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This study was designed to compare the direct actions of bupivacaine and lidocaine on the isolated perfused guinea pig Langendorff heart preparation. Sixty min after mounting, either bupivacaine HCl (0.3 or 3 μg/ml) or lidocaine HCl (10 or 30 μg/ml) was added to the perfusate, and the effect (if any) was compared to untreated control values 30, 60, and 90 min later. Although the highest concentrations of both drugs invariably produced statistically significant reductions in heart rate, df/dt, coronary blood flow, and myocardial oxygen consumption (MV̇O2), these reductions were consistently greater after bupivacaine. Moreover, arrhythmias occurred in 6 of 12 preparations in those hearts exposed to 3 μg/ml of bupivacaine. Most often these arrhythmias consisted of heart block and bi-or trigeminy. Additional studies indicated that the reduction in coronary blood flow and MV̇O2 produced by 3 μg/ml of bupivacaine was a consequence of its direct negative inotropic and chronotropic action. Although the myocardial depression produced by bupivacaine and lidocaine could be reversed readily by substituting fresh perfusate, increasing the extracellular calcium concentration in stepwise increments did not augment the negative inotropic or chronotropic effect produced by 3 μg/ml of bupivacaine or 10 μg/ml of lidocaine. We conclude that 3 ng/ml of unbound bupivacaine is more cardiotoxic than 30 μg/ml of unbound lidocaine in this model.