Calcium Channel Antagonists: Pharmacologic and Radioligand Binding Approaches to Mechanisms of Action

  • D. J. Triggle
  • R. A. Janis
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 39)


The chemical heterogeneity of the group of agents known as the Ca2+ channel blockers or Ca2+ channel antagonists (Figure 1) has long suggested that these agents impair Ca2+ channel function by different mechanisms (for reviews see references 1 and 2). Accordingly, these agents exhibit important differences in their pharmacologic properties including variations in cardiac:smooth muscle selectivity (3,4) and differences in the extent to which they exhibit frequency- or use-dependence. Thus, verapamil/D600 and diltiazem are approximately equieffective in smooth and cardiac muscle, whereas nifedipine, and other 1,4-dihydropyridines, are significantly more selective for smooth muscle, both vascular and nonvascular (3–5). Similarly, verapamil/D600 and diltiazem exhibit to a significant degree the phenomena of use- and voltage-dependence whereby activity increases with increasing frequency of stimulation and with increasing membrane depolarization. This suggests that verapami1/D600 and diltiazem, unlike nifedipine, have a marked preference for interaction with channels in the open or depolarized state (6). Additionally, verapami1/D600 and diltiazem interact with a number of receptor systems, including muscarinic, adrenergic α1 and α2 and opiate, as well as with K+ channels, at concentrations (10-6M) that are similar to those achieved clinically (for reviews see references 1,2,7). In contrast nifedipine is relatively free from such additional actions.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Janis RA, Triggle DJ: New developments in Ca2+ channel antagonists. J Med Chem (26): 776–785, 1983.CrossRefGoogle Scholar
  2. 2.
    Trigqle DJ, Swamy VC: Calcium antagonists. Some chemical- pharmacologic aspects. Circ Res (52: Suppl. I): 17–28, 1983.Google Scholar
  3. 3.
    Fleckenstein A: Calcium antagonism in heart and smooth muscle. Experimental facts and therapeutic prospects. Wiley and Sons, Inc., New York, N.Y., 1983.Google Scholar
  4. 4.
    Henry PD: Comparative cardiac pharmacology of calcium blockers. In: Flaim SF and Zelis R (Eds) Calcium blockers. Mechanisms of action and clinical applications. Urban and Schwarzenberg, Baltimore, 1982, pp. 135–154.Google Scholar
  5. 5.
    Flaim SF: Comparative pharmacology of calcium blockers based on studies of vascular smooth muscle. In: Flaim SF and Zelis R (Eds) Calcium blockers. Mechanisms of action and clinical applications. Urban and Schwarzenberg, Baltimore, 1982, pp. 155–178.Google Scholar
  6. 6.
    Lee KS, Tsien RW: Mechanism of calcium channel blockade by verapamil, D600, diltiazem and nitrendipine in sinqle dialysed heart cells. Nature (302): 790–794, 1983.PubMedCrossRefGoogle Scholar
  7. 7.
    Triggle DJ: Chemical pharmacology of calcium antagonists. In: Rahwan RG and Witiak D (Eds) Calcium regulation by calcium antagonists. American Chemical Society, Washington, D.C., 1982, pp. 17 - 37.CrossRefGoogle Scholar
  8. 8.
    Triggle DJ, Janis RA: Ca2+ channel antagonists. New perspectives from the radioligand binding assay. In: Back N and Spector S (Eds) Modern Methods in Pharmacology, Vol. II, Alan R. Liss, Inc., New York, N.Y., 1983, in press.Google Scholar
  9. 9.
    Böiger GT, Gengo P, Klockowski R, Luchowski E, Siegel H, Janis RA, Triggle AM, Triggle DJ: Characterization of binding of the Ca++ channel antagonist, [3H]nitrendipine, to guinea pig ileal smooth muscle. J Pharmacol Exptl Therap (22): 291–309, 1983.Google Scholar
