Advertisement

Mechanisms of the Beneficial Effects of Some Ca2+ Antagonists on the Ca2+-Paradox in Myocardium

  • N. S. Dhalla
  • P. K. Singal
  • S. Takeo
  • D. B. McNamara
Chapter
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 39)

Abstract

Electrophysiological experiments have provided evidence that Ca2+ antagonists such as verapamil and diltiazem alter cardiac function by inhibiting the entry of Ca2+ through slow calcium channels (1–3). These agents therefore can be seen to protect myocardium under pathophysiological conditions which are associated with a massive amount of Ca2+ entry and the occurrence of intracellular Ca2+ overload. Reperfusion of an isolated rat heart with a medium containing Ca2+ after a brief period of perfusion with a Ca2+ -free medium has been shown to produce contractile abnormalities, myocardial cell damage, depletion of high energy phosphate stores, alterations in cation contents, enzyme leakage and changes in subcellular Ca2+ -transport (5–12). These Ca2+ -paradoxic effects have been attributed to the occurrence of intracellular Ca2+ -overload (8); however, the mechanisms of these changes in the myocardium are far from clear. Some investigators have shown the protective effects of both verapamil and diltiazem against the Ca2+ -paradox related myocardial injury and have interpreted their results to mean that the massive Ca2+ -influx during Ca2+ -paradox is occurring through the slow calcium channels (13–15). On the other and, concentrations of verapamil, which are known to block Ca2+ -currents, were reported to be ineffective in preventing the Ca2+ -paradoxic changes (16,17). Accordingly, it has been suggested that some other mechanism of Ca2+ influx or efflux such as Na –Ca2+ exchange may also be involved in eliciting Ca2+ -paradoxic effects on the myocardium (18,19). This study was therefore undertaken to examine the effects of both low and high concentrations of verapamil and diltiazem on some Ca2+ -paradox changes in the myocardium. Furthermore, the actions of these agents Na+ -Ca2+ exchange mevhanism in the sarcolemmal preparations were studied.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Fleckenstein A: Specific pharmacology of calcium in myocardium, cardiac pacemakers and vascular smooth muscle. Ann Rev Pharmacol Toxicol (17): 149–166, 1977.CrossRefGoogle Scholar
  2. 2.
    Opie LH: Drug and the Heart III. Calcium antagonists. Lancet (1): 806–809, 1980.PubMedCrossRefGoogle Scholar
  3. 3.
    Braunwald E: Mechanism of action of calcium-channel blocking agents. New Engl J Med (307): 1618–1627, 1982.PubMedCrossRefGoogle Scholar
  4. 4.
    Zimmerman ANE, Daems W, Hulsmann WC, Snijder J, Wisse E, Durrer D: Morphological changes of heart muscle caused by successive perfusion with calcium-free and calcium-containing solutions (calcium paradox). Cardiovasc Res (1): 201–209, 1967.CrossRefGoogle Scholar
  5. 5.
    Yates JC, Dhalla NS: Structural and functional changes associated with failure and recovery of hearts after perfusion with Ca2+-free medium. J Mol Cell Cardiol (7): 91–103, 1975.PubMedCrossRefGoogle Scholar
  6. 6.
    Boink AB, Ruigrok TJC, Maas AHJ, Zimmerman ANE: Changes in high- energy phosphate compounds of isolated rat heart during Ca2+-free perfusion and reperfusion with Ca2+. J Mol Cell Cardiol (8): 973–979, 1976.CrossRefGoogle Scholar
  7. 7.
    Dhalla NS, Singh JN, McNamara DB, Bernatsky A, Singh A, Harrow JAC: Energy production and utilization in contractile failure due to intracellular calcium overload. Adv Exp Med Biol (161): 305–316, 1983.PubMedCrossRefGoogle Scholar
