Protective Effects of the Potent Na/H Exchange Inhibitor Methylisobutyl Amiloride Against Post-ischemic Contractile Dysfunction in Rat and Guinea-pig Hearts

Abstract

We studied the effects of the potent Na/H exchange inhibitor methylisobutyl amiloride (MIA, 1 μM) on post-ischemic ventricular recovery and energy metabolic status in spontaneously contracting, isolated rat and guinea-pig hearts subjected to 45 min zero-flow ischemia followed by reperfusion. For both species, MIA was added either 15 min prior to ischemia and was present throughout reperfusion or was added at the time of reperfusion only. In control rat hearts, force recovery after 30 min of reperfusion was 25.6 ± 6.0% of the pre-ischemic value whereas in hearts pre-treated with MIA recovery was enhanced to 55.4 ± 9% ( P < 0.05). Elevation of resting tension during the first 20 min of reperfusion was also significantly reduced by MIA pre-treatment. When MIA was added at the time of reperfusion only, recovery was generally lower than that seen with MIA pre-treatment although significantly higher values were seen through much of the reperfusion period. In rat hearts, MIA reduced the time required for return to sustained contractile recovery particularly in those hearts where the drug was added prior to ischemia (control, 11.4 ± 2.7 min; MIA, 2.6 ± 0.5 min, P < 0.05). Similar effects of MIA pre-treatment were seen in guinea-pig hearts in terms of contractile recovery, time to recovery and reduction in resting tension although MIA addition at the time of reperfusion was without beneficial effect either on the magnitude of contractile recovery or time required for restoration of function. In guinea-pig hearts, recovery of function was accompanied by substantial bradycardia. However, maintenance of ventricular rate through electrical pacing exerted no significant influence on the protective effects of MIA pre-treatment. There was no effect of MIA on energy metabolites in reperfused rat hearts or paced guinea-pig hearts, although in spontaneously contracting guinea-pig hearts improved recovery of function was associated with significantly higher levels of high energy phosphates. No effects of tissue metabolites were seen in ischemic non-reperfused hearts irrespective of treatment. The protective effects of MIA are not related to diminished release of creatine kinase during reperfusion. Our results demonstrate marked protective effects of MIA, on the reperfused rat and guinea-pig myocardium. These studies also demonstrate, for the first time, that the effects of amiloride analogues are not species specific and further support the concept that Na/H exchange inhibition may represent an effective therapeutic approach for the protection of reperfused cardiac tissue.