Pflügers Archiv

, Volume 414, Issue 6, pp 690–700 | Cite as

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
  • S. Hering
  • T. Kleppisch
  • E. N. Timin
  • R. Bodewei
Excitable Tissues and Central Nervous Physiology

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.

Key words

Single neonatal ventricular heart cells Whole-cell patch clamp analysis 1,4-dihydropyridine action Calcium channel state transitions Nonmodulated receptor model 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bean BP (1984) Nitrendipine block of cardiac calcium channels: high affinity binding to the inactivated state. Proc Natl Acad Sci USA 81:6388–6392Google Scholar
  2. Bean BP (1985) Two kinds of calcium channels in canine atrial cells. J Gen Physiol 86:1–30Google Scholar
  3. Bechem M, Schramm M (1987) Calcium-agonists. J Mol Cell Cardiol 19 (Suppl II):63–75Google Scholar
  4. Brown AM, Kunze DL, Yatani A (1986) Dual effects of dihydropyridines on whole cell and unitary calcium currents in single ventricular cells of guinea-pig. J Physiol (Lond) 379:495–514Google Scholar
  5. Cavaliè A, Pelzer D, Trautwein W (1986) Fast and slow gating behaviour of single calcium channels in cardiac cells. Relation to activation and inactivation of calcium-channel current. Pflügers Arch 406:241–258Google Scholar
  6. Cohen NM, Lederer WJ (1987) Calcium current in isolated neonatal rat ventricular myocytes. J Physiol (Lond) 391:169–191Google Scholar
  7. Fenwick EM, Marty A, Neher E (1982) Sodium and calcium channels in bovine chromaffin cells. J Physiol (Lond) 331:599–635Google Scholar
  8. Glossmann H, Ferry DR, Goll A, Striessnig J, Zernig G (1985) Calcium channels and calcium channel drugs: recent biochemical and biophysical findings. Drugs Res 35:1917–1935Google Scholar
  9. Gurney AM, Nerbonne JM, Lester HA (1985) Photoinduced removal of nifedipine reveals mechanisms of calcium antagonist action on single heart cells. J Physiol 86:353–379Google Scholar
  10. Hagiwara S, Ohmori H (1983) Studies of single calcium channel currents in rat clonal pituitary cells. J Physio (Lond) 336:649–661Google Scholar
  11. Halle W, Wollenberger A (1970) Differentiation and behaviour of isolated embryonic and neonatal heart cells in a chemically defined medium. Am J Cardiol 25:292–299Google Scholar
  12. Halle W, Wollenberger A (1971) Myocardial and other muscle cell cultures. In: Schwartz A (ed) Methods in pharmacology, vol 1. Appleton Century Croft, New York, pp 191–246Google Scholar
  13. Hamill OP, Marty A, Neher E, Sakman B, Sigworth FJ (1981) Improved patch-clamp techniques for high resolution current recording from cells and cell free membrane patches. Pflügers Arch 391:85–100Google Scholar
  14. Hamilton SL, Yatani A, Brush K, Schwartz A, Brown AM (1987) A comparison between the binding and electrophysiological effects of dihydropyridines on cardiac membranes. Mol Pharmacol 31:221–231Google Scholar
  15. Hering S, Beech DJ, Bolton TB (1987a) A simple method of fast extracellular solution exchange for the study of whole-cell or single channel currents using patch-clamp technique. Pflügers Arch 410:335–337Google Scholar
  16. Hering S, Beech DJ, Bolton TB (1987b) Voltage dependence of the action of nifedipine and Bay K 8644 on barium currents recorded from single smooth muscle cells from the rabbit ear artery. Biomed Biochim Acta 8/9:657–661Google Scholar
  17. Hering S, Beech DJ, Bolton TB, Lim SP (1988) Action of nifedipine or Bay K 8644 is dependent on calcium channel state in single smooth muscle cells from rabbit ear artery. Pflügers Arch 411:590–592Google Scholar
  18. Hering S, Bolton TB, Beech DJ, Lim SP (1989) On the mechanism of calcium channel block by D600 in single smooth muscle cells from rabbit ear artery. Circ Res 64:928–936Google Scholar
  19. Hering S, Bodewei R, Wollenberger A (1983) Sodium current in freshly isolated and in cultured single rat myocardial cells: frequency and voltage-dependent block by mexiletine. J Mol Cell Cardiol 15:413–444Google Scholar
  20. Hess P, Lansman JB, Tsien RW (1984) Different modes of Ca channel gating behaviour favoured by dihydropyridine Ca agonists and antagonists. Nature 311:538–544Google Scholar
