Myocardial protection during ventricular fibrillation by inhibition of the sodium-hydrogen exchanger isoform-1

Abstract

Activation of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) in response to the intense intracellular acidosis that develops during ischemia has been identified as an important mechanism of myocardial cell injury. NHE-1 inhibition in the quiescent (nonfibrillating) heart ameliorates functional manifestation of ischemia and reperfusion injury. We investigated in isolated heart and intact rat models of ventricular fibrillation whether NHE-1 inhibition, by using the selective inhibitor cariporide, could ameliorate myocardial abnormalities that develop during ventricular fibrillation and limit resuscitability and survival. In the isolated rat heart, cariporide significantly reduced the magnitude of ischemic contracture during ventricular fibrillation and the accompanying increases in coronary vascular resistance. Hearts that had received cariporide during ventricular fibrillation had no diastolic dysfunction after resuscitation and recovered their systolic function earlier. In intact rats, cariporide given immediately before starting chest compression allowed generation of a coronary perfusion pressure and end-tidal Pco2 comparable with control rats but with significantly less depth of compression. Cariporide had an unprecedented effect in this rat model, prompting spontaneous defibrillation after approximately 8 mins of chest compression. After resuscitation, rats treated with cariporide had significantly less ventricular ectopic activity, better hemodynamic function, and higher survival rates (22 of 24 [94%] vs. 15 of 24 [63%] in control rats, p <.05). We conclude that NHE-1 inhibition may represent a novel and highly effective form of treatment for resuscitation from ventricular fibrillation.

Role of NHE1 in the Cellular Dysfunction of Acute Metabolic Acidosis

“…Its effect on myocardial carbon dioxide concentration is not clear. Be that as it may, elegant studies of cardiac arrest induced by ventricular fibrillation revealed improvement in cardiac function during fibrillation [25] and significant attenuation of postresuscitation ventricular arrhythmias including prevention of recurrent episodes of ventricular fibrillation with cariporide and other NHE1 inhibitors in both pig and rat models (table 1) [26,27,28,29,30,31,32]. …”

Optimal timing for electrical defibrillation after prolonged untreated ventricular fibrillation

“…Three series were designed to examine the optimal timing for attempting defibrillation, the effects of repetitive electrical shocks, and the effect of ameliorating myocardial ischemia by inhibition of the sarcolemmal sodiumhydrogen exchanger isoform-1 (NHE-1) (11,16,17) (Fig. 1).…”

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

“…(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. The other relates to more recent work using erythropoietin in a rat model of cardiac arrest (42) and in a small clinical study in patients suffering out-of-hospital cardiac arrest.…”

“…Effects of NHE-1 inhibition on resuscitation: 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. Some of these studies, highlighting key aspects of NHE-1 inhibition during resuscitation, are succinctly discussed below.…”