Stereospecific effect of bupivacaine isomers on atrioventricular conduction in the isolated perfused guinea pig heart

Background: The local anesthetic bupivacaine is an equal mixture of two optically active isomers known to exert different cardiotoxic profiles in vivo. Enantiomer-specific forms of bupivacaine may have differential effects on cardiovascular function, specifically can cardiac electrophysiology. The authors' aim was to determine if there mere any direct functional differences in the cardiac effects of bupivacaine isomers. The isolated heart was used to avoid possible indirect cardiac effects of bupivacaine, such as autonomic nervous and hormonal influences, as well as preload and afterload factors. Methods: The hearts of 12 ketamine-anesthetized guinea pigs mere perfused with Krebs-Ringer's solution (97% oxygen, 3% carbon dioxide) at constant perfusion pressure using the Langendorff technique. Atrial and ventricular bipolar electrodes mere placed to measure heart rate (HR) and atrioventricular (AV) conduction time. Left ventricular pressure (LVP), coronary flow, and inflow and outflow oxygen tensions were also measured. Oxygen delivery, oxygen consumption (MVO(2)), and percentage of oxygen extraction were calculated. Each heart was perfused with increasing randomized concentrations (0.5, 1, 5, 10 mu M) of both isomers and the racemate of bupivacaine. Results: Racemic and isomeric bupivacaine equally and dose dependently decreased cardiac function. At 10 mu M bupivacaine these changes mere HR, -17 +/- 2%; LVP, -50 +/- 3%; coronary flow, -20 +/- 4%; and MVO(2), -46 +/- 4%. The (+) isomer significantly prolonged AV conduction compared with the racemate and the (-) isomer at all concentrations. At 10 mu M, AV time was 54 +/- 6% longer with the (+) isomer and 30 +/- 4% longer with the (+/-) racemate than with the (-) isomer. The greater delay in AV time with the (+) than the racemate or (-) isomer led to a second-degree AV dissociation In 10 of 12 of hearts treated with (+) bupivacaine. Conclusions: This study shows that bupivacaine has an enantiomer-specific effect to delay AV conduction and to produce second-degree API dissociation in the isolated perfused heart. This suggests that bupivacaine Isomers probably have differential effects on one or more ion-specific channels regulating AV conduction. Other measured direct cardiac effects of bupivacaine appear to be independent of the isomeric form.