EFFECTS OF L-ARGININE AND L-NITRO-ARGININE METHYL-ESTER ON RECOVERY OF NEONATAL LAMB HEARTS AFTER COLD ISCHEMIA - EVIDENCE FOR AN IMPORTANTROLE OF ENDOTHELIAL PRODUCTION OF NITRIC-OXIDE

Myocardial ischemia and reperfusion results in both ventricular and en dothelial dysfunction. We have found that the endothelial defect is a reduced vasodilator response to an intraarterial infusion of acetylcho line that is likely due to reduced nitric oxide release, and we have h ypothesized that reduced endothelial nitric oxide production contribut es to postischemic cardiac dysfunction. However, others report that ni tric oxide is deleterious after ischemia. We therefore examined the ef fects of infusions of L-arginine (3 mmol/L), a precursor of nitric oxi de, D-arginine (3 mmol/L), an inactive stereoisomer of L-arginine, L-n itro-arginine methyl ester (1 mmol/L); a competitive inhibitor of nitr ic oxide synthase, and L-nitro-arginine methyl ester (1 mmol/L) plus L -arginine (3 mmol/L) versus controls in isolated blood-perfused neonat al lamb hearts having 2 hours of cold cardioplegic ischemia. L-nitro-a rginine methyl ester was given before reperfusion, and L-arginine and D-arginine were infused for the first 20 minutes of postischemic reper fusion. At 30 minutes of reperfusion, by comparison with the control g roup, 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-diastoli c 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 coronar y 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 fun ction than the control group. These effects of L-nitro-arginine methyl ester were reversed to equal control values by adding a 3 mmol/L conc entration of L-arginine to L-nitro-arginine methyl ester. There were n o significant differences in the recovery of any variables between the D-arginine and control groups. These results point to an important sa lutary role for the endothelial production of nitric oxide in cardiac recovery after hypothermic ischemia in neonatal lamb hearts. The mecha nism of these beneficial effects of L-arginine after ischemia and repe rfusion is likely due to enhancement of the endothelial production of nitric oxide.