Effects of proton buffering and of amiloride derivatives on reperfusion arrhythmias in isolated rat hearts. Possible evidence for an arrhythmogenic role of Na(+)-H+ exchange.

We investigated the hypothesis that an accelerated Na+o-H+i exchange on reperfusion may lead to a displacement of the 3[Na+] [Ca2+]i/o equilibrium in favor of an arrhythmogenic rise in cytosolic [Ca2+]. Supporting evidence was obtained by subjection of isolated rat hearts to 15 minutes of low-flow (5% of control) ischemia and 2 minutes of reperfusion in the presence of a Krebs-Henseleit HEPES buffer (pH 7.4) containing lactate (10 mM). At first, the [HEPES] was fixed at 5 mM; then, 2 minutes before reflow, either the [HEPES] was varied from 50 to 1 mM to slow H+o washout, or increasing concentrations of 5-(N,N-dimethyl)-amiloride (Ki 7 microM) or 5-(N,N-hexamethylene)-amiloride (Ki 0.2 microM) were added for inhibition of Na(+)-H+ exchange. In each case, reperfusion ventricular arrhythmias were reduced by 69-73% (p less than 0.001).