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.