Nitric oxide synthesis inhibition modifies the cardiotoxicity of tetracaine and lidocaine.
Suppression of nitric oxide (NO) production alters the toxicity of cocaine and bupivacaine. We undertook this study to determine whether the systemic toxicity of two other local anesthetics that differ in antiarrhythmic activity, plasma clearance, and biotransformation are similarly affected by nitric oxide synthase (NOS) inhibition. Sprague-Dawley rats anesthetized with 70% N2O and 0.5% halothane mixed with O2 were pretreated with saline (0.2 mL x kg(-1) x min(-1) i.v.) or N(omega)-nitro-L-arginine methyl ester (L-NAME; a competitive inhibitor of NOS) (2 mg x kg(-1) x min(-1) i.v.) for 30 min. The animals were then given tetracaine (3 mg x kg(-1) x min(-1) i.v.) or lidocaine (8 mg x kg(-1) x min(-1) i.v.) until cardiac arrest (asystole). Doses of lidocaine or tetracaine that produced arrhythmias, seizures, isoelectric encephalogram, and asystole were determined. Hemodynamic recordings were performed throughout the experiments, and plasma was collected to measure the concentration of lidocaine or tetracaine. L-NAME decreased tetracaine and lidocaine doses that produced arrhythmias (> or = 2 degrees atrioventricular conduction block) (tetracaine 14 +/- 2 mg/kg; lidocaine 102 +/- 9 mg/kg) versus saline treatment (tetracaine 28 +/- 2 mg/kg; lidocaine 136 +/- 9 mg/kg; P < 0.05). The tetracaine and lidocaine doses required to produce asystole were also smaller in animals with L-NAME pretreatment than those in saline-pretreated animals. L-NAME reduced the arrhythmia dose of tetracaine more than the arrhythmia dose of lidocaine (28 of 14 = 2.0 fold and 136 of 102 = 1.3-fold). The plasma concentration of lidocaine, but not tetracaine, was significantly higher at each sample time in L-NAME-pretreated animals than in saline-pretreated animals. Inhibition of NOS by L-NAME enhances the cardiotoxicity of lidocaine and tetracaine, with a greater effect on tetracaine than on lidocaine. Altered drug clearance by L-NAME was insufficient to explain these findings because L-NAME pretreatment increased the plasma levels of only lidocaine, not tetracaine.


CONCLUSIONS
Inhibition of nitric oxide production in rats markedly enhances the cardiovascular toxicity of lidocaine and tetracaine. Altered drug clearance by N(omega)-nitro-L-arginine methyl ester was insufficient to explain these findings because N(omega)-nitro-L-arginine methyl ester pretreatment increased the plasma levels of only lidocaine, not tetracaine.
Heavner
J E
JE
Department of Anesthesiology, Texas Tech University Health Sciences Center, Lubbock 79430, USA. anejeh@ttuhsc.edu
Shi
B
B
Pitkänen
M
M
D000779:Anesthetics, Local / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D001784:Blood Gas Analysis; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006331:Heart Diseases / Q000139:chemically induced*; D006439:Hemodynamics; D008012:Lidocaine / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013748:Tetracaine / Q000493:pharmacokinetics / Q000633:toxicity*
D000779:Anesthetics, Local; D004791:Enzyme Inhibitors; D013748:Tetracaine; D008012:Lidocaine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester