Motor nerve blockade potency and toxicity of non-racemic bupivacaine in rats.
BACKGROUND
Racemic [RS(+/-)] bupivacaine can be associated with severe cardiotoxicity. The S(-) isomer is known to be less neuro- and cardiotoxic, but demonstrates a lower potency to block motor activity than RS(+/-) bupivacaine. Thus, the potency and toxicity of a non-racemic bupivacaine mixture were studied.


METHODS
Gastrocnemic muscle twitches induced by electrical stimulation of sciatic nerves in rats were used to compare the impact by bupivacaine solutions on motor activity. Field stimulation at 1 Hz eliciting ventricular muscle twitches was used to investigate the effects on cardiac contractility. The lethal dose of each local anesthetic agent was determined following drug infusions during general anesthesia in mechanically ventilated rats.


RESULTS
Non-racemic (75S:25R) bupivacaine was more potent (P<0.05) than S(-) or R(+) enantiomers to block motor nerve activity. The concentrations of RS(+/-), 75S:25R, R(+) and S(-) bupivacaine to inhibit nerve conduction by 50% were 0.84 (0.37- 2.20), 0.84 (0.47-2.48), 2.68 (0.98-3.42) and 2.11 mM (1.5-4.03), respectively. Pronounced reductions in ventricular muscle twitches were observed with RS(+/-) and R(+) bupivacaine at low concentrations (0.5-4 microM). Lethal doses for 75S:25R (39.9 mg kg(-1)), and S(-) (34.7 mg kg(-1)) were higher (P<0.05) than for R(+) (16.2 mg kg(-1)) and RS(+/-) bupivacaine (18.4 mg kg(-1)), respectively.


CONCLUSIONS
The potency of S(-) bupivacaine to block the motor activity in the sciatic nerve was enhanced when 25% of the S(-) isomer was replaced by the antipode R(+) bupivacaine. This effect was not associated with increased toxicity.
Trachez
M M
MM
Universidade Federal Fluminense, Rio de Janeiro, Brazil.
Zapata-Sudo
G
G
Moreira
O R
OR
Chedid
N G B
NG
Russo
V F T
VF
Russo
E M S
EM
Sudo
R T
RT
D000779:Anesthetics, Local / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D002045:Bupivacaine / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D007928:Lethal Dose 50; D009046:Motor Neurons / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000294:innervation; D009407:Nerve Block; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism
D000779:Anesthetics, Local; D002045:Bupivacaine