Perioperative Medicine  |   June 2018
In Vitro Negative Inotropic Effect of Low Concentrations of Bupivacaine Relates to Diminished Ca2+ Sensitivity but Not to Ca2+ Handling or β-Adrenoceptor Signaling
Author Notes
  • From the Department of Experimental Pharmacology and Toxicology (F. Flenner, M.N., F. Friedrich, T.C.) and Institute of Experimental Cardiovascular Research, Cardiovascular Research Center (S.S., V.N.), University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Pharmacology and Toxicology (N.A., U.R., T.C.) and Department of Anesthesiology and Intensive Care Medicine (N.A., T.K., S.N.S.), Medical Faculty Carl Gustav Carus, Dresden, Germany; Department of Anesthesiology and Intensive Care Medicine, University of Leipzig, Germany (S.N.S.); and the German Center for Cardiovascular Research, partner site Hamburg/Kiel/Lübeck, Germany (F. Flenner, S.S., F. Friedrich, V.N., T.C.). Current position: Institute for Experimental Cardiovascular Medicine, University Heart Center, Medical Center, and Faculty of Medicine, University of Freiburg, Freiburg, Germany (U.R.).
  • T.C. and S.N.S. contributed equally to this article.
    T.C. and S.N.S. contributed equally to this article.×
  • Submitted for publication August 14, 2017. Accepted for publication February 12, 2018.
    Submitted for publication August 14, 2017. Accepted for publication February 12, 2018.×
  • Address correspondence to Dr. Stehr: Department of Anesthesiology and Critical Care Medicine, University of Leipzig, Liebigstr. 20, 04103 Leipzig, Germany. sebastian.stehr@gmx.de. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Basic Science / Pharmacology
Perioperative Medicine   |   June 2018
In Vitro Negative Inotropic Effect of Low Concentrations of Bupivacaine Relates to Diminished Ca2+ Sensitivity but Not to Ca2+ Handling or β-Adrenoceptor Signaling
Anesthesiology 6 2018, Vol.128, 1175-1186. doi:10.1097/ALN.0000000000002180
Anesthesiology 6 2018, Vol.128, 1175-1186. doi:10.1097/ALN.0000000000002180
Abstract

Background: Systemic toxicity of local anesthetics is predominantly complicated by their myocardial toxicity. Especially long-acting local anesthetics exert a negative inotropic effect that has been described at lower concentrations than defined for blockade of myocardial ion channels. We evaluated the negative inotropic effect of bupivacaine at a concentration described for clinical toxicity testing the hypothesis that negative inotropy is a result of reduced Ca2+ sensitivity rather than blockade of ion channels.

Methods: We simultaneously measured force development and action potentials in guinea pig right papillary muscles (n = 5 to 7). L-type Ca2+ currents (n = 8 to 16) and Ca2+ transients (n = 10 to 11) were measured in isolated cardiomyocytes. Sensitivity of myofilaments to Ca2+ was assessed in skinned fibers (n = 10). Potential effects of bupivacaine on 3′,5′-cyclic adenosine monophosphate concentrations were measured using Förster Resonance Energy Transfer (n = 12 to 14) microscopy.

Results: Bupivacaine reduced force in a concentration-dependent manner from 173 ± 119 µN at baseline to 28 ± 13 µN at 300 µM (mean ± SD). At concentrations giving half-maximum negative inotropic effects (5 µM), the maximum upstroke velocity of action potentials, as a surrogate of sodium channel activity, was unaffected. Maximum positive inotropic effects of isoprenaline were also reduced to 50%. Neither basal nor isoprenaline-induced 3′,5′-cyclic adenosine monophosphate accumulation, L-type Ca2+ currents, or Ca2+ transients were affected by 5 µM bupivacaine, but this concentration significantly decreased Ca2+ sensitivity of myofilaments, changing the negative logarithm of the half-maximum effective Ca2+ concentrations from 5.66 to 5.56 –log[M].

Conclusions: We provide evidence that the negative inotropic effect of bupivacaine may be caused mainly by a reduction in myofilament sensitivity to Ca2+.