Protective Effect of FR183998, a Na+H+ Exchange Inhibitor, Against Postischemic Injury After Normothermic and Prolonged Hypothermic Ischemia in Isolated Perfused Rat Hearts

Abstract

ABSTRACT-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+ 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´10 -8 -3.21 0 -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, FR183998 (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.

Functional role of the Na+/H+ exchanger in the regulation of cerebral arteriolar tone in rats

“…13,25,31 There are several diseases that may be associated with or induced by altered NHE activity, including hypertension, cardiac ischemia, and reperfusion injury. 2,7,9,29,35,36 An increased [Na ϩ ] i activates the Na ϩ /Ca ϩϩ exchanger and results in an increase in free [Ca ϩ ] i . 26 As expected, not only [Na ϩ ] i overload but also ischemic Ca ϩϩ overload is substantially reduced by Na ϩ /H ϩ exchange inhibitors.…”

“…3,25,31 It has been reported in preclinical studies that Na ϩ /H ϩ exchange inhibitors have cardioprotective effects. 2,7,9,29,35,36 Recently, it has been reported that inhibition of NHE by FR183998 may have beneficial effects in reducing infarct volume and brain edema during cerebral ischemia in rats. 17 Horikawa, et al, 11 reported that the protective effect of Na ϩ / H ϩ exchange inhibitor on ischemic brain injury in rats may be at least partially mediated by the prevention of endothelial dysfunction.…”