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A Proposed Pharmacological Role for Dihydropyridine Binding Sites in Heart and Coronary Smooth Muscle

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Cardiovascular Effects of Dihydropyridine-Type Calcium Antagonists and Agonists

Part of the book series: Bayer-Symposium ((BAYER-SYMP,volume 9))

Abstract

The recent discovery of the dihydropyridine derivatives Bay k 8644 [55, 56, 62] YC-170 [61] and CGP 28392 [14, 68] together with the well-known nifedipine-like drugs have provided an avenue for a classification of dihydropyridines (DHPs) into two separate groups (Table 1). The members of the first group are termed “Ca2+ antagonists” or “Ca2+ channel inhibitors.” These drugs inhibit voltage-dependent Ca2+ influx both in smooth and cardiac muscle. This results in vasodilation in the former and negative inotropy in the latter [38, 58]. The second group of compounds activate Ca2+ channels, producing vasoconstriction and positive inotropy, i. e., effects which are opposite to those produced by the “Ca2+ antagonists” [55, 56, 61-63, 68]. These drugs have been termed “Ca2+ agonists” or “Ca2+ channel activators” [35, 55, 56, 65].

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References

  1. Bellemann P (1984) Binding properties of a novel calcium channel activating dihydropyridine in monolayer cultures of beating myocytes. FEBS LETT 167:88–92.

    Article  PubMed  CAS  Google Scholar 

  2. Bellemann P, Ferry D, Lubbecke F, Glossman H (1981) [3H]-Nitrendipine, a potent calcium antagonist, binds with high affinity to cardiac membranes. Arzneim. Forsch Drug Res 31:2064–2067.

    CAS  Google Scholar 

  3. Bolger GT, Gengo P, Klockowski R, Luchowski E, Siegel H, Janis RA, Triggle AM, Triggle DJ (1983) Characterization of binding of the Ca++ channel antagonist, [3H]-nitrendipine, to guinea-pig ileal smooth muscle. J Pharmacol Exp Ther 225:291–309.

    PubMed  CAS  Google Scholar 

  4. Bristow MR, Ginsburg R, Laser JA, McAuley BJ, Minobe W (1984) Tissue response selectivity of calcium antagonists is not due to heterogeneity of [3H]-nitrendipine binding sites. Br J Pharmacol 82:309–320.

    PubMed  CAS  Google Scholar 

  5. Brown AM, Kunze DL, Yatani A (1984) The agonist effect of dihydropyridine on Ca channels. Nature 311:570–572.

    Article  PubMed  CAS  Google Scholar 

  6. DeLean A, Munson PJ, Rodbard D (1978) Simultaneous analysis of families of sigmoidal curves: Application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol 235:E97–E102.

    PubMed  CAS  Google Scholar 

  7. DeLean A, Munson PJ, Rodbard D (1979) Multi-subsite receptors for multivalent ligands. Application to drugs, hormones, and neurotransmitters. Molec Pharmacol 15:60–70.

    CAS  Google Scholar 

  8. DePover A, Matlib MA, Lee SW, Dube GP, Grupp IL, Grupp G, Schwartz A (1982) Specific binding of [3H]-nitrendipine to membranes from coronary arteries and heart in relation to pharmacological effects. Paradoxical stimulation by diltiazem. Biochem Biophys Res Commun 108:110–117.

    Article  PubMed  CAS  Google Scholar 

  9. DePover A, Grupp IL, Grupp G, Schwartz A (1983) Diltiazem potentiates the negative inotropic action of nimodipine in heart. Biochem Biophys Res Commun 114:922–929.

    Article  PubMed  CAS  Google Scholar 

  10. DePover A, Lee SW, Matlib MA, Withmer K, Davis BA, Powell T, Schwartz A (1983) [3H]-Nimodipine specific binding to cardiac myocytes and subcellular fractions. Biochem Biophys Res Commun 113:185–191.

    Article  PubMed  CAS  Google Scholar 

  11. Dube GP, Baik YH, Schwartz A (1985) Effects of a novel calcium channel agonist dihydropyridine analogue, Bay k 8644, on pig coronary artery: Biphasic mechanical response and paradoxical potentiation of contraction by diltiazem and by nimodipine. J Cardiovasc Pharmacol 7:377–389.

