Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 318, Issue 3, pp 234–240 | Cite as

Assessment of “Ca2+-antagonist” effects of drugs in K+-depolarized smooth muscle

Differentiation of antagonist subgroups
  • M. Spedding


  1. 1.

    Taenia preparations from the guinea-pig caecum yielded reproducible concentration-response curves to Ca2+ (EC 50 134±8 μmol/l) when maintained in depolarizing Tyrode solution containing K+ (40 mmol/l). Drugs which are claimed to be “Ca2--antagonists” displaced the curves to the right without depression of the maximum response. In this test nifedipine, verapamil, diltiazem, pimozide, cinnarizine, flunarizine and fendiline appeared qualitatively similar but had different potencies.

  2. 2.

    The antagonist effects of nifedipine, verapamil and diltiazem were readily reversed by washout of the drugs from the bathing fluid, but the effects of the other drugs were not.

  3. 3.

    Cinnarizine, flunarizine, pimozide and fendiline were only weakly active as relaxants of Ca2+ (100 μmol/l)-induced contractions, when compared with their antagonist activity when applied initially in Ca2+-free media. As the presence of Ca2+ (100 μmol/l) in the K+-Tryrode reduced the antagonist effects of cinnarizine and pimozide, but not that of verapamil and diltiazem, the weak activity of some of the antagonists as relaxants of Ca2+-induced contractions can be attributed to a protective effect of Ca2+ during the incubation period with the antagonist.

  4. 4.

    The problems associated with the assessment of the potency of drugs as “Ca2+-antagonists” are discussed and it is proposed that three subgroups of drugs may exist within the overall classification.


