Inhibition of the Na+/H+ exchanger attenuates phase 1b ischemic arrhythmias and reperfusion-induced ventricular fibrillation

The sodium-hydrogen exchanger-isotype 1 (NHE-1) plays a critical role in myocardial ischemia-reperfusion injury. While studies employing less selective sodium-hydrogen inhibitors have demonstrated antiarrhythmic activity, only one study has examined the in vivo efficacy of selective NHE-1 inhibition in a canine model of ischemia-reperfusion-induced arrhythmia. In the present study, the antiarrhythmic activity of Benzamide,N-(aminoiminomethyl)-4-[4-(2-furanylcarbonyl)-1-piperazinyl]-3-(methylsulfonyl), methanesulfonate (BIIB 513), a novel NHE-1 inhibitor, was examined. An in vivo canine model of myocardial ischemia-reperfusion injury in which 60 min of left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion was employed. BIIB 513 was infused either prior to ischemia or prior to reperfusion. Arrhythmias were quantified by single lead electrocardiogram. Infarct size, determined by triphenyltetrazolium staining, was expressed as a percent of the area-at-risk. In vivo, NHE-1 inhibition did not affect phase la arrhythmias, which occur within the first 10 min of occlusion, however, BIIB 513 significantly reduced the incidence of ischemia-induced phase Ib arrhythmias which occur between 10 and 30 min following occlusion and the incidence of reperfusion-induced ventricular fibrillation. Furthermore, NHE-1 inhibition significantly reduced infarct size, when the drug was administered either prior to ischemia or prior to reperfusion. NHE-1 inhibition selectively reduces both ischemia-induced phase Ib arrhythmias and reperfusion-induced ventricular fibrillation, and also markedly reduces myocardial infarct size when the drug is administered prior to ischemia or prior to reperfusion. (C) 2000 Elsevier Science B.V. All rights reserved.