    Article  PubMed  CAS  Google Scholar 

  12. Ehlert FH, Itoga E, Roeske WR, Yamamura HI (1982) The interaction of [3H]-nitrendipine with receptors for calcium antagonists in the cerebral cortex and heart of rats. Biochem. Biophys Res Commun 104:937–943.

    Article  PubMed  CAS  Google Scholar 

  13. Ehlert FJ, Roeske WR, Itoga E, Yamamura HI (1982) The binding of 3H]-nitrendipine to receptors for calcium channel antagonists in the heart, cerebral cortex and ileum of rat. Life Sci 30:2191–2202.

    Article  PubMed  CAS  Google Scholar 

  14. Erne P, Burgisser E, Buhler FR, Dubach B, Kuhnis H, Meier M, Rogg H (1984) Enhancement of calcium influx in human platelets by CGP 28392, a novel dihydropyridine. Biochem Biophys Res Commun 118:842–847.

    Article  PubMed  CAS  Google Scholar 

  15. Ferry DR, Glossmann H (1982) Evidence for multiple receptor sites within the putative calcium channel. N.S. Arch Pharmacol 321:80–83.

    Article  CAS  Google Scholar 

  16. Ferry DR, Goll A, Glossmann H (1983) Differential labelling of putative skeletal muscle calcium channels by [3H]-nifedipine, [3H]-nitrendipine, [3H]-nimodipine and [3H]-PN 200 110. N.S. Arch Pharmacol 323:276–277.

    Article  CAS  Google Scholar 

  17. Fosset M, Jaimovich E, Delpont E, Lazdunski M (1983) [3H]Nitrendipine labelling of the Ca2+ channel in skeletal muscle. Eur J Pharmacol 86:141–142.

    Article  Google Scholar 

  18. Glossmann H, Ferry DR, Lubbecke F, Mewes R, Hofmann F (1982) Calcium channels: Direct identification with radioligand binding studies. Trends in Pharmacol Sci 3:431–437.

    Article  CAS  Google Scholar 

  19. Glossmann H, Ferry DR (1983) Molecular approach to the calcium channel. Drug Develop Evaluation 9:63–98.

    CAS  Google Scholar 

  20. Glossmann H, Ferry DR, Goll A, Rombusch M (1984) Molecular pharmacology of the calcium channel. J Cardiovasc Pharmacol 6:S608–S621.

    Article  PubMed  Google Scholar 

  21. Grant AO, Starmer CF, Strauss HC (1984) Antiarrhythmic drug action. Blockade of the inward sodium current. Circ Res 55:427–439.

    PubMed  CAS  Google Scholar 

  22. Grupp IL, Dube GP, Baik YH, Lathrop D, Grupp G, Schwartz A (1984) Effects of dihydropyridine Ca++ agonist Bay k 8644 on porcine coronary artery, isolated rat hearts and canine Purkinje and trabecular action potentials. Fed Proc 43:937.

    Google Scholar 

  23. Grupp IL, Grupp G (1984) Isolated heart preparations perfused or superfused with balanced salt solution. In: Schwartz A (ed) Methods in pharmacology, vol 5. Plenum Press, New York, pp 111–128.

    Google Scholar 

  24. Hess P, Lansman JB, Tsien RW (1984) Different models of Ca channel gating behaviour favoured by dihydropyridine Ca agonists and antagonists. Nature 311:538–544.

    Article  PubMed  CAS  Google Scholar 

  25. Hille B (1977) Local anesthetics: Hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol 69:497–515.

    Article  PubMed  CAS  Google Scholar 

  26. Hille B (1978) Local anesthetic action on inactivation of the Na channel in nerve and skeletal muscle: Possible mechanisms for antiarrhythmic agents. In Morad M (ed) Biophysical aspects of cardiac muscle. Academic Press, New York, pp 55–74.

    Google Scholar 

  27. Hille B (1984) Ionic channels of excitable membranes. Sinauer publishers, MA.

    Google Scholar 

  28. Himori N, Ono H, Taira N (1975) Dual effects of a new coronary vasodilator, diltiazem on the contractile force of the blood-perfused papillary muscle of the dog. Japan J Pharmacol 25:350–352.

