Effects of acidic reperfusion on arrhythmias and Na(+)-K(+)-ATPase activity in regionally ischemic rat hearts

Abstract

We studied the effects of acidic reperfusion on 1) the incidence of ventricular fibrillation (VF) and 2) sarcolemmal Na(+)-K(+)-adenosinetriphosphatase (ATPase) activity. Isolated rat hearts (n = 12/group) were subjected to independent perfusion (15 min) of left and right coronary beds with pH 7.4 buffer followed by zero-flow ischemia (10 min) of the former bed. This was then reperfused for 5 min, with acidic (pH 6.6) buffer for the first 0 (control), 0.5,1,2, or 4 min and with pH 7.4 buffer thereafter. In the control group, 92% of hearts developed VF within 20 s of reperfusion and remained in VF. In the 0.5-, 1-, 2-, and 4-min acidic reperfusion groups, only 17, 17, 42, and 25% of hearts (P < 0.05 vs. control for all groups), respectively, exhibited VF during acidic reperfusion. However, on switching to pH 7.4, VF occurred in a further 50, 58, 0, and 0% of hearts, respectively; thus the overall incidences of VF were 67, 75, 42 (P < 0.05 vs. control), and 25% (P < 0.05 vs. control), respectively. Additional hearts (n = 8/group) were used for cytochemical determination of sarcolemmal Na(+)-K(+)-ATPase activity in both the ischemic/reperfused left ventricular (LV) and the nonischemic right ventricular (RV) free walls. Ischemia (10 min) reduced LV Na2(+)-K(+)-ATPase activity from 110 +/- 8 to 25 +/- 3% of the RV value. After 0.5, 1, 2, 3, and 4 min of acidic reperfusion, LV Na(+)-K(+)-ATPase activity was 24 +/- 3, 29 +/- 3, 37 +/- 5, 55 +/- 6, and 70 +/- 4, respectively (P < 0.05 vs. 10-min ischemia). No significant recovery of LV Na(+)-K(+)-ATPase activity occurred following up to 4 min of pH 7.4 reperfusion. In conclusion, 1) at least 2 min of acidic reperfusion is required to achieve sustained protection against VF and 2) the protective mechanism may involve enhanced recovery of Na(+)-K(+)-ATPase activity as well as inhibition of Na+ influx.

A KATP channel opener inhibited myocardial reperfusion action potential shortening and arrhythmias

“…Activity of the Na + ,K + pump (Na + ,K + -ATPase), which is thought to play a key role in the development of reperfusion arrhythmias (Tani and Neely, 1991), was markedly reduced after only 10 min of ischaemia in the rat (Avkiran et al, 1996). Reperfusion-induced [K + ] o -undershoot is thought to result largely from recovery of Na + ,K + -ATPase activity upon restoration of coronary flow (Coronel et al, 1992; Tani and Neely, 1991;Avkiran et al, 1996).…”

“…Reperfusion-induced [K + ] o -undershoot is thought to result largely from recovery of Na + ,K + -ATPase activity upon restoration of coronary flow (Coronel et al, 1992; Tani and Neely, 1991;Avkiran et al, 1996). This enzyme, whilst extruding the excess (Na + ) i that accumulated during ischaemia, would also rapidly remove K + from the extracellular space, possibly leading to a [K + ] o undershoot.…”

Limiting sarcolemmal Na+entry during resuscitation from ventricular fibrillation prevents excess mitochondrial Ca2+accumulation and attenuates myocardial injury

“…Conclusions: Na ϩ -limiting interventions prevented excess Ca 2ϩ m accumulation induced by ischemia and reperfusion and ameliorated myocardial injury and dysfunction. calcium; cardiopulmonary resuscitation; myocardial ischemia; sodium INCREASED SARCOLEMMAL Na ϩ influx with consequent cytosolic Na ϩ accumulation due to inability of the Na ϩ -K ϩ -ATPase to extrude Na ϩ represents an important pathophysiological mechanism responsible for cell injury during ischemia and reperfusion (3,28). Main routes for sarcolemmal Na ϩ entry include the sodium-hydrogen exchanger isoform-1 (NHE-1), Na ϩ channels, and the Na ϩ -HCO 3 Ϫ cotransporter.…”

“…calcium; cardiopulmonary resuscitation; myocardial ischemia; sodium INCREASED SARCOLEMMAL Na ϩ influx with consequent cytosolic Na ϩ accumulation due to inability of the Na ϩ -K ϩ -ATPase to extrude Na ϩ represents an important pathophysiological mechanism responsible for cell injury during ischemia and reperfusion (3,28). Main routes for sarcolemmal Na ϩ entry include the sodium-hydrogen exchanger isoform-1 (NHE-1), Na ϩ channels, and the Na ϩ -HCO 3 Ϫ cotransporter. However, NHE-1 and Na ϩ channels appear to be the preferred routes for Na ϩ entry during ischemia and reperfusion (21,38,54).…”

NHE-1 Inhibitors and Erythropoietin for Maintaining Myocardial Function during Cardiopulmonary Resuscitation

“…One line relates to work using NHE-1 inhibitors in various animal models of cardiac arrest over a period of approximately 10 years. (10,17,23,28,(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55) Research over the last decade in our laboratory using various translational rat and pig models of cardiac arrest has shown consistent myocardial benefit associated with inhibition of NHE-1 activity during resuscitation from VF. (10,17,23,28,(37)(38)(39)(40)(41)(56)(57)(58)(59)(60) Mechanistically, these benefits are associated with less cytosolic Na+ overload, less mitochondrial Ca2+ overload, and preservation of oxidative phosphorylation.…”