1. Effects of highly neurotoxic, inorganic lead ions (Pb2+) on voltage-dependent calcium channels were investigated with the use of the whole cell patch-clamp technique in bovine adrenal chromaffin cells maintained in short-term primary culture (1-5 days). 2. Extracellularly applied Pb2+ induced a concentration-dependent, reversible inhibition of Ca2+ currents, with an estimated IC50 approximately equal to 3.0 x 10(-7) M free Pb2+. 3. Elevation of the intracellular free Ca2+ concentration above 10(-8) M dose-dependently reduced the amplitude of the initial Ca2+ current and increased the exponential rate of current rundown. 4. Intracellularly applied Pb2+ prevented the Ca(2+)-dependent reduction of the initial Ca2+ current amplitude and altered the current rundown kinetics from exponential to linear. The effect was dose dependent and saturable, with an estimated EC50 approximately equal to 2.0 x 10(-10) M free Pb2+. 5. These results indicate that in contrast to extracellular blockade, intracellular Pb2+ promotes Ca2+ currents by attenuating the Ca(2+)-dependent, steady-state inactivation of calcium channels. This provides a novel mechanism through which Pb2+ may disrupt calcium signaling in chronically lead-exposed cells.