Abstract
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 monoor 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.
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This work forms part of a dissertation by T. Kleppisch to be submitted to the Humboldt-Universität in partial fulfillment of the requirements for a doctoral degree in medicine. Present address: Physiologisches Institut der Humboldt-Universität, 1040 Berlin, DDR
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Hering, S., Kleppisch, T., Timin, E.N. et al. Characterization of the calcium channel state transitions induced by the enantiomers of the 1,4-dihydropyridine Sandoz 202 791 in neonatal rat heart cells. Pflugers Arch. 414, 690–700 (1989). https://doi.org/10.1007/BF00582137
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DOI: https://doi.org/10.1007/BF00582137