Is comparative cardiotoxicity of S(-) and R(+) bupivacaine related to enantiomer-selective inhibition of L-type Ca(2+) channels?
Cardiac toxicity can occur after accidental intravascular injection of bupivacaine. Racemic bupivacaine can inhibit both cardiac Na(+) and Ca(2+) channels, but the contribution of these actions to cardiac depression is not totally understood. We tested whether the effect of R(+) bupivacaine on cardiac electrical activity in isolated hearts and on L-type Ca(2+) channels (I(Ca-L)) in isolated cardiac myocytes could be responsible for its increased cardiotoxicity compared with S(-) bupivacaine. Cardiac electrical activity of spontaneously beating isolated hearts was recorded before and after exposure to increasing concentrations of R(+) and S(-) bupivacaine. An increase of the PR interval (80%) and the QRS duration (370%) by 10microM R(+) bupivacaine (80% and 370%) was significantly higher than for S(-) bupivacaine (25% and 200%, respectively). R(+) but not S(-) bupivacaine produced severe arrhythmias at concentrations larger than 2.5microM. The intensity of I(Ca-L) inhibition did not differ between bupivacaine isomers. At 0 mV, I(Ca-L) was irreversibly reduced by 40.2% +/- 8.8% and 51.4% +/- 3.8% in the presence of 10microM R(+) and S(-) bupivacaine, respectively. The arrhythmogenic effect of R(+) bupivacaine could not be explained by stereoselectivity on the I(Ca-L) inhibition. Thus, other mechanisms could contribute to the cardiac electrical and contractile dysfunction induced by R(+) bupivacaine.
Zapata-Sudo
G
G
Departamento de Farmacologia Básica e Clinica, ICB, Universidade Federal do Rio de Janeiro, Brazil. gsudo@farmaco.ufrj.br
Trachez
M M
MM
Sudo
R T
RT
Nelson
T E
TE
D000779:Anesthetics, Local / Q000633:toxicity*; D000818:Animals; D002045:Bupivacaine / Q000633:toxicity*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000187:drug effects; D013237:Stereoisomerism
D000779:Anesthetics, Local; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D015222:Sodium Channels; D002045:Bupivacaine