Effect of Methylisobutyl Amiloride on [Na⁺]_i, Reperfusion Arrhythmias, and Function in Ischemic Rat Hearts

With 2 μM methylisobutyl amiloride (MIA), an inhibitor of Na⁺/H⁺ exchange, we tested the hypothesis that ion imbalance due to H⁺/Na⁺/Ca²⁺ exchange exacerbates reperfusion injury and arrhythmias. Isolated rat hearts were subjected to 25-min global ischemia and 30-min reperfusion. In the MIA-treated group, MIA was added throughout the perfusion protocol. Left ventricular pressure (LVP), arrhythmias, myocardial Na⁺ and K⁺ content, ⁴⁵Ca²⁺ uptake, and the levels of energy metabolites were analyzed. The recovery of LV developed pressure (LVDP) and + dP/dt and - dP/dt were improved in the MIA group (53 vs. 80, 71 vs. 86, 77 vs. 94%: each p < 0.05). MIA inhibited the increase in Na⁺ content and the decrease in K⁺ content that occurred at the end of the ischemic phase and reduced ⁴⁵Ca²⁺ uptake after reperfusion (28.6 vs. 17.1, 248 vs. 296, 2.79 vs. 1.36 μM/g dry weight of tissue; each p < 0.05). The incidence of ventricular tachycardia (VT) or ventricular fibrillation (VF) was lower in the MIA group [VT 11 of 20 (55%) vs. 4 of 20 (20%), p < 0.05; VF 13 of 20, (65%) vs. 6 of 20 (30%), 0.05 < p < 0.1], although the incidence of VF just escaped statistical significance. ATP level was higher in the MIA group after the ischemic phase and reperfusion (5.3 vs. 9.9, 12.3 vs. 14.7 μM/g dry weight of tissue; each p < 0.05). Our results suggest that MIA reduced reperfusion arrhythmias and improved functional recovery in isolated rat hearts subjected to global ischemia apparently by preserving high-energy phosphates during ischemia and by inhibiting Na⁺/H⁺ exchange, with attenuated cellular imbalance between Na⁺ and Ca²⁺.