ROLE OF NA-H+ EXCHANGE IN MEDIATING EFFECTS OF ENDOTHELIN-1 ON NORMALAND ISCHEMIC()REPERFUSED HEARTS/

Endothelin (ET) has been shown to be elevated under conditions of card iac pathology and to produce diverse cardiac effects, including corona ry constriction and a positive inotropic influence. We characterized t he concentration- and time-dependent effects of the most potent of the ET isoforms, ET-1 (0.4, 2, and 4 nmol/L), on myocardial contractility and coronary resistance and assessed its effects on the ischemic and reperfused heart. Because ET-1 has been shown to activate the Na+-H+ e xchanger in cardiac myocytes, we determined the contribution of the an tiport by examining the effects of ET-1 in the presence of the Na+-Hexchange inhibitor methylisobutyl amiloride (MIA). At all three concen trations, ET-1 produced an initial positive inotropic effect that was reversed with continued perfusion, the degree of the reversal being de pendent on ET-1 concentration. With 0.4 nmol/L, contractility returned to pre-ET-1 values, whereas after 75 minutes of perfusion with 4 nmol /L ET-1, contractility was depressed by 75%. At all concentrations, ET -1 produced a coronary-constricting effect, whereas an elevation in re sting tension was observed only with 4 nmol/L ET-1. MIA significantly prevented the positive inotropic effect of ET-1 but had no effect on l oss in function or elevation in resting tension produced by 4 nmol/L E T-1. Furthermore, MIA partially, but not significantly, attenuated the constricting effects of all ET-1 concentrations. In the ischemic hear t, 0.4 nmol/L ET-1 appeared to delay the loss in contractility produce d by cessation of flow, although the effect was not significant. Highe r concentrations of ET-1 were without effect on ischemia-induced contr actile depression, although their presence produced a marked elevation in resting tension during ischemia that was attenuated by MIA. Recove ry in contractility was reduced by all concentrations of ET-1, althoug h the effects of the lowest concentration were associated primarily wi th defective relaxation. The depressant effects of ET-1 either in norm al or ischemic/reperfused hearts were irreversible. The inhibitory eff ects of ET-1 on contractile recovery were associated with diminished t issue glycogen and elevated lactate levels. High-energy phosphates aft er reperfusion were depressed in hearts treated with 4 nmol/L ET-1. Th e attenuation in contractile recovery and alterations in metabolite co ntent were prevented by MIA. These results provide evidence that ET-1 produces complex effects on heart function that are likely mediated vi a different mechanisms and demonstrate its ability to aggravate ischem ic and reperfusion injury through a mechanism possibly involving Na+-H + exchange activation.