Blocking Na+-H+ exchange by cariporide reduces Na+-overload in ischemia and is cardioprotective

被引:102
作者
Hartmann, M
Decking, UKM
机构
[1] Univ Dusseldorf, Dept Anesthesiol, D-4000 Dusseldorf, Germany
[2] Univ Dusseldorf, Dept Physiol, D-4000 Dusseldorf, Germany
关键词
cariporide; Na+-H+-exchange; guinea-pig; ischemia; reperfusion; P-31 NMR spectroscopy; Na-23 NMR spectroscopy;
D O I
10.1006/jmcc.1999.1029
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (Na-23 NMR spectroscopy), cardiac function and energy metabolism (P-31 NMR) in ischemia and reperfusion. In the well-oxygenated, isolated guinea-pig heart, cariporide (10 mu 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 pH(i). 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. (C) 1999 Academic Press.
引用
收藏
页码:1985 / 1995
页数:11
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