Modification of bupivacaine toxicity by nonselective versus neuronal nitric oxide synthesis inhibition

We have previously shown that pretreatment of rats with a nonselective nitric oxide synthase (NOS) inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), enhances the cardiovascular system (CVS) toxicity and reduces the central nervous system (CNS) toxicity of local anesthetics. This study was performed to differentiate the neuronal from the endothelial effects of L-NAME on the CNS and CVS toxicity of bupivacaine by comparing the effects of L-NAME with a neuronal selective NOS inhibitor, 7-nitroindazole (7-NI). Lightly anesthetized rats were premedicated for 30 min with L-NAME (2 mg . kg(-1). min(-1) intravenously [IV]), 7-NI (30 mg/kg intraperitoneally), or saline (control) then bupivacaine (2 mg kg-l min-l) was infused IV until asystole occurred. Bupivacaine doses required to produce seizures were the same among groups (saline = 10.1 +/- 2.6 mg/kg; L-NAME = 9.0 +/- 1.2 mg/kg; 7-NI = 10.2 +/- 1.0 mg/kg). However, plasma bupivacaine concentration (mu g/mL) at seizure onset was significantly higher in animals preheated with L-NAME (16.4 +/- 2.1) and, to a lesser degree, 7-NI (11.6 +/- 1.3) than that of control (9.7 +/- 1.6). Seizure duration and the number of epileptiform bursts were significantly reduced in L-NAME versus the other two groups. Doses for arrhythmias and asystole as well as plasma bupivacaine concentrations at arrhythmia onset were dramatically smaller in L-NAME-pretreated rats than in the other two groups. In summary, endothelial NOS inhibition dramatically alters both the CVS and CNS toxicity of bupivacaine with neuronal NOS inhibition playing a minor role.