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REGIONAL ANESTHESIA AND PAIN MEDICINE

Is Comparative Cardiotoxicity of S(-) and R(+) Bupivacaine Related to Enantiomer-Selective Inhibition of L-Type Ca²⁺ Channels?

Gisele Zapata-Sudo, MD, PhD^*, Margarete M. Trachez, MD, PhD, Roberto T. Sudo, MD, PhD^*, and Thomas E. Nelson, PhD

*Departamento de Farmacologia Básica e Clinica, ICB, Universidade Federal do Rio de Janeiro; Departamento de Anestesiologia, Universidade Federal Fluminense, Rio de Janeiro, Brazil; and Department of Anesthesiology, Wake Forest University School of Medicine, Winston Salem, North Carolina

Address correspondence and reprint requests to Dr. Gisele Zapata-Sudo, Departamento de Farmacologia Básica e Clínica, Universidade Federal do Rio de Janeiro, Centro de Ciencias da Saude, Instituto de Ciencias Biomedicas, Bloco J, Sala 14, Rio de Janeiro, Brazil 21941-590. Address e-mail to gsudo{at}farmaco.ufrj.br

Cardiac toxicity can occur after accidental intravascular injection of bupivacaine. Racemic bupivacaine can inhibit both cardiac Na⁺ and Ca²⁺ 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 Ca²⁺ 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 10µM 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 2.5µM. 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 10µM 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.

Implications: Accidental intravascular injection of bupivacaine can induce toxic effects on the heart. We investigated the sensitivity of different bupivacaine structures’ actions on the Ca²⁺ conducting channels in rat ventricular cells and concluded that the increased toxicity of R(+) bupivacaine is not explained by actions on the Ca²⁺ channels’ inhibition.

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				S. N. Stehr, J. C. Ziegeler, A. Pexa, R. Oertel, A. Deussen, T. Koch, and M. Hubler The Effects of Lipid Infusion on Myocardial Function and Bioenergetics in l-Bupivacaine Toxicity in the Isolated Rat Heart Anesth. Analg., January 1, 2007; 104(1): 186 - 192. [Abstract] [Full Text] [PDF]

				N. G. B. Chedid, R. T. Sudo, M. I. S. Aguiar, M. M. Trachez, M. O. Masuda, and G. Zapata-Sudo Regulation of intracellular calcium by bupivacaine isomers in cardiac myocytes from wistar rats. Anesth. Analg., March 1, 2006; 102(3): 792 - 798. [Abstract] [Full Text] [PDF]

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999