Na ⁺ /H ⁺ Exchange Inhibitor Cariporide Attenuates Cell Injury Predominantly During Ischemia and Not at Onset of Reperfusion in Porcine Hearts With Low Residual Blood Flow

Abstract

Background-This study investigated whether myocardial protection by inhibition of Na ϩ /H ϩ exchange (NHE) occurs during ischemia and/or during reperfusion. Methods and Results-The left anterior descending coronary artery was occluded in 32 pigs for 60 minutes and then reperfused for 24 hours. Infarct sizes (nitroblue tetrazolium [NBT] stain, histology) were determined at the end of the experiments. An extracorporeal bypass was used to achieve a constant residual blood flow of 3 mL/min in the myocardium at risk during ischemia. The NHE-1 inhibitor cariporide or distilled water was infused into the extracorporeal bypass system. In group 1, active treatment was administered from the onset of ischemia until 10 minutes of reperfusion (nϭ8). In group 2, active treatment was infused during the first 30 minutes of ischemia only (nϭ8). The group 3 animals (nϭ8) received intracoronary cariporide after 45 minutes of ischemia until 10 minutes of reperfusion. The control animals (group 4, nϭ7) were treated similarly to group 1 animals, with the cariporide solution being replaced by distilled water. Infarct sizes of group 1 (NBT stain, 41.5Ϯ20%; histology, 44.6Ϯ12%) and group 2 (NBT stain, 33.5Ϯ14%; histology 34.9Ϯ15%) differed significantly (at least Pϭ0.012) from infarct sizes of group 3 (NBT stain, 71.6Ϯ15%; histology, 69.2Ϯ12%) and the control group (NBT stain, 76Ϯ9%; histology 72.4Ϯ12%). Cariporide treatment in group 1 and group 2 significantly improved functional recovery after 24 hours of reperfusion. Conclusions-Myocardial protection by cariporide is predominantly achieved by NHE inhibition during ischemia and not during early reperfusion.

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).…”

“…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.…”

Prostaglandin-mediated inhibition of Na+/H+exchanger isoform 2 stimulates recovery of barrier function in ischemia-injured intestine

“…injury in various tissues (20,36,47), we assessed the role of the basolaterally expressed NHE1 in the ischemia-injured ileum. However, blockade of NHE1 in the ischemia-injured mucosa with serosal application of the selective NHE1 inhibitors HOE-694 (25 M) or HOE-642 (cariporide, 25 M) had no effect on the recovery of TER, suggesting that NHE1 is not directly involved in mucosal barrier repair in this model.…”

“…There are numerous studies (20,36,47) that have reported protective properties of NHE1 inhibitors in ischemiareperfusion-injured porcine cardiac myocytes. In our intestinal ischemia model, inhibition of NHE2 appears to be responsible for the repair of ischemia-injured tissue.…”