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) x min(-1) intravenously [I.V.]), 7-NI (30 mg/kg intraperitoneally), or saline (control) then bupivacaine (2 mg x kg(-1) x min(-1)) was infused I.V. 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 (microg/mL) at seizure onset was significantly higher in animals pretreated 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.
Shi
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Department of Anesthesiology, Texas Tech University Health Sciences Center, Lubbock 79430, USA.
Heavner
J E
JE
D000779:Anesthetics, Local / Q000633:toxicity*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001921:Brain / Q000187:drug effects; D002045:Bupivacaine / Q000097:blood / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009474:Neurons / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D000779:Anesthetics, Local; D004791:Enzyme Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D002045:Bupivacaine