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 activ ity, plasma clearance, and biotransformation are similarly affected by nitr ic oxide synthase (NOS) inhibition. Sprague-Dawley rats anesthetized with 7 0% N2O and 0.5% halothane mixed with O-2 were pretreated with saline (0.2 m L.kg(-1).min(-2) IV) or N-omega-nitro-L-arginine methyl ester (L-NAME; a co mpetitive inhibitor of NOS) (2 mg.kg(-1).min(-1) IV) for 30 min. The animal s were then given tetracaine (3 mg.kg(-1).min(-1) IV) or lidocaine (8 mg.kg (-1).min(-1) IV) until cardiac arrest (asystole). Doses of lidocaine or tet racaine 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 th at produced arrhythmias (greater than or equal to 2 degrees atrioventricula r 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 asyst ole were also smaller in animals with L-NAME pretreatment than those in sal ine-pretreated animals. L-NAME reduced the arrhythmia dose of tetracaine mo re than the arrhythmia dose of lidocaine (28 of 14 = 2.0 fold and 136 of 10 2 = 13-fold). The plasma concentration of lidocaine, but not tetracaine, wa s significantly higher at each sample time in L-NAME-pretreated animals tha n in saline-pretreated animals. Inhibition of NOS by L-NAME enhances the ca rdiotoxicity of lidocaine and tetracaine, with a greater effect on tetracai ne than on lidocaine. Altered drug clearance by L-NAME was insufficient to explain these findings because L-NAME pretreatment increased the plasma lev els of only lidocaine, not tetracaine. Implications: Inhibition of nitric o xide production in rats markedly enhances the cardiovascular toxicity of li docaine and tetracaine. Altered drug clearance by N-omega-nitro-L-arginine methyl ester was insufficient to explain these findings because N-omega-nit ro-L-arginine methyl ester pretreatment increased the plasma levels of only lidocaine, not tetracaine.