 pH. 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.
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