Effects of Ca++-Agonistic and Ca++-Antagonistic 1,4-Dihydropyridine Compounds on Tonic and Phasic Activation of Extramural Coronary Vasculature

  • G. Fleckenstein-Grün
  • Y. Makita
  • Y. K. Byon
  • A. Fleckenstein
Part of the Bayer-Symposium book series (BAYER-SYMP, volume 9)


The administration of calcium antagonists as antiangmal, antiarrhythmic, antihypertensive or cardioprotective drugs, makes use of the different manifestations of one and the same elementary membrane action, i.e. inhibition of transmembrane Ca++ entry in myocardial fibres, nomotopic and ectopic cardiac pacemakers, as well as in various types of vascular smooth muscle cells1 (Fig. 1). How ever, it must be emphasized, that these particular effects are differently accentuated, depending on the individual calcium antagonist used. For instance, the classical calcium antagonists verapamil and D 600 (the generic name of D 600 is gallopamil) exert their damping influence on myocardium, pacemakers, and arterial smooth muscle with comparable intensity. On the other hand, the BAYER compound nifedipine and further dihydropyridine calcium antagonists preferentially suppress Ca++-dependent smooth muscle functions, whereas, at least in humans, the influence of such dihydropyridines on cardiac tension development and pacemaker activity in situ is rather modest. The fundamental Ca++-antagonistic potency of the prototypical substance nifedipine on isolated myocardium and vascular smooth muscle has first been established by Fleckenstein and his group in the years 1969–1972 [5–11]. Since that time, a considerable number of further 1,4-dihydropyridine derivatives were synthesized in the BAYER laboratories and also elsewhere. All these compounds, listed in Table 1, share their preferential Ca++-antagonistic action on the vascular system with the prototypical substance nifedipine. This is true of nimodipine, nisoldipine, nitrendipine, ryosidine, niludipine, felodipine, nicardipine and PY-108-068. However, with the recent discovery of other nifedipine-derivatives (”Calcium-Agonists”) which promote transmembrane Ca++ entry (see Table 2), it became clear that 1,4-dihydropyridine compounds may exert a “Januslike” influence on passive transmembrane Ca++ transport.


