EFFECTS OF ENDOTHELIN-1 AND ENDOTHELIN-A RECEPTOR ANTAGONIST ON RECOVERY AFTER HYPOTHERMIC CARDIOPLEGIC ISCHEMIA IN NEONATAL LAMB HEARTS

Background Prior studies suggest an important role for coronary endoth elium in ischemia/reperfusion (IIR) injury. Decreased endothelial rele ase of the vasodilator nitric oxide occurs after IIR, but the role of the endothelium-derived vasoconstrictor endothelin-l (ET-I) in IIR is unknown. Methods and Results We measured plasma ET-1 concentrations by radioimmunoassay in isolated blood-perfused neonatal Lamb hearts befo re and after 2 hours of 10 degrees C cardioplegic ischemia and examine d the effects of ET-1 and the endothelin-A (ET-A) receptor antagonist BE-18257B on the postischemic recovery of isolated hearts. ET-1 levels in coronary sinus blood before ischemia and at 0 and 30 minutes of re perfusion in 8 control hearts were constant (2.2+/-1.2 fmol/L, 2.2+/-1 .3 fmol/L, and 2.5+/-1.0 fmol/L, respectively). In group 2 (n=6), 10 m u mol/L of BE-18257B was given just before reperfusion. In group 3 (n= 8), 10 pmol/L ET-1 was given just before the start of reperfusion. At 30 minutes of reperfusion, the ET-A antagonist hearts had significantl y greater recovery of LV systolic (positive dP/dt and dP/dt at V10) an d diastolic function (negative dP/dt), coronary blood flow (CBF), and MVo(2), compared with controls (P<.05). The ET-1 hearts showed signifi cantly reduced recovery of LV systolic (positive maximum and volume-no rmalized dP/dt) and diastolic (negative maximum dP/dt) function, CBF, and myocardial oxygen consumption compared with controls (P<.05). Conc lusions These results, combined with prior studies, suggest that IIR c auses reduced production of endogenous vasodilators(eg, nitric oxide), leaving unopposed the vasoconstriction that is caused by the continue d presence of ET-1. This imbalance may contribute to I/R injury. ET-A receptor antagonists may be useful therapeutic agents in reducing the injury that results from IIR.