Bupivacaine is more cardiotoxic than lidocaine and can produce fatal arrhythmias during accidental overdose or intravascular injection. Studies using Vmax in adult guinea pig myocytes suggest that this toxicity is due to the greater inhibition of sodium current by bupivacaine. Human neonates and cardiac tissue from neonatal animals show resistance to the cardiac effects of many local anesthetic and antiarrhythmic drugs, and a slower onset of use-dependent block. We used whole-cell patch clamp (20 degrees C, [Na]o = 50 mmol/L) to examine directly the kinetics of sodium current block by bupivacaine and lidocaine in ventricular myocytes from 1- to 2-day-old rats. We found that 1 microgram/mL bupivacaine and 5 micrograms/mL lidocaine produced equivalent amounts of use-dependent block for protocols corresponding to 30-200 depolarizations per minute (cell resting potential of -85 mV). Block due to bupivacaine surpassed that from lidocaine (37.6% +/- 3.4% vs 26.4% +/- 2.7%) (P < 0.01) only after the resting membrane potential was hyperpolarized to -110 mV and the length of depolarization and repolarization were increased to nonphysiologic durations (1 s and 0.5 s, respectively). Double-pulse protocols were used to measure the underlying rate of onset and recovery from block. At these concentrations, blockade development was more than seven times slower for bupivacaine (4.11 +/- 0.32 s vs 0.57 +/- 0.06 s) (P < 0.01, and recovery from block was five times slower (10.81 +/- 0.54 s vs 2.14 +/- 0.50 s) (P < 0.01). In these neonatal myocytes, bupivacaine does not produce more use-dependent block than lidocaine, and the effect of bupivacaine is limited by its slow binding to the sodium channel.