Role of Endothelin-A Receptors in Ischemic Contracture and Reperfusion Injury

Abstract

Background —Circulating endothelin (ET)-1 is elevated in ischemia/reperfusion and may exert proischemic effects. The aim of the present study was to characterize the effects of ET-1 in rat isolated hearts using subtype-selective ET receptor antagonists, agents modulating the cytosolic Ca 2+ concentration, or the activity of cGMP-dependent protein kinase. Methods and Results —Rat hearts perfused at constant pressure were made ischemic by reducing flow to 0.2 mL · min -1 · g −1 , followed by reperfusion at normal pressure (each phase, 25 minutes). Drugs were infused during the ischemic phase only. Parameters monitored were extent and time-to-onset of contracture in ischemia, left ventricular developed pressure (LVDevP), coronary flow (CF), and diastolic relaxation during reperfusion. The ET A receptor-selective antagonist PD 155080 (50 nmol/L) reduced peak ischemic contracture (−49%) and delayed its time to onset (+56%) and improved recovery of reperfusion LVDevP (+12%), CF (+16%), and diastolic relaxation (+50%). Infusion of an ET A /ET B -nonselective antagonist, PD 142893 (200 nmol/L), had similar effects on all parameters, whereas infusion of BQ-788 (20 nmol/L), an ET B receptor-selective antagonist, was without effect. Exogenous ET-1 (100 pmol/L) hastened contracture and increased its extent (+23%) and reduced recovery of both LVDevP (−31%) and CF (−18%), effects that were counteracted by HOE 642 (10 μmol/L), a Na + /H + exchange inhibitor, but not by nicardipine (30 μmol/L), a Ca 2+ entry blocker; activation of cGMP-dependent protein kinase by the cell-permeable cGMP analog Sp-8-p-chlorophenylthioguanosine-3’,5’-cyclic monophosphorothioate (10 μmol/L) improved function without preventing the effects of ET-1. Conclusions —The data indicate that ET-1 exacerbates ischemic contracture and worsens ventricular and coronary reperfusion dysfunction by activating ET A receptors via a mechanism likely involving activation of Na + /H + exchange in this model.