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 my ocardial ischemia-reperfusion injury. While studies employing less selectiv e sodium-hydrogen inhibitors have demonstrated antiarrhythmic activity, onl y one study has examined the in vivo efficacy of selective NHE-1 inhibition in a canine model of ischemia-reperfusion-induced arrhythmia. In the prese nt 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 o f myocardial ischemia-reperfusion injury in which 60 min of left anterior d escending coronary artery (LAD) occlusion followed by 3 h of reperfusion wa s employed. BIIB 513 was infused either prior to ischemia or prior to reper fusion. Arrhythmias were quantified by single lead electrocardiogram. Infar ct size, determined by triphenyltetrazolium staining, was expressed as a pe rcent of the area-at-risk. In vivo, NHE-1 inhibition did not affect phase l a arrhythmias, which occur within the first 10 min of occlusion, however, B IIB 513 significantly reduced the incidence of ischemia-induced phase Ib ar rhythmias which occur between 10 and 30 min following occlusion and the inc idence of reperfusion-induced ventricular fibrillation. Furthermore, NHE-1 inhibition significantly reduced infarct size, when the drug was administer ed either prior to ischemia or prior to reperfusion. NHE-1 inhibition selec tively reduces both ischemia-induced phase Ib arrhythmias and reperfusion-i nduced ventricular fibrillation, and also markedly reduces myocardial infar ct size when the drug is administered prior to ischemia or prior to reperfu sion. (C) 2000 Elsevier Science B.V. All rights reserved.