Calcium Antagonist Contractile Response Dihydropyridine Calcium Antagonist Coronary Smooth Muscle Coronary Constriction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Fleckenstein A (1970/71 a) Specific inhibitors and promoters of calcium action in the excitation-contraction coupling of heart muscle and their role in the production of prevention of myocardial lesions. In: Harris P, Opie L (eds) Calcium and the heart. Proceed. of the Meeting of the Europ. Section of the Internat. Study Group for Research in Cardiac Metabolism, London, Sept. 1970. Academic Press, London New York, pp 135-188.Google Scholar
  2. 2.
    Fleckenstein A (1977) Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Ann Rev Pharmacol Toxicol 17:149–166.CrossRefGoogle Scholar
  3. 3.
    Fleckenstein A (1983) History of calcium antagonists. In: Schwartz A, Taira N (eds) Calcium channel-blocking drugs: A novel intervention for the treatment of cardiac disease. Monograph No. 95 of the American Heart Association, Circ. Research, Part II, vol 52, No. 2, pp 3-16.Google Scholar
  4. 4.
    Fleckenstein A (1983) Calcium antagonism in heart and smooth muscle — Experimental facts and therapeutic prospects. Wiley, New York Chichester Brisbane Toronto Singapore.Google Scholar
  5. 5.
    Grün G, Fleckenstein A, Tritthart H (1969) Excitation-contraction uncoupling on the rat’s uterus by some “musculotropic” smooth muscle relaxants. Pflügers Arch Ges Physiol 264:239.Google Scholar
  6. 6.
    Fleckenstein A (1970/71 b) Neuere Ergebnisse zur Physiologie, Pharmakologie und Pathologie der elektromechanischen Koppelungsprozesse im Warmblütermyokard. In: Vorträge der Erlanger Physiologentagung 1970. W.D. Keidel u. K.H. Plattig Hrsg., S 13-52, Springer, Berlin Heidelberg New York, 1971.Google Scholar
  7. 7.
    Grün G, Fleckenstein A (1971) Ca-antagonism, a new principle of vasodilation. Naunyn-Schmiedeberg’s Arch Exper Path Pharmakol 270 (Suppl), R 48.Google Scholar
  8. 8.
    Grim G, Fleckenstein A, Byon YK (1971 a) Hemmung der Motilität isolierter Uterus-Streifen aus gravidem und nicht-gravidem menschlichem Myometrium durch Ca++-Antagonisten und Sympathomimetica. Arzneimittelforsch (Drug Res) 21:1585–1590.Google Scholar
  9. 9.
    Grim G, Fleckenstein A, Byon YK (1971 b) Ca antagonism, a new principle of vasodilation. In: Proceed. 25th Congress Internat. Union Physiol Sciences, Munich, 1971, vol 9, p 221.Google Scholar
  10. 10.
    Fleckenstein A, Tritthart H, Fleckenstein B, Herbst A, Grün G (1969) A new group of competitive Ca antagonists (Iproveratril, D 600, Prenylamine) with highly potent inhibitory effects on excitation-contraction coupling in mammalian myocardium. Pflügers Arch Ges Physiol 307:R25.Google Scholar
  11. 11.
    Grün G, Fleckenstein A (1972) Die elektro-mechanische Entkoppelung der glatten Gefäß-muskulatur als Grundprinzip der Coronardilatation durch 4-(2’-Nitrophenyl)-2,6-dimethyl-1,4-dihydropyridin-3,5-dicarbonsäure-dimethylester (Bay a 1040, Nifedipin). Arzneimittelforsch (Drug Res) 22:334–344.Google Scholar
  12. 12.
    Ginsburg R, Briston MR, Harrison DC, Stinson EB (1980) Studies with isolated human coronary arteries. Chest 78 (Suppl) 180–186.PubMedGoogle Scholar
  13. 13.
    Godfraind T, Miller RC (1983) Specificity of action of Ca entry blockers. A comparison of their actions in rat arteries and in human coronary arteries. In: Schwartz A, Taira N (eds) Calcium channel-blocking drugs: A novel intervention for the treatment of cardiac disease. Monograph No. 95 of the American Heart Association, Circ. Research, Part II, vol 52, No.2, pp 81-91.Google Scholar
  14. 14.
    Taira N, Satoh K, Maruyama M, Yamashita S (1983) Sustained coronary constriction and its antagonism by calcium-blocking agents in monkeys and baboons. In: Schwartz A, Taira N (eds) Calcium channel-blocking drugs: A novel intervention for the treatment of cardiac disease. Monograph No. 95 of the American Heart Association. Circ. Research, Part II, vol 52, No. 2, pp 40-46.Google Scholar
  15. 15.
    Godfraind T, Kaba A (1969) Blockade or reversal of the contraction induced by calcium and adrenaline in depolarized arterial smooth muscle. Brit J Pharmacol 36:549–560.Google Scholar
  16. 16.
    Bevan JA, Garstka W, Su C, Su MO (1973) The bimodal basis of the contractile response of the rabbit ear artery to norepinephrine and other agonists. Europ J Pharmacol 22:47–53.CrossRefGoogle Scholar
  17. 17.
    Fleckenstein-Grün G, Frey M, Fleckenstein A (1984) Calcium antagonists: mechanisms and therapeutic uses. In: Trends in pharmacological sciences, vol 5, No. 7. Elsevier Biomedical Press, Cambridge, pp 283–286.Google Scholar
  18. 18.
    Fleckenstein-Grün G, Fleckenstein A (1978/80) Calcium-Antagonismus, ein Grundprinzip der Vasodilatation. In: Fleckenstein A, Roskamm H (eds) Calcium-Antagonismus, Proceed, eines Internat. Symp., Frankfurt, 1978. Springer, Berlin Heidelberg New York, pp 191–207.Google Scholar
  19. 19.
    van Breemen C, Hwang OK, Meisheri KD (1981) The mechanism of inhibitory action of diltiazem on vascular smooth muscle contractility. J Pharmacol Exper Therapeutics 218, No. 2, pp 459–463.Google Scholar
  20. 20.
    Nakayama K, Fleckenstein-Grün G, Byon YK, Fleckenstein A (1976) Opposite effects of cardiac glycosides and Ca-antagonistic compounds on vascular smooth muscle contractility under electrical, mechanical and pharmacological stimulation (Observations on helical strips from rabbit coronary and brain arteries). Pflügers Arch Ges Physiol Suppl to vol 365, R 7.Google Scholar
  21. 21.
    Fleckenstein-Grün G (1985) Suppression of experimental coronary spasms by major calcium antagonists. In: Rubin RP, Weiss GB, Putney JW Jr (eds) Calcium in biological systems. FASEB-Meeting, Chicago, April 1983. Plenum, New York.Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1985

Authors and Affiliations

  • G. Fleckenstein-Grün
  • Y. Makita
  • Y. K. Byon
  • A. Fleckenstein

There are no affiliations available

Personalised recommendations