Biomaterial Database

Nitric oxide synthesis inhibition enhances bupivacaine cardiotoxicity. 1996

J E Heavner, and B Shi, and M Pitkänen

Department of Anesthesiology, Texas Tech University Health Sciences Center, Lubbock 79430, USA.

OBJECTIVE 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 omega-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 micrograms/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.

UI	MeSH Term	Description	Entries
D008297	Male		Males
D001921	Brain	The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.	Encephalon
D002045	Bupivacaine	A widely used local anesthetic agent.	1-Butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide,Bupivacain Janapharm,Bupivacain-RPR,Bupivacaina Braun,Bupivacaine Anhydrous,Bupivacaine Carbonate,Bupivacaine Hydrochloride,Bupivacaine Monohydrochloride, Monohydrate,Buvacaina,Carbostesin,Dolanaest,Marcain,Marcaine,Sensorcaine,Svedocain Sin Vasoconstr,Bupivacain RPR
D006321	Heart	The hollow, muscular organ that maintains the circulation of the blood.	Hearts
D006439	Hemodynamics	The movement and the forces involved in the movement of the blood through the CARDIOVASCULAR SYSTEM.	Hemodynamic
D000779	Anesthetics, Local	Drugs that block nerve conduction when applied locally to nerve tissue in appropriate concentrations. They act on any part of the nervous system and on every type of nerve fiber. In contact with a nerve trunk, these anesthetics can cause both sensory and motor paralysis in the innervated area. Their action is completely reversible. (From Gilman AG, et. al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed) Nearly all local anesthetics act by reducing the tendency of voltage-dependent sodium channels to activate.	Anesthetics, Conduction-Blocking,Conduction-Blocking Anesthetics,Local Anesthetic,Anesthetics, Topical,Anesthetic, Local,Anesthetics, Conduction Blocking,Conduction Blocking Anesthetics,Local Anesthetics,Topical Anesthetics
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001120	Arginine	An essential amino acid that is physiologically active in the L-form.	Arginine Hydrochloride,Arginine, L-Isomer,DL-Arginine Acetate, Monohydrate,L-Arginine,Arginine, L Isomer,DL Arginine Acetate, Monohydrate,Hydrochloride, Arginine,L Arginine,L-Isomer Arginine,Monohydrate DL-Arginine Acetate
D001145	Arrhythmias, Cardiac	Any disturbances of the normal rhythmic beating of the heart or MYOCARDIAL CONTRACTION. Cardiac arrhythmias can be classified by the abnormalities in HEART RATE, disorders of electrical impulse generation, or impulse conduction.	Arrhythmia,Arrythmia,Cardiac Arrhythmia,Cardiac Arrhythmias,Cardiac Dysrhythmia,Arrhythmia, Cardiac,Dysrhythmia, Cardiac
D017207	Rats, Sprague-Dawley	A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.	Holtzman Rat,Rats, Holtzman,Sprague-Dawley Rat,Rats, Sprague Dawley,Holtzman Rats,Rat, Holtzman,Rat, Sprague-Dawley,Sprague Dawley Rat,Sprague Dawley Rats,Sprague-Dawley Rats