ENDOGENOUS NITRIC-OXIDE (NO) PROTECTS AGAINST ISCHEMIA-REPERFUSION INJURY IN THE RABBIT

Objectives: Recent studies suggest that nitric oxide (NO) is deleterio us in models of shock and hypoxia-reoxygenation However, the role of e ndogenous NO in ischaemia-reperfusion injury in vivo remains controver sial. We tested the hypothesis that blockade of endogenous NO produced during myocardial ischaemia-reperfusion or during reperfusion alone i n vivo increases infarct size after coronary occlusion in the rabbit, and conversely, supplementation with L-arginine would reduce infarct s ize. Methods: Ketamine-xylazine anaesthetised New Zealand white rabbit s were subjected to left coronary artery occlusion for 30 min and repe rfusion for 120 min. The rabbits were divided into five groups: (1) sa line (VEH); (2) L-nitro arginine (L-NA), a NO-synthase inhibitor, was infused intravenously (15 mg/kg bolus followed by 7.5 mg/kg h(-1)) bef ore coronary occlusion to block NO synthase activity during ischaemia and reperfusion (IR); (3) L-NA was administered during reperfusion onl y (R) at the same dose as in the IR group; (4) D-arginine (D-ARG) (25 mg/kg bolus followed by 4 mg/kg min(-1)), the non-metabolised enantiom er of L-arginine was infused intravenously during reperfusion only; (5 ) L-arginine (L-ARG) (25 mg/kg bolus followed by 4 mg/kg min(-1)), the physiological precursor of NO, was infused intravenously during reper fusion only. Results: L-NA infusion in the IR and R groups caused an i ncrease in mean arterial pressure and a decrease in heart rate; howeve r, no significant change in pressure rate product (PRP) occurred immed iately after drug infusion. PRP did not change significantly during th e experiment across groups except at the end of reperfusion. The area at risk was comparable in all groups, averaging 29(1)%. The infarct si ze (triphenyltetrazolium chloride) expressed as a percent of area at r isk was 27(2)% for the untreated vehicle group. In contrast, L-NA sign ificantly (P < 0.05) increased infarct size in the IR group, 51(2)%; t his augmented infarct size persisted when NO synthase activity was blo cked during reperfusion only in the R group, 50(2)%. There was no sign ificant (P < 0.05) difference in infarct size between the IR and the R groups. D-ARG-treated group showed a comparable increase in infarct s ize 48(2)% versus the IR and R groups. However, supplementation of NO with L-arginine (L-ARG) showed no reduction in infarct size, 24(3)%, o ver vehicle group (VEH). Conclusions: We conclude that (1) blockade of NO synthase activity with L-NA increases infarct size, (2) this effec t was expressed primarily during reperfusion, (3) D-arginine mimicked the infarct augmentation of L-NA, while (4) L-arginine supplementation did not reduce infarct size. These data imply that endogenous NO prod uction exerts a tonic cardioprotective effect on myocardial infarct fo llowing coronary reperfusion.