Effects of L-arginine and L-nitro-arginine methyl ester on recovery of neonatal lamb hearts after cold ischemia. Evidence for an important role of endothelial production of nitric oxide.

Myocardial ischemia and reperfusion results in both ventricular and endothelial dysfunction. We have found that the endothelial defect is a reduced vasodilator response to an intraarterial infusion of acetylcholine that is likely due to reduced nitric oxide release, and we have hypothesized that reduced endothelial nitric oxide production contributes to postischemic cardiac dysfunction. However, others report that nitric oxide is deleterious after ischemia. We therefore examined the effects of infusions of L-arginine (3 mmol/L), a precursor of nitric oxide, D-arginine (3 mmol/L), an inactive stereoisomer of L-arginine, L-nitro-arginine methyl ester (1 mmol/L); a competitive inhibitor of nitric oxide synthase, and L-nitro-arginine methyl ester (1 mmol/L) plus L-arginine (3 mmol/L) versus controls in isolated blood-perfused neonatal lamb hearts having 2 hours of cold cardioplegic ischemia. L-nitro-arginine methyl ester was given before reperfusion, and L-arginine and D-arginine were infused for the first 20 minutes of postischemic reperfusion. At 30 minutes of reperfusion, by comparison with the control group, the L-arginine group showed significantly better recovery (p < 0.05) of left ventricular systolic function (maximum developed pressure, developed pressure at V10 [balloon volume to produce an end-diastolic pressure of 10 mm Hg during baseline measurement], positive maximum dP/dt, and dP/dt at V10), diastolic function (negative maximum dP/dt), coronary blood flow, and endothelial function assessed by the coronary vascular resistance response to acetylcholine. The L-nitro-arginine methyl ester hearts showed a significantly poorer recovery (p < 0.05) in left ventricular function, coronary blood flow, and endothelial function than the control group. These effects of L-nitro-arginine methyl ester were reversed to equal control values by adding a 3 mmol/L concentration of L-arginine to L-nitro-arginine methyl ester. There were no significant differences in the recovery of any variables between the D-arginine and control groups. These results point to an important salutary role for the endothelial production of nitric oxide in cardiac recovery after hypothermic ischemia in neonatal lamb hearts. The mechanism of these beneficial effects of L-arginine after ischemia and reperfusion is likely due to enhancement of the endothelial production of nitric oxide.