  10. 10.
    Triggle DJ, Janis RA: Nitrendipine: binding sites and mechanisms of action. In: Scriabine A, Vanov S and Deck K (Eds) Nitrendipine. Urban and Schwarzenberg, Baltimore, 1983, in press.Google Scholar
  11. 11.
    Luchowski EM, Yousif F, Triggle DJ, Maurer SC, Sarmiento JG,Janis RA: The effects of metal cations and calmodulin antagonists on [3H]nitrendipine binding in smooth and cardiac muscle. Submitted for publication.Google Scholar
  12. 12.
    Fosset M, Jaimovich E, Delpont E, Lazdunski M: [3H]Nitrendipine receptors in skeletal muscle. Properties and preferential localization in transverse tubules. J Biol Chem (258): 6086–6092, 1983.PubMedGoogle Scholar
  13. 13.
    Bellemann P, Schade A, Towart R: Dihydropyridine receptor in rat brain labeled with [3H]nimodipine. Proc Nat Acad Sei USA (80): 2356–2360, 1983.CrossRefGoogle Scholar
  14. 14.
    Mannhold R, Rodenkirchen R,Bayer R: Qualitative and quantitative structure-activity relationships of specific Ca antagonists. Prog Pharmacol (5): 25–52, 1982.Google Scholar
  15. 15.
    Nachshen DA, Blaustein MP: The efects of some organic “calcium antagonists” on calcium influx in presynaptic nerve terminals. Mol Pharmacol (16): 579–586, 1979.Google Scholar
  16. 16.
    Kaplita PV, Triggle DJ: Actions of Ca2+ antagonists on the guinea pig ileal myenteric plexus preparation. Biochem Pharmacol (32): 65–68, 1983.PubMedCrossRefGoogle Scholar
  17. 17.
    Triggle DJ: Ca2+ channels revisited: problems and promises. Trends in Pharmacol Sei, in press, 1983.Google Scholar
  18. 18.
    Gengo PJ, Luchowski EM, Rampe DE, Rutledge A, Triggle AM, Triggle DJ, Janis RA: Chemical and pharmacological approaches to the definition and quantitation of Ca++ channels. In: Watson JD (Ed) Cold Spring Harbor Symposium on Molecular Neurobiology. Cold Spring Harbor, New York, in press.Google Scholar
  19. 19.
    Bean BP, Nowycky MC, Tsien RW: Electrical estimates of Ca channel density in heart cell membranes. Biophys J (41): 295a, 1983.Google Scholar
  20. 20.
    Murphy KMM, Gould RJ, Largent BL, Snyder SH:A unitary mechanism of calcium antagonist drug action. Proc Nat Acad Sei USA (80): 860–864, 1983.CrossRefGoogle Scholar
  21. 21.
    Glossmann H, Ferry DR, Lübbecke F, Mewes R, Hofmann F: Identification of voltage operated calcium channels by binding studies: differentiation of calcium antagonist drugs with 3H-nimodipine radioligand binding. J Recept Res (3): 177–190, 1983.PubMedGoogle Scholar
  22. 22.
    Norman RI, Borsotto M, Fosset M, Lazdunski M, Ellory JC: Determination of the molecular size of the nitrendipine-sensitive Ca2+ channel by radiation inactivation. Biochem Biophys Res Comm (111): 878–883, 1983.PubMedCrossRefGoogle Scholar
  23. 23.
    Venter JC, Fraser CM, Schaber JS, Yung CY, Böiger G, Triggle DJ: Molecular properties of the slow inward calcium channel. J Biol Chem (258): 9344–9348, 1983.PubMedGoogle Scholar
  24. 24.
    Gould RJ, Murphy KMM, Snyder SH: 3H-Nitrendipine-labeled calcium channels discriminate inorganic calcium agonists and antagonists. Proc Nat Acad Sei USA (79): 3656–3660, 1982.CrossRefGoogle Scholar
  25. 25.
    Hagiawara S, Byerly L: Calcium channel. Ann Rev Neuroscience (4): 69–125, 1981.CrossRefGoogle Scholar
  26. 26.
    Schramm M, Thomas G, Towart R, Franckowiak G: Novel dihydropyridines with positive inotropic action through activation of Ca2+ channels. Nature (303): 535–537, 1983.PubMedCrossRefGoogle Scholar

Copyright information

© Martinus Nijhoff Publishing, Boston 1984

Authors and Affiliations

  • D. J. Triggle
  • R. A. Janis

There are no affiliations available

Personalised recommendations