Key words

“Ca2+-Antagonists” Calcium K+-Depolarization Relaxation Verapamil 


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  1. Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol Chemother 14:48–58Google Scholar
  2. Bossert VF, Horstmann H, Meyer H, Vater W (1979) Einfluß der Esterfunktion auf die vasodilatierenden Eigenschaften von 1,4-dihydro-2,6-dimethyl-4-nitrophenyl-pyridin-3,5-dicarbonsäureestern. Arzneim Forsch 29:226–229Google Scholar
  3. Bayer R, Ehara T (1977) Comparative studies on calcium antagonists. Prog Pharmacol 2:31–37Google Scholar
  4. Brading AF, Sneddon P (1980) Evidence for multiple sources of calcium for activation of the contractile mechanism of guinea-pig taenia coli on stimulation with carbachol. Br J Pharmacol 70:229–240Google Scholar
  5. Church J, Zsotér TT (1980) Calcium antagonist drugs. Mechanism of action. Can J Physiol Pharmacol 58:254–264Google Scholar
  6. Durbin RP, Jenkinson DH (1961) The calcium dependence of tension development in depolarized smooth muscle. J Physiol Lond 157:90–96Google Scholar
  7. Ferrari M (1970) Interactions between calcium and some myolytic agents on depolarized vascular smooth muscle. J Pharm Pharmacol 22:71–72Google Scholar
  8. Ferrari M, Carpenedo F (1968) On the mechanism of action of some myolytic agents on depolarized guinea, pig taenia coli. Arch Int Pharmacodyn 174:223–232Google Scholar
  9. Fleckenstein A (1977) Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Ann Rev Pharmacol Toxicol 17:149–166Google Scholar
  10. Fleckenstein A, Fleckenstein-Grün G, Byon YK (1977) Cardiovascular effects of the Ca2+-antagonistic coronary drug Fendiline (Sensit). Arzneim Forsch 27:562–571Google Scholar
  11. Frank JS, Langer GA, Nudd LM, Seraynoudarian K (1977) The myocardial cell surface, its histochemistry, and the effects of sialic acid and calcium removal on its structure and cellular ionic exchange. Circ Res 41:702–714Google Scholar
  12. Godfraind T, Kaba A (1969) Blockade or reversal of the contraction induced by calcium and adrenaline in depolarized arterial smooth muscle. Br J Pharmacol 36:549–560Google Scholar
  13. Golenhofen K, Wagner B, Weston AH (1977) Calcium systems of smooth muscle and their selective inhibition. In: Casteels R, Godfraind T, Rüegg JC (eds) Excitation-contraction coupling in smooth muscle. Elsevier, Amsterdam, pp 131–136Google Scholar
  14. Haeusler G (1972) Differential effects of verapamil on excitation-contraction coupling in smooth muscle and on excitation-secretion coupling in adrenergic nerve terminals. J Pharmacol Exp Ther 180:672–682Google Scholar
  15. Hashimoto K, Nakagawa Y, Nabata H, Imai S (1978) In vitro analysis of Ca-antagonistic effects of prenylamine as mechanisms for its cardiac actions. Arch Int Pharmacodyn 231:212–221Google Scholar
  16. Henry PD (1980) Comparative pharmacology of calcium antagonists: nifedipine, verapamil and diltiazem. Am J Cardiol 46:1047–1058Google Scholar
  17. Hille B (1977) Local anaesthetics: hydrophilic and hydrophobic pathways for the drug receptor reaction. J Gen Physiol 69:497–515Google Scholar
  18. Imai S (1979) Antiangial drugs-revival of interest in vasodilators. Trends Pharmacol Sci 1:87–89Google Scholar
  19. Jetley M, Weston AH (1980) Some effects of sodium nitroprusside, methoxyverapamil (D600) and nifedipine on rat portal vein. Br J Pharmacol 68:311–319Google Scholar
  20. Levin RM, Weiss B (1979) Selective binding of antipsychotics and other psychoactive agents to the calcium-dependent activator of cyclic nucleotide phosphodiesterase. J Pharmacol Exp Ther 208:454–459Google Scholar
  21. Loev B, Goodman MM, Snader KM, Tedeschi R, Macko E (1974) “Hantzsch-type” dihydropyridine hypotensive agents. J Med Chem 17:956–965Google Scholar
  22. Morel N, Godfraind T (1978) Action of calcium antagonists on microsomal calcium activated ATPase of rat aorta. Arch Int Pharmacodyn 236:315–316Google Scholar
  23. Nabata H (1977) Effects of calcium-antagonistic coronary vasodilators on myocardial contractility and membrane potentials. Jpn J Pharmacol 27:239–249Google Scholar
  24. Nakayama K, Kasuya Y (1980) Selective abolition of Ca-dependent responses of smooth and cardiac muscles by flunarizine. Jpn J Pharmacol 30:731–742Google Scholar
  25. Opie LH (1980) Calcium antagonists. Lancet I:806–810Google Scholar
  26. Quintana A (1978) Effects of pimozide on the response of smooth muscle to non-dopamine agonists and calcium. Eur J Pharmacol 53:113–116Google Scholar
  27. Racker E (1980) Fluxes of Ca2+ and concepts. Fed Proc 39:2422–2426Google Scholar
  28. Rahwan RG, Piascik MF, Witiak DT (1979) The role of calcium antagonism in the therapeutic action of drugs. Can J Physiol Pharmacol 57:443–460Google Scholar
  29. Sanner JH, Prusa CM (1980) Inhibition by verapamil of contractions produced by calcium on depolarized rabbit aortic strips. Life Sci 27:2565–2570Google Scholar
  30. Spedding M (1981) Marked differences in the effects of “Ca2+-antagonists” on CaCl2-induced contractions in K+-depolarized smooth muscle Br J Pharmacol 72: 144PGoogle Scholar
  31. Spedding M, Weetman DF (1978) The mechanism of the relaxant effect of 2-2′-pyridylisatogen on the isolated taenia of the guinea-pig caecum. Br J Pharmacol 63:659–664Google Scholar
  32. Stephenson RP (1956) A modification of receptor theory. Br J Pharmacol Chemother 11:379–393Google Scholar
  33. Thorens S, Haeusler G (1979) Effects of some vasodilators on calcium translocation in intact and fractionated vascular smooth muscle. Eur J Pharmacol 54:79–91Google Scholar
  34. Tomiyama A, Takayanagi I, Takagi K (1973) Relaxation of intestinal smooth muscle and calcium movements. J Pharm Pharmacol 25:65–68Google Scholar
  35. Van Breemen C (1977) Calcium requirement for activation of intact aortic smooth muscle. J Physiol Lond 272:317–329Google Scholar
  36. Van Nueten JM, Vanhoutte PM (1980) Improvement of tissue perfusion with inhibitors of calcium ion influx. Biochem Pharmacol 29:479–481Google Scholar
  37. Van Nueten JM, Van Beck J, Janssen PAJ (1978) Effect of flunarizine on calcium-induced responses of peripheral vascular smooth muscle. Arch Int Pharmacodyn 232:42–52Google Scholar
  38. Van Rossum JM (1963) Cumulative dose-response curves. II. Technique for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch Int Pharmacodyn 143:299–330Google Scholar
  39. Weston AH (1978) The effect of noradrenaline on electrical activity and calcium fluxes in rat portal vein. In: Szabadi E, Bradshaw CM, Bevan P (eds) Recent advances in the pharmacology of adrenoceptors. Elsevier, Amsterdam, pp 15–22Google Scholar

Copyright information

© Springer-Verlag 1982

Authors and Affiliations

  • M. Spedding
    • 1
  1. 1.Centre de Recherche Merrell InternationalStrasbourg, CedexFrance

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