Na ⁺ /H ⁺ Exchange Inhibition With HOE642 Improves Postischemic Recovery due to Attenuation of Ca ²⁺ Overload and Prolonged Acidosis on Reperfusion

Abstract

Background —Na + /H + exchange inhibition with HOE642 (cariporide) improves postischemic recovery of cardiac function, but the mechanisms of action remain speculative. Because Na + /H + exchange is activated on reperfusion, it was hypothesized that its inhibition delays realkalinization and decreases intracellular Na + and, via Na + /Ca 2+ exchange, Ca 2+ overload. Attenuated Ca 2+ overload and prolonged acidosis are known to be cardioprotective. Methods and Results —Left ventricular developed and end-diastolic pressures were measured in isolated buffer-perfused rat hearts subjected to 30 minutes of no-flow ischemia and 30 minutes of reperfusion (37°C) with or without 1 μmol/L HOE642 added to the perfusate 15 minutes before ischemia. Intracellular Ca 2+ concentration ([Ca 2+ ] i ) and pH i were measured with aequorin (n=10 per group) and 31 P NMR spectroscopy (n=6 per group), respectively. HOE642 did not affect preischemic mechanical function, [Ca 2+ ] i , or pH i . Mechanical recovery after 30 minutes of reperfusion was substantially improved with HOE642: left ventricular developed pressure (in percent of preischemic values) was 92±3 versus 49±7 and left ventricular end-diastolic pressure was 16±3 versus 46±5 mm Hg ( P <0.05 for HOE642-treated versus untreated hearts). End-ischemic [Ca 2+ ] i was significantly lower in HOE642-treated than in untreated hearts (1.04±0.06 versus 1.84±0.02 μmol/L, P <0.05). Maximal intracellular Ca 2+ overload during the first 60 seconds of reperfusion was attenuated with HOE642 compared with untreated hearts: 2.0±0.3 versus 3.2±0.3 μmol/L ( P <0.05). pH i was not different at end ischemia (≈5.9±0.05). Realkalinization was similar in the first 90 seconds of reperfusion and significantly delayed in the next 3 minutes (eg, 6.8±0.07 in HOE642-treated hearts compared with 7.2±0.07 in untreated hearts; P <0.05). Conclusions —HOE642 improves postischemic recovery by reducing Ca 2+ overload during ischemia and early reperfusion and by prolonging postischemic acidosis.

Excitation-contraction coupling and mitochondrial energetics

“…This could be achieved by inhibiting I NHE or late I Na . Both approaches were cardioprotective in experimental models of ischemia/ reperfusion, since in this situation, an excessive increase of [Na + ] i contributes to progressive cytosolic and mitochondrial Ca 2+ -overload and thus, the induction of apoptosis through activation of the mitochondrial PTP [78,135,168,189]. Also in animal models of heart failure, both the inhibition of I NHE by cariporide and of late I Na by ranolazine reduced [Na + ] i and improved EC coupling and LV remodeling [6,34,38,62,163,202].…”

Creatine kinase-deficient hearts exhibit increased susceptibility to ischemia-reperfusion injury and impaired calcium homeostasis

“…This is the first report on measurements of Ca 2ϩ transients with aequorin in perfused mouse hearts at 37°C, and the protocol is therefore described in detail. After an initial perfusion period of 5-10 min at 30°C with a Ca 2ϩ concentration ([Ca 2ϩ ]) in the coronary perfusate of 1.0 mM, aequorin was macroinjected with a technique adapted from the rat whole heart preparation (22) and modified for the intact mouse heart. Specifically, 3-5 l of an aequorin-containing solution (1 g/ml) were injected with a glass micropipette into the interstitium of the inferoapical region of the LV.…”

Inhibition of Na + -H + Exchange Prevents Hypertrophy, Fibrosis, and Heart Failure in β 1 -Adrenergic Receptor Transgenic Mice

“…8,9 Activation of this exchanger in myocardial ischemia appears to be causally related to the calcium overload observed during ischemia, 10 and several studies have demonstrated protection from ischemic injury by NHE inhibition both in animal models of myocardial ischemia (MI) and in patients undergoing coronary interventions. [11][12][13] A protective effect of cariporide has recently been demonstrated in the setting of post-MI remodeling, 14 where protection could be demonstrated up to 3 months after MI.…”

“…20 This increased intracellular sodium might be exchanged against calcium via the cardiac Na ϩ -Ca 2ϩ exchanger, as has been proposed for the NHE1 activation observed during myocardial ischemia. 12 The resulting increase in diastolic calcium might then exert numerous deleterious effects, including the activation of protein kinase C and calcium-dependent transcription factors. Interestingly, we have found alterations in intracellular calcium handling in ␤ 1 -adrenergic receptor transgenic mice that are similar to human heart failure and include markedly prolonged calcium transients.…”