Effects of endothelin-1 and L-arginine after cold ischemia in lamb hearts

Background. Prior studies from our laboratory have suggested an important role for the coronary endothelium in the injury resulting from hypothermic ischemia and reperfusion. A decreased endothelial response to intraarterial acetylcholine occurs after ischemia/reperfusion, implying a reduced release of the vasodilator nitric oxide by endothelial cells, but the role of endothelial-derived vasoconstrictor endothelin-1 in ischemia/reperfusion and interactions between endothelin-1 and nitric oxide in ischemia/reperfusion are still unclear. Methods. We examined the effects of endothelin-1 and L-arginine, the precursor for nitric oxide, on functional recovery of isolated, blood-perfused neonatal lamb hearts undergoing 2 hours of ischemia at 10°C. One group (n = 8) received 10 pmol/L endothelin-1 before reperfusion, and a second 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 endothelin-1 and L-arginine groups. The fourth group underwent the same period of hypothermic ischemia without interventions during reperfusion. Results. After 30 minutes of reperfusion, the endothelin-1-treated hearts showed significantly reduced recovery of left ventricular systolic 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 values observed in controls having unmodified reperfusion by adding L-arginine. The L-arginine group had significantly greater recovery of left ventricular systolic function (positive maximum dP/dt, maximum developed pressure, dP/dt at V10, and developed pressure at V10) and diastolic function (negative maximum dP/dt), coronary blood flow, and myocardial oxygen consumption compared with the control group (p < 0.05). Conclusion. These results, combined with our previous observations that endothelin-1 levels are unchanged by hypothermic ischemia and reperfusion, suggest that there is an imbalance between the endothelial production of endothelin-1 and nitric oxide, which affects postischemic coronary blood flow and the recovery of ventricular function. Interventions that modify this imbalance of endothelially derived substances could favorably influence the outcome after a period of hypothermic ischemia and reperfusion.