title: 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.
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 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.
authors.affiliation: Zentralinstitut für Herz-Kreislauf-Forschung, Akademie der Wissenschaften der DDR, Berlin-Buch.
authors.forename: S
authors.initials: S
authors.lastname: Hering
authors.forename: T
authors.initials: T
authors.lastname: Kleppisch
authors.forename: E N
authors.initials: EN
authors.lastname: Timin
authors.forename: R
authors.initials: R
authors.lastname: Bodewei
mesh_terms: D000818:Animals; D001464:Barium / Q000494:pharmacology; D017609:Barium Compounds; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D002478:Cells, Cultured; D002712:Chlorides; D004095:Dihydropyridines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
chemical_list: D017609:Barium Compounds; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002712:Chlorides; D004095:Dihydropyridines; C024986:barium chloride; D001464:Barium; C045796:SAN 202791