Comparative effect of lidocaine, bupivacaine and RAC 109 on myocardial conduction and contractility in the rabbit

Local anesthetic toxicity includes a decrease in ventricular conduction velocity and a decrease in myocardial contractile force. We tested the hypothesis that, like conduction, contraction was stereoselectively impaired by bupivacaine. We compared R(+) and S(−) bupivacaine to S(+) and R(−) RAC 109 in order to study the effects of hydrophobicity and ionization. We measured the changes in QRS duration and developed pressure in isolated perfused rabbit hearts. Binding of bupivacaine and RAC 109 to the ryanodine receptor was measured. The effect on cell shortening and relenghtening was measured on isolated rabbit cardiomyocytes. A mixed-effect pharmacodynamic model was used. The decrease in conduction velocity induced by the molecules was markedly stereospecific. All local anesthetics decreased ventricular velocity in a stereospecific manner with a RAC I(+)/II(−) and bupivacaine R(+)/S(−) potency ratio of maximum effect of 1.7 and 2.25 respectively. Contractility decreased in a dose dependent manner but this negative inotropic effect was not stereospecific with a C50 (concentration leading to half maximum effect) of 30 and 23 μM for RAC and bupivacaine respectively. The two drugs exhibited two-site binding to ryanodyne that may partly explain the observed effect. An effect on relaxation was observed only at very high concentrations. In conclusion, bupivacaine, a long acting local anesthetic, decreases ventricular conduction in a stereospecific manner, and decreases contractility non-stereospecifically.