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The effects of bupivacaine and lidocaine on cardiac conduction were compared in guinea pig ventricular muscle. Membrane potential was controlled using a single sucrose gap voltage clamp technique, and the maximum upstroke velocity of the action potential (Vmax) was used as an indicator of peak sodium current. Bupivacaine blocked cardiac sodium channels in a time- and voltage-dependent fashion. Although bupivacaine has a low affinity for rested and activated sodium channels, it avidly blocks inactivated channels (K4 = 9 X 10−7 M). Bupivacaine-associated channels do not conduct and have their voltage dependence of inactivation shifted by about 33 m V to more negative potentials. At bupivacaine concentrations above 0.2 μg/ml, a substantial fraction of the channels become blocked during the cardiac action potential, while recovery from block during diastole proceeds relatively slowly with a time constant (r) of 1,557 ± 304 ms (n = 8). Thus, bupivacaine blocks sodium channels in a fast-in-slow-out fashion, and substantial block accumulates at 60–150 beats/min. In comparison, 5–10 μg/ml lidocaine also blocks a substantial fraction of channels during the action potential, but diastolic recovery from block is more rapid (r = 153.8 ± 51.2 ms, n = 4). Thus, lidocaine blocks channels in a fast-in-fast-out fashion. Consequently, even at toxic doses of lidocaine (i.e., 10 μg/ml), little accumulation of block occurs at normal heart rates. Sodium channel block by bupivacaine can be minimized by reducing heart rate, hyperpolarization, and shortening of action potential duration. However, alteration of these variables over clinically applicable ranges does not produce marked changes in bupivacaine effect. Our results provide a possible explanation for the clinical observation that when bupivacaine accidently gains access to the general circulation, cardiac conduction can be depressed seriously and such depression may be difficult to reverse.