Effect of bupivacaine and levobupivacaine on exocytotic norepinephrine release from rat atria.
BACKGROUND
The cardiotoxic mechanism of local anesthetics may include interruption of cardiac sympathetic reflexes. The authors undertook this investigation to determine if clinically relevant concentrations of bupivacaine and levobupivacaine interfere with exocytotic norepinephrine release from cardiac sympathetic nerve endings.


METHODS
Rat atria were prepared for measurements of twitch contractile force and [H]-norepinephrine release. After nerve endings were loaded with [H]-norepinephrine, the tissue was electrically stimulated in 5-min episodes during 10 10-min sampling periods. After each period, a sample of bath fluid was analyzed for radioactivity and [H]-norepinephrine release was expressed as a fraction of tissue counts. Atria were exposed to buffer alone during sampling periods 1 and 2 (S1 and S2). Control atria received saline (100 microl each, n = 6 atria) in S3-S10. Experimental groups (n = 6 per group) received either bupivacaine or levobupivacaine at concentrations (in microM) of 5 (S3-S4), 10 (S5-S6), 30 (S7-S8), and 100 (S9-S10).


RESULTS
Bupivacaine and levobupivacaine decreased stimulation-evoked fractional [H]-norepinephrine release with inhibitory concentration 50% values of 5.1 +/- 0.5 and 6.1 +/- 1.3 microM. The inhibitory effect of both local anesthetics (approximately 70%) approached that of tetrodotoxin. Local anesthetics abolished the twitch contractions of atria with inhibitory concentration 50% values of 12.6 +/- 5.0 microM (bupivacaine) and 15.7 +/- 3.9 microM (levobupivacaine). In separate experiments, tetrodotoxin inhibited twitch contractile force by only 30%.


CONCLUSIONS
The results indicate that clinically relevant cardiotoxic concentrations of bupivacaine and levobupivacaine markedly depress cardiac sympathetic neurotransmission. A possible mechanism of local anesthetics in reducing evoked norepinephrine release from sympathetic endings is blockade of tetrodotoxin-sensitive fast sodium channels.
Joseph
Antony
A
Department of Anesthesiology, John H. Stroger, Jr. Hospital of Cook County, University of Illinois College of Medicine, Chicago, USA.
Montiague
Raul
R
Effendi
Ali R
AR
Urbanska
Renata A
RA
Vogel
Stephen
S
Winnie
Alon P
AP
Rabito
Sara F
SF
D000779:Anesthetics, Local / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005089:Exocytosis / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013779:Tetrodotoxin / Q000494:pharmacology
D000779:Anesthetics, Local; D013779:Tetrodotoxin; D009638:Norepinephrine; D002045:Bupivacaine