Stimulation‐dependent facilitation of the high threshold calcium current in guinea‐pig ventricular myocytes.

1. Stimulation‐dependent modulation of Ca currents was examined in guinea‐pig ventricular myocytes at room temperature. Whole‐cell recordings of Ca currents were made under conditions which minimized ionic fluxes through other channels. 2. Stimulation from rest at a rate of 2 Hz resulted in a decrease of the low threshold Ca current within one pulse and facilitation of the high threshold Ca current within five pulses. Facilitation was associated with a reduction in the rate of inactivation. 3. Pulse durations as short as 10 ms facilitated the high threshold Ca current in subsequent pulses. Facilitation produced by a single pulse decayed with a half‐time of several seconds. 4. Substitution of Ba2+ or Sr2+ for external Ca2+ reduced the rate of inactivation of the high threshold Ca current and abolished facilitation of the current. 5. Facilitation persisted with 40 microM‐Ruthenium Red added to the internal solution or 0.2‐2 microM‐ryanodine added to the bath solution to reduce Ca2+ release from the sarcoplasmic reticulum. 6. Facilitation was modulated by isoprenaline. Low concentrations of isoprenaline (5‐10 nM) increased the amount of facilitation. Isoprenaline (1 microM) increased the Ca current approximately 3‐fold, however, facilitation was nearly abolished. 7. Caffeine (0.5 and 1 mM) affected the Ca current and facilitation in a manner similar to 1 microM‐isoprenaline. It increased the Ca currents approximately 2.5‐fold and facilitation was not observed. 8. We conclude that stimulation‐dependent facilitation of the high threshold Ca current is mediated by calcium and hypothesize that calcium affects a site near the Ca channel that modifies the rate of inactivation. The common actions of caffeine and high concentrations of isoprenaline suggest that calcium modulates a phosphorylation step.