Characterization of the calcium channel state transitions induced by the enantiomers of the 1,4-dihydropyridine Sandoz 202 791 in neonatal rat heart cells. A nonmodulated receptor model.

The actions of the optical enantiomers of Sandoz 202 791 were studied in barium inward currents recorded from single cultured neonatal rat ventricular heart cells, using the whole-cell configuration of the patch clamp technique. The enantiomers were applied by bath perfusion or rapidly by the technique of concentration jumps during single voltage clamp steps. (1) (-)-202 791 reduced the barium current in response to depolarizations positive to 0 mV. The peak current amplitude in the threshold range (-40 to 0 mV) was either not affected or slightly increased by the substance. (2) The agonist enantiomer (+)-202 791 increased the inward current over the whole voltage range, where the increase in peak inward current amplitude was most prominent in the voltage range from -40 mV to 0 mV. (3) The antagonist enantiomer (10(-6) M) induced a 18.2 +/- 2.1 mV (n = 6) shift of the midpoint of the steady state inactivation curve in the hyperpolarizing direction; in contrast (+)-202 791 at the same concentration did cause only a small but not significant shift of the Ca-channel availability curve (n = 5). (4) Rapid extracellular application of (-)-202 791 (10(-6) M), during the sustained current component at a test potential of 0 mV was followed by a sudden acceleration in barium current decay. The drug-induced barium current block developed with a mean time constant of 214.7 +/- 20.6 ms (n = 5). (5) (+)-202 791 (10(-6) M) rapidly applied during test pulses to 0 and -20 mV caused an increase in barium current with a mono- or biexponential time course. The estimated mean time constant of the drug activated Ba2+ current at 0 mV membrane potential was 617.3 +/- 49.3 ms (n = 4). (6) The interaction of Sandoz 202 791 with the Ca-channels is discussed in terms of a "nonmodulated receptor" model.