Modulation of slow gating process of calcium channels by isoprenaline in guinea-pig ventricular cells.

1. The mechanism of enhancement of Ca2+ current by isoprenaline was studied by recording single-channel activity from cell-attached patches on isolated guinea-pig ventricular cells using patch pipettes containing 50 or 100 mM-Ba2+. 2. Isoprenaline (100 nM) increased the amplitude of ensemble average currents by increasing the rate of non-blank sweeps (availability). The current decay during 400 ms steps was significantly slowed by isoprenaline. However, the open probability for the non-blank sweeps elicited by 100 ms steps was only slightly increased by the application of isoprenaline. 3. The durations of the available state (TS) and the unavailable state (TF) were estimated by the number of non-blank and blank sweeps per run, respectively, applying repetitively 100 ms steps at 2 Hz. 4. At large negative holding potentials the distribution of TS was well fitted by an exponential curve, whose time constant was increased from 1.6 to 3.1 sweeps by 100 nM-isoprenaline, while TF distributed approximately single exponentially with a time constant of 2.0 sweeps in control and 1.3 sweeps in the presence of the drug. 5. At depolarized holding potentials a slow voltage-dependent component appeared in the histogram of TF and its time constant was markedly decreased by 100 nM-isoprenaline. 6. The availability-voltage relationship was simulated by the Boltzmann equation with a maximal value of 0.4 in the control. The maximal value was increased to 0.7 and the curve was shifted to a depolarizing direction by 7 mV by 100 nM-isoprenaline. 7. Isoprenaline increased the availability of cardiac Ca2+ channels by increasing the forward rate constant and decreasing the backward rate constant in both voltage-dependent and independent slow state transitions.