    Article  CAS  Google Scholar 

  29. Himori N, Ono M, Taira N (1976) Simultaneous assessment of effects of coronary vasodilators on the coronary blood flow and the myocardial contractility by using the blood perfused canine papillary muscle. Japan J Pharmacol 26:427–435.

    Article  CAS  Google Scholar 

  30. Hondeghem LM, Katzung BG (1977) Time-and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochem Biopyhs Acta 472:373–398.

    CAS  Google Scholar 

  31. Hondeghem LM, Katzung BG (1984) Antiarrhythmic agents: The modulated receptor mechanism of sodium and calcium channel-blocking drugs. Ann Rev Pharmacol Toxicol 24:387–423.

    Article  CAS  Google Scholar 

  32. Janis RA, Scriabine A (1983) Sites of action of Ca2+ channel inhibitors. Biochem Pharamcol 32:3499–3507.

    Article  CAS  Google Scholar 

  33. Janis RA, Rampe D, Sarmiento JG, Triggle DJ (1984) Specific binding of a calcium channel activator, [3H] Bay k 8644, to membranes from cardiac muscle and brain. Biochem Biophys Res Commun 121:317–323.

    Article  PubMed  CAS  Google Scholar 

  34. Janis RA, Sarmiento JG, Maurer SC, Bolger GT, Triggle DJ (1984) Characteristics of the binding of [3H]nitrendipine to rabbit ventricular membranes. Modification by other Ca++ channel antagonists and by the Ca++ channel agonist Bay K 8644. J Pharmacol Exper Ther 231:8–15.

    CAS  Google Scholar 

  35. Janis RA, Triggle DJ (1984) 1,4-dihydropyridine Ca2+ channel antagonists and activators: A comparison of binding characteristics with pharmacology. Drug Dev Res 4:257–274.

    Article  CAS  Google Scholar 

  36. Kenakin TP (1984) The classification of drugs and drug receptors in isolated tissues. Pharmacol Rev 35:165–222.

    Google Scholar 

  37. Kenessey A, Cantor EH, Spector S (1984) Low affinity dihydropyridine binding site in rat heart membranes. Fed Proc 43:550.

    Google Scholar 

  38. Lee KS, Tsien RW (1983) Mechanism of calcium channel blockade by verapamil, D600, diltiazem and nitrendipine in single dialysed heart cells. Nature 302:790–794.

    Article  PubMed  CAS  Google Scholar 

  39. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurements with the Folin phenol reagent. J Biol Chem 193:265–275.

    PubMed  CAS  Google Scholar 

  40. Marsh JD, Loh E, Lachance D, Barry WH, Smith TW (1983) Relationship of binding of a calcium channel blocker to inhibition of contraction in intact cultured embryonic chick ventricular cells. Circ Res 53:539–543.

    PubMed  CAS  Google Scholar 

  41. Millard RW, Grupp G, Grupp IL, DiSalvo J, DePover A, Schwartz A (1983) Chronotropic, inotropic and vasodilator actions of diltiazem, nifedipine and verapamil. A comparative study of physiological responses and membrane receptor activity. Circ Res 52(Suppl I): 29–39.

    CAS  Google Scholar 

  42. Munson PJ (1983) LIGAND: A computerized analysis of ligand binding data. Methods in Enzymology 92:543–577.

    Article  PubMed  CAS  Google Scholar 

  43. Munson PJ, Rodbard D (1980) LIGAND: A versatile computerized approach for characterization of ligand-binding systems. Anal Biochem 107:220–239.

    Article  PubMed  CAS  Google Scholar 

  44. Murphy KMM, Snyder SH (1982) Calcium antagonist receptor binding sites labeled with [3H]nitrendipine. Eur J Pharmacol 77:201–202.

    Article  PubMed  CAS  Google Scholar 

  45. Murphy KMM, Gould RJ, Largent BL, Snyder SH (1983) A unitary mechanism of calcium antagonist drug action. Proc Natl Acad Sci 80:860–864.

    Article  PubMed  CAS  Google Scholar 

  46. Murphy KMM, Gould RJ, Snyder SH (1984) Regulation of [3H]nitrendipine binding: A single allosteric site for verapamil, diltiazem and prenylamine. In: Scriabine A, Vanov S, Deck K (eds) Nitrendipine. Urban & Schwarzenberg, Baltimore, pp 107–131.

