Background and Objectives There is evidence that local anesthetic-induced seizures may be mediated by receptors for N-methyl-D-aspartate (NMDA) which activate production of nitric oxide (NO). The objective of this study was to determine the effects, if any, of inhibition of NO synthesis on the responses of the central nervous and cardiovascular systems to bupivacaine.

Methods Sprague-Dawley rats were assigned to two groups. The lightly anesthetized (0.5% halothane, 70% nitrous oxide) and paralyzed (doxacurium) animals were given N^ω-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, 2 mg/kg/min (n = 6) or saline (n = 5) intravenously for 30 minutes. Then bupivacaine was administered intravenously (2 mg/kg/min) to both groups of animals until asystole. Arterial blood samples for bupivacaine concentration analysis (by high-pressure liquid chromatography) were taken during the stabilization period and during local anesthetic infusion. Student's t-test was used to determine significant differences (P < .05) between groups.

Results Average doses of bupivacaine that produced arrhythmias and asystole were remarkably lower in L-NAME-treated than in saline-treated rats (arrhythmia, 5.1 ± 2.0 vs 15.8 ± 3.8 mg/kg; asystole, 15.9 ± 3.2 vs 27.8 ± 6.1 mg/kg; both P < .05). The doses producing seizures and isoelectric electroencephalograms and the duration of seizures did not differ significantly between the two treatment groups. However, electroencephalographic epileptiform activity was less intense (lower amplitude, shorter duration of ictal activity) in the L-NAME-treated animals. Arterial plasma concentrations of bupivacaine 5 minutes after the start of bupivacaine infusion were significantly higher in the L-NAME than in the saline group (22.3 ± 2.9 vs 12.8 ± 1.5 μg/mL, P < .05).

Conclusions These results suggest that NO synthase inhibition by L-NAME enhances the cardiac toxicity of bupivacaine, probably by a pharmacokinetic action, and reduces its central nervous system toxicity, probably by a pharmacodynamic action.