Role of Na+/H+ exchange in cardiac physiology and pathophysiology: mediation of myocardial reperfusion injury by the pH paradox

Abstract

Na+/H+ exchange, an electroneutral cotransport system, is activated by reperfusion of the ischaemic heart. While activation can restore intracellular pH following an acid load, the concomitant increase in intracellular Na+ can also aggravate existing derangements of ionic homeostasis, particularly with respect to calcium overload, and result in exacerbation and acceleration of tissue injury, a phenomenon which has been termed the pH paradox. In addition, Na+/H+ exchange has been shown to participate in the activation of both platelets and neutrophils, factors widely acknowledged to participate in ischaemic and reperfusion injury. All studies thus far reported (summarised in the table) have shown desirable and beneficial effects of Na+/H+ exchange inhibitors on various cellular processes which contribute to myocardial reperfusion injury. These multiple effects of Na+/H+ exchange inhibitors are unique and unmatched by any other group of pharmacological agents. They offer the hope of superior tissue protection and salvage, with limited potential for toxicity, following reperfusion protocols. We propose, therefore, that activation of the Na+/H+ exchanger mediates reperfusion injury and that suppression of the exchanger will be of superior benefit in reduction of such injury during restoration of flow. The rapid development of new and highly specific Na+/H+ exchange inhibitors offers substantial promise for the use of these agents as adjunct therapy in numerous reperfusion protocols.

Protein Kinase C Contributes to the Maintenance of Contractile Force in Human Ventricular Cardiomyocytes

“…Our data add to the range of these effects, suggesting that PKC is also involved in the maintenance of contractile force in case of prolonged increased intracellular Ca 2ϩ concentrations, a condition that generally occurs upon ischemia-reperfusion (38). This beneficial effect of PKC was totally unexpected in light of the wealth of evidence for decreased contractility upon PKC activation.…”

Role of Intracellular Na + Kinetics in Preconditioned Rat Heart

“…To measure intracellular Na ϩ concentration ([Na ϩ ] i ), we acquired 23 Na-MRS spectra obtained on a Bruker AMX-400wb spectrometer; the resonance frequency for 23 Na was 105.843 MHz, as described previously. 1,[15][16][17] Two hundred fifty-six free induction decays were collected into 1 23 Na-spectrum; it took 90 seconds to obtain 1 spectrum.…”

“…1,[15][16][17] Two hundred fifty-six free induction decays were collected into 1 23 Na-spectrum; it took 90 seconds to obtain 1 spectrum. To distinguish intra-and extracellular 23 Na-nuclear magnetic resonance signals, the perfusate with the following composition (in mmol/L) was used for 23 Na-MRS measurement: NaCl 18, KCl 5, MgCl 2 Na-MRS spectrum were measured by using planimetry, normalized by the peak for the reference, and corrected with the measured weight of each heart, resulting in the intracellular concentration in units of micromoles per gram wet weight ([Na ϩ ] i ).…”

“…The hearts were then reperfused for 30 minutes. 23 Na-MRS spectra were acquired during ischemia and during the initial 6 minutes of reperfusion. The perfusate was switched back to the standard after 6 minutes.…”

“…In particular, when the recovery process was assessed by the time constant in the regression with %⌬[Na It was reported that IPC stimulates Na ϩ accumulation during ischemia. 18 Although this was detected by 23 Na-MRS, the appropriate methods to improve the resolution between intra-and extracellular Na ϩ peaks were not applied. In contrast, we carefully measured to assess [Na ϩ ] i by 23 Na-MRS with a shift reagent.…”