    Google Scholar 

  47. Ochi R, Hino N, Niimi Y (1984) Prolongation of calcium channel open time by the diyhdropyridine derivative Bay K 8644 in cardiac myocytes. Proc Japan Acad 60:153–156.

    Article  Google Scholar 

  48. Rogart RB, deBruyn Kops A, Janis RA, Dzau VJ (1984) Nimodipine binding to two calcium channel subtypes in rat heart. Proc IUPHAR, London, 409.

    Google Scholar 

  49. Uehara A, Hume JR (1984) Voltage clamp comparison of the organic calcium channel blockers D-600 and nisoldipine. Proc West Pharmacol Soc 27:343–347.

    PubMed  CAS  Google Scholar 

  50. Sanguinetti MC, Kass RS (1984) Regulation of cardiac calcium channel current and contractile activity by the dihydropyridine Bay k 8644 is voltage dependent. J Mol Cell Cardiol 16:667–670.

    Article  PubMed  CAS  Google Scholar 

  51. Sanguinetti MD, Kass RS (1984) Voltage dependent block of calcium channel current in the calf cardiac Purkinje fiber by dihydropyridine calcium channel antagonists. Circ Res 55:336–348.

    PubMed  CAS  Google Scholar 

  52. Sarmiento JG, Janis RA, Colvin RA, Triggle DJ, Katz AM (1983) Binding of the calcium channel blocker nitrendipine to its receptor in purified sarcolemma from canine cardiac ventricle. J Mol Cell Cardiol 15:135–137.

    Article  PubMed  CAS  Google Scholar 

  53. Sarmiento JG, Colvin RA, Janis RA, Messineo FC, Katz AM (1984) Biochemical effects of nitrendipine on membranes from skeletal and cardiac muscle. In: Scriabine A, Vanov S, Deck K (eds) Nitrendipine. Urban & Schwarzenberg, Baltimore, pp 53–66.

    Google Scholar 

  54. Schefler WC (1979) Statistics for the biological sciences. Addison-Wesley, Reading, Massachusetts.

    Google Scholar 

  55. Schramm M, Thomas G, Towart R, Franckowiak G (1983) Novel dihydropyridines with positive inotropic action through activation of Ca2+ channels. Nature 303:535–537.

    Article  PubMed  CAS  Google Scholar 

  56. Schramm M, Thomas G, Towart R, Franckowiak G (1983) Activation of calcium channels by novel 1,4-dihydropyridines. A new mechanism for positive inotropics or smooth muscle stimulants. Arzneim Forsch/Drug Res 33:1268–1272.

    CAS  Google Scholar 

  57. Schwartz A, Grupp IL, Grupp G, Williams JS, Vaghy PL (1984) Effects of dihydropyridine calcium channel modulators in the heart: Pharmacological and radioligand binding correlations. Biochem Biophys Res Commun 125:387–394.

    Article  PubMed  CAS  Google Scholar 

  58. Schwartz A, Triggle DJ (1984) Cellular action of calcium channel blocking drugs. Ann Rev Med 35:325–339.

    Article  PubMed  CAS  Google Scholar 

  59. Strauer BE (1974) Inotropic effects of nifedipine: A new coronary dilating agent. Int J Clin Pharmacol 9:101–107.

    PubMed  CAS  Google Scholar 

  60. Surprenant A (1983) Effects of calcium antagonists on action potentials and contractions in peripheral and cerebral arterial smooth muscle. Blood Vessels 20:207.

    Google Scholar 

  61. Takenaka T, Maeno H (1982) A new vasoconstrictor 1,4-dihydropyridine derivative, YC-170. Japan J Pharmacol 32: Supplement 139p.

    Google Scholar 

  62. Thomas G, Schramm M, Franckowiak G (1983) Dihydropyridines that exert positive inotropic effects in isolated cardiac muscle: Evidence for Ca channel modulation. Pharmacologist 25:206.

    Google Scholar 

  63. Thomas G, Gross R, Schramm M (1984) Calcium channel modulation: The ability to inhibit or promote calcium influx resides in the same dihydropyridine molecule. J Cardiovasc Pharmacol 6:1170–1176.

