Protective effect of FR183998, a Na+/H+ exchange inhibitor, against postischemic injury after normothermic and prolonged hypothermic ischemia in isolated perfused rat hearts.

Inhibition of Na+/H+ exchanger has been reported to protect hearts from ischemia and reperfusion injury. However, the effect of Na+/H+ exchange inhibition on hypothermic ischemic injury has not been extensively studied and the results are inconsistent. The purpose of this study was to investigate whether inhibition of Na+/H+ exchange with FR183998 (5-(2,5-dichlorothiphen-3-yl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoylguanidine dihydrochloride), a potent Na+/H+ exchange inhibitor, would show protective effects against postischemic cardiac dysfunction after hypothermic as well as normothermic ischemia and furthermore, after hypothermic cardioplegic arrest in isolated rat hearts. FR183998 (3.2 x 10(-8)-3.2 x 10(-7) M) improved post-ischemic recovery of left ventricular developed pressure and suppressed the increase of left ventricular end diastolic pressure in a dose-dependent manner, after not only 45 min of normothermic ischemia but also 6 h of hypothermic ischemia. Furthermore, FRI 83998 (10(-7)-10(-6) M) significantly reduced creatine kinase release during reperfusion after 3 h of hypothermic ischemia with cardioplegia. These results indicate that FR183998 has a potent protective effect on postischemic cardiac dysfunction after normothermic and hypothermic ischemia, and also on reperfusion injury after hypothermic cardioplegic arrest, suggesting that its effect would be additive to cardioplegia.