EFFECTS OF ENDOTHELIN-1 AND L-ARGININE AFTER COLD ISCHEMIA IN LAMB HEARTS

Background. Prior studies from our laboratory have suggested an import ant role for the coronary endothelium in the injury resulting from hyp othermic ischemia and reperfusion. A decreased endothelial response to intraarterial acetylcholine occurs after ischemia/reperfusion, implyi ng a reduced release of the vasodilator nitric oxide by endothelial ce lls, but the role of endothelial-derived vasoconstrictor endothelin-1 in ischemia/reperfusion and interactions between endothelin-1 and nitr ic oxide in ischemia/reperfusion are still unclear. Methods. We examin ed the effects of endothelin-1 and L-arginine, the precursor for nitri c oxide, on functional recovery of isolated, blood-perfused neonatal l amb hearts undergoing 2 hours of ischemia at 10 degrees C. One group ( n = 8) received 10 pmol/L endothelin-1 before reperfusion, and a secon d group (n = 8) received a continuous infusion of 3 mmol/L L-arginine during the initial 20 minutes of reperfusion. The third,group (n = 8) received both endothelin-1 and L-arginine in the same way as in the en dothelin-1 and L-arginine groups. The fourth group underwent the same period of hypothermic ischemia without interventions during reperfusio n. Results. After 30 minutes of reperfusion, the endothelin-1-treated hearts showed significantly reduced recovery of left ventricular systo lic function (positive maximum dP/dt and volume normalized [V10] dP/dt ) and diastolic function (negative maximum dP/dt), coronary blood flow , and myocardial oxygen consumption compared with the control group (p < 0.05). These effects of endothelin-1 were offset to equal the value s observed in controls having unmodified reperfusion by adding L-argin ine. The L-arginine group had significantly greater recovery of left v entricular systolic function (positive maximum dP/dt, maximum develope d pressure, dP/dt at V10, and developed pressure at V10) and diastolic function (negative maximum dP/dt), coronary blood flow, and myocardia l oxygen consumption compared with the control group (p < 0.05). Concl usion. These results, combined with our previous observations that end othelin-1 levels are unchanged by hypothermic ischemia and reperfusion , suggest that there is an imbalance between the endothelial productio n of endothelin-1 and nitric oxide, which affects postischemic coronar y blood flow and the recovery of ventricular function. Interventions t hat modify this imbalance of endothelially derived substances could fa vorably influence the outcome after a period of hypothermic ischemia a nd reperfusion.