  21. Hess P, Lansman JB, Tsien RW (1985) Mechanism of calcium channel modulation by dihydropyridine agonists and antagonists. In: Fleckenstein A, van Breemen C, Gross R, Hoffmeister f (eds) Bayer-Symposium IX, Cardiovascular effects of dihydropyridine-type calcium antagonists and agonists. Springer, Berlin Heidelberg New York, pp 34–55Google Scholar
  22. Hille B (1977) Local anesthetics: hydrophilic and hydrophobic pathways for drug-receptor reaction. J Gen Physiol 69:497–515Google Scholar
  23. Hof PR, Ruegg UT, Hof A, Vogel A (1985) Stereoselectivity at the calcium channel: opposite action of enantiomers of a 1,4-dihydropyridine. J Cardiovasc Pharmacol 7:689–693Google Scholar
  24. Hondeghem LM, Katzung BG (1977) Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 472:373–398Google Scholar
  25. Janis RA, Triggle DJ (1984) 1,4-Dihydropyndine Ca2+ channel antagonists and activators: a comparison of binding characteristics with pharmacology. Drug Dev Res 4:257–274Google Scholar
  26. Kass RS (1987) Voltage-dependent modulation of cardiac calcium channel current by optical isomers of Bay K 8644: implications for channel gating. Circ Res 61 (Suppl I):11–15Google Scholar
  27. Kass RS, Krafte DS (197) Negative surface charge density near heart calcium channels. Relevance to block by dihydropyridines. J Gen Physiol 89:629–644Google Scholar
  28. Kokubun S, Prod'hum B, Becker C, Porzig H, Reuter H (1986) Studies on Ca channels in intact cardiac cells: voltage-dependent effects and cooperative interactions of dihydropyridine enantiomers. Mol Pharmacol 30:571–584Google Scholar
  29. Lee KS, Tsien RW (1983) Mechanism of calcium channel blockade by verapamil, D600, diltiazem and nitrendipine in single dialysed heart cells. Nature 302:790–794Google Scholar
  30. Lee KS, Marban E, Tsien RW (1985) Inactivation of calcium channels in mammalian heart cells: joint dependence on membrane potential and intracellular calcium. J Physiol (Lond) 364:395–411Google Scholar
  31. Lipp P, Mechmann S, Pott L (1987) Effects of calcium release from sarcoplasmic reticulum on membrane currents in guinea pig atrial cardioballs. Pflügers Arch 410:121–131Google Scholar
  32. Marquardt PW (1963) An algorithm for least-square estimation of non-linear parameters. J Soc Industr Appl Math 11:431–444Google Scholar
  33. Nilius B, Hess P, Lansman JB, Tsien RW (1985) A novel type of cardiac calcium channel in ventricular cells. Nature 316:443–446Google Scholar
  34. Reich JG, Wangermann G, Falck M, Rohde K (1972) A general strategy for parameter estimation from isosteric and allosterickinetic data and binding measurements. Eur J Biochem 26:368–379Google Scholar
  35. Sanguinetti MC, Kass RS (1984) Voltage-dependent block of calcium channel current in the calf cardiac Purkinje fiber by dihydropyridine calcium channel antagonists. Circ Res 55:336–348Google Scholar
  36. Sangjinetti MS, Krafte DS, Kass RS (1986) Voltage-dependent modulation of Ca channel current by Bay K 8644. J Gen Physiol 88:369–392Google Scholar
  37. Schwartz A, Grupp IL, Williams JS, Vaghy PL (1984) Effects of dihydropyridine calcium channel modulators in the heart: pharmacological and radioligand binding correlations. Biochem Biophys Res Commun 125:33387–33394Google Scholar
  38. Terada K, Nakao K, Okabe K, Kitamura K, Kuriyama H (1987) Action of the 1,4-dihydropyridine derivative, KW-3049, on the smooth muscle membrane of the rabbit mesenteric artery. Br J Pharmacol 92:615–625Google Scholar
  39. Triggle DJ, Skattebol A, Rampe D, Joslyn A, Gengo P (1986) Chemical pharmacology of Ca2+ channel ligands. In: Poste G, Crooke ST (eds) New insights into cell and membrane transport processes. Plenum Press, New York, pp 125–143Google Scholar
  40. Williams JS, Grupp IL, Grupp G, Vaghy PL, Dumont L, Schwartz A, Yatani A, Hamilton SL, Brown AM (1985) Profile of the oppositively acting enantiomers of the dihydropyridine 202 791 in cardiac preparations: receptor binding, electrophysiological and pharmacological studies. Biochem Biophys Res Commun 131:13–21Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • S. Hering
    • 1
  • T. Kleppisch
    • 1
  • E. N. Timin
    • 2
  • R. Bodewei
    • 1
  1. 1.Zentralinstitut für Herz-Kreislauf-ForschungAkademie der Wissenschaften der DDRBerlin-BuchDDR
  2. 2.A. V. Vishnevsky Institute of SurgeryAcademy of Medical Sciences of the USSRMoscowUSSR

Personalised recommendations