Prevention of ischemic rigor contracture during coronary occlusion by inhibition of Na+–H+ exchange

Abstract

These results indicate that inhibition of Na(+)-H+ exchange during ischemia is necessary to limit myocardial necrosis secondary to transient coronary occlusion, and that this action could by mediated by a protective effect against ischemic contracture. Inhibition of Na(+)-H+ exchange only during reperfusion has a partial and transient beneficial effect, but only when the inhibitor reaches the area at risk before reflow.

Cariporide preserves mitochondrial proton gradient and delays ATP depletion in cardiomyocytes during ischemic conditions

“…The protective effect of cariporide against cell death secondary to ischemiareperfusion was, therefore, fully explained in this model by its effect on ATP decay during the ischemic period. This result is consistent with previous studies showing that cariporide needs to be present during the ischemic period to be protective (6,16).…”

“…Slowed ATP depletion during ischemic conditions. The present observations in cultured cardiomyocytes exposed to simulated ischemia and in intact myocardium submitted to zero-flow ischemia are in agreement with previous studies showing that NHE inhibition slows-down the rate of ATP depletion during ischemia and delays the onset of rigor contracture (6,11,25). Moreover, in the present study, modulation of the rate of ATP depletion during ischemia by modifying myocardial temperature within the physiological range (35.5-38.5°C) allowed us to evaluate the contribution of the effect of cariporide on ATP content to its protective effect against ischemia-reperfusion injury.…”

“…In a recent study (31), pretreatment with the selective NHE inhibitor SM-20550 was associated with attenuated Ca 2ϩ overload in mitochondria obtained from rat hearts submitted to 40 min of ischemia and 20 min of reperfusion, a result in agreement with the protective effect of NHE inhibition against cell necrosis secondary to ischemia-reperfusion, but [Ca 2ϩ ] m during ischemia was not measured. Our observation that cariporide, at concentrations that have been consistently found cardioprotective in isolated cells (25,27) and intact myocardium in vivo (6,16), enhanced mitochondrial Ca 2ϩ accumulation during simulated ischemia may appear surprising. Although increased [Ca 2ϩ ] m has been shown to have detrimental effects (4), there is a lack of information on the consequences of mitochondrial Ca 2ϩ overload during ischemia.…”

“…However, the observed delay in pH recovery is very small, and other studies (27) have shown that the NaHCO 3 cotransporter may compensate for NHE inhibition, allowing a rapid normalization of intracellular pH during reperfusion. Although with some discrepancies (10), studies in different models have shown that to be effective, NHE inhibition must act during coronary occlusion (6,16) or cardioplegia (28), whereas its application at the time of reperfusion affords little, if any, protection against cell death. Recent reports (6,18,25) indicate that NHE inhibition delays the progression of ischemic injury as manifested by ATP depletion or development of rigor contracture.…”

“…Although with some discrepancies (10), studies in different models have shown that to be effective, NHE inhibition must act during coronary occlusion (6,16) or cardioplegia (28), whereas its application at the time of reperfusion affords little, if any, protection against cell death. Recent reports (6,18,25) indicate that NHE inhibition delays the progression of ischemic injury as manifested by ATP depletion or development of rigor contracture. It has been suggested that NHE1 is markedly inhibited during severe ischemia (23).…”