• Frederik Flenner, Nicole Arlt, Mahtab Nasib, Sophie Schobesberger, Thea Koch, Ursula Ravens, Felix Friedrich, Viacheslav Nikolaev, Torsten Christ, and Sebastian N Stehr.
• From the Department of Experimental Pharmacology and Toxicology (F. Flenner, M.N., F. Friedrich, T.C.) 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.) 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.) 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.).
• Anesthesiology. 2018 Jun 1; 128 (6): 1175-1186.

BackgroundSystemic 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 Ca sensitivity rather than blockade of ion channels.MethodsWe simultaneously measured force development and action potentials in guinea pig right papillary muscles (n = 5 to 7). L-type Ca currents (n = 8 to 16) and Ca transients (n = 10 to 11) were measured in isolated cardiomyocytes. Sensitivity of myofilaments to Ca 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.ResultsBupivacaine 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 Ca currents, or Ca transients were affected by 5 µM bupivacaine, but this concentration significantly decreased Ca sensitivity of myofilaments, changing the negative logarithm of the half-maximum effective Ca concentrations from 5.66 to 5.56 -log[M].ConclusionsWe provide evidence that the negative inotropic effect of bupivacaine may be caused mainly by a reduction in myofilament sensitivity to Ca.

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