    PubMed  CAS  Google Scholar 

  64. Towart R, Schramm M (1984) Recent advances in the pharmacology of the calcium channel. Trends in Pharmacol Sci 5:111–113.

    Article  CAS  Google Scholar 

  65. Triggle, DJ (1984) Ca2+channel revisited: Problems and promises. Trends in Pharmacol. Sci 5:4–5.

    Article  CAS  Google Scholar 

  66. Triggle DJ, Janis RA (1984) Ca2+ channel antagonists: New Perspectives from the radioligand binding assay. In: Back N, Spector S (eds) Modern methods in pharmacology, vol 2. Alan R Liss, New York, pp 1–28.

    Google Scholar 

  67. Triggle DJ, Janis RA (1984) Nitrendipine: Binding sites and mechanism of action. In: Scriabine A, Vanov S, Deck K (eds) Nitrendipine. Urban & Schwarzenberg, Baltimore, pp 33–52.

    Google Scholar 

  68. Truog AG, Brunner H, Criscione L, Fallert M, Kuhnis H, Meier M, Rogg H (1984) CGP 28392, a dihydropyridine Ca2+ entry stimulator. In: Weiss GB (ed) Calcium in biological systems. Plenum Press, New York, pp 441–449.

    Google Scholar 

  69. Vaghy PL, Grupp IL, Grupp G, Schwartz A (1984) Effects of Bay k 8644, a dihydropyridine analog, on [3H]nitrendipine binding to canine cardiac sarcolemma and the relationship to a positive inotropic effect. Circ Res 55:549–553.

    PubMed  CAS  Google Scholar 

  70. Vaghy PL, Grupp IL, Grupp G, Balwierczak JL, Williams JS, Schwartz A (1984) Correlation of nitrendipine and Bay k 8644 binding to isolated canine heart sarcolemma with their pharmacological effects on the canine heart. Eur J Pharmacol 102:373–374.

    Article  PubMed  CAS  Google Scholar 

  71. Van Alstyne E, Burch RM, Knickelbein RG, Hungerford RT, Gower EJ, Webb JG, Poe SL, Lindenmayer GE (1980) Isolation of sealed vesicles highly enriched with sarcolemma markers from canine ventricle. Biochim Biophys Acta 602:131–143.

    Article  PubMed  Google Scholar 

  72. Yamamura HI, Schoemaker H, Boles RG, Roeske WR (1982) Diltiazem enhancement of [3H]nitrendipine binding to calcium channel associated drug receptor sites in rat brain synaptosomes. Biochem Biophys Res Comm 108:640–646.

    Article  PubMed  CAS  Google Scholar 

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Authors
  1. P. L. Vaghy
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  2. G. P. Dubé
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  3. I. L. Grupp
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  4. G. Grupp
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  5. J. S. Williams
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  6. Y. H. Baik
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  7. A. Schwartz
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Editor information

Editors and Affiliations

  1. Physiologisches Institut, Universität Freiburg, Hermann-Herder-Straße 7, D-7800, Freiburg i. Br., Germany

    Albrecht Fleckenstein

  2. Department of Pharmacology, University of Miami School of Medicine, P.O. Box 016189, Miami, FL, 33101, USA

    Cornelius Van Breemen D.V.M., Ph.D.

  3. Abteilung Herz-Kreislauf-Pharmakologie II, Bayer AG, Institut für Pharmakologie, Postfach 10 1709, D-5600, Wuppertal 1, Germany

    Rainer Gross

  4. Bayer AG, Institut für Pharmakologie, Postfach 10 1709, D-5600, Wuppertal 1, Germany

    Friedrich Hoffmeister

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Vaghy, P.L. et al. (1985). A Proposed Pharmacological Role for Dihydropyridine Binding Sites in Heart and Coronary Smooth Muscle. In: Fleckenstein, A., Van Breemen, C., Gross, R., Hoffmeister, F. (eds) Cardiovascular Effects of Dihydropyridine-Type Calcium Antagonists and Agonists. Bayer-Symposium, vol 9. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-70499-4_10

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  • DOI: https://doi.org/10.1007/978-3-642-70499-4_10

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