  8. 8.
    Alto LE, Dhalla NS: Myocardial cation contents during induction of calcium paradox. Am J Physiol (237): H713–H719, 1979.PubMedGoogle Scholar
  9. 9.
    Hearse DJ, Humphrey SM, Bullock GR: The oxygen paradox and the calcium paradox: two facets of the same problem. J Mol Cell Cardiol (10): 641–668, 1979.CrossRefGoogle Scholar
  10. 10.
    Lee SL, Dhalla NS: Subcellular calcium transport in failing hearts due to calcium deficiency and overload. Am J Physiol (231): 1159–1165, 1976.PubMedGoogle Scholar
  11. 11.
    Alto LE, Dhalla NS: Role of changes in microsomal calcium uptake in the effects of reperfusion of Ca2+ -deprived rat hearts. Circ Res (48): 17–24, 1981.PubMedCrossRefGoogle Scholar
  12. 12.
    Singal PK, Matsukubo MP, Dhalla NS: Calcium-related changes in the ultrastructure of mammalian myocardium. Br J Exp Pathol (60): 96–106, 1979.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Hearse DJ, Baker JE, Humphry SM: Verapamil and the calcium paradox. J Mol Cell Cardiol (12): 715–725, 1980.CrossRefGoogle Scholar
  14. 14.
    Ashraf M, Onda M, Hirohata Y, Schwartz A: Therapeutic effects of diltiazem on myocardial cell injury during the calcium paradox. J Mol Cell Cardiol (14): 323–327, 1982.PubMedCrossRefGoogle Scholar
  15. 15.
    Ashraf M, Onda M, Benedict JB, Millard RW: Prevention of calcium paradox-related myocardial cell injury with diltiazem, a calcium channel blocking agent. Am J Cardiol (49): 1675–1681, 1982.PubMedCrossRefGoogle Scholar
  16. 16.
    Ruigrok TJC, Boink AB, Slade A, Zimmerman ANE, Meijler FL, Nayler, WG: The effect of verapamil on the calcium paradox. Am J Pathol 98: 769–782, 1980.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Nayler WG, Grinwald PM: The effect of verapamil on calcium accumulation during the calcium paradox. J Mol Cell Cardiol (13): 435–441, 1981.PubMedCrossRefGoogle Scholar
  18. 18.
    Grinwald PM, Nayler, WG: Calcium entry in the calcium paradox. J Mol Cell Cardiol 13: 867–880, 1981.PubMedCrossRefGoogle Scholar
  19. 19.
    Dhalla NS, Alto LE, Singal PK: Role of Na+ -Ca2+ exchange in the development of cardiac abnormalities due to calcium paradox. Europ Heart J: in press, 1983.Google Scholar
  20. 20.
    Pitts BJR: Stoichiometry of sodium-calcium exchange in cardiac sarcolemmal vesicles. Coupling to the sodium pump. J Biol Chem (254): 6232–6235, 1979.PubMedGoogle Scholar
  21. 21.
    Fairhurst AS, Whittaker ML, Ehlert FJ: Interactions of D600 (Methosy- verapamil) and local anesthetics with rat brain a-adrenergic and muscarinic receptors. Biochem Pharmacol (29): 155–162, 1980.PubMedCrossRefGoogle Scholar
  22. 22.
    Kass RS, Tsein RW: Multiple effects of calcium antagonists on plateau currents in cardiac purkinje fibres. J Gen Physiol (66): 169–192, 1976.CrossRefGoogle Scholar
  23. 23.
    Kostyuk PG, Krishtal OA: Effects of calcium and calcium-chelating agents on the inward and outward currents in the membrane of mollusc neurons. J Physiol (270): 569–580, 1977.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Vaghy PL, Johnson JD, Matbile MA, Wang T, Schwartz A: Selective inhibition of Na+ -induced Ca2+ release from heart mitochondria by diltiazem and certain other Ca2+-antagonist drugs. J Biol Chem (257): 6000–6002, 1982.PubMedGoogle Scholar

Copyright information

© Martinus Nijhoff Publishing, Boston 1984

Authors and Affiliations

  • N. S. Dhalla
    • 1
  • P. K. Singal
    • 1
  • S. Takeo
    • 1
    • 2
  • D. B. McNamara
    • 1
  1. 1.Experimental Cardiology Section, Department of Physiology, Faculty of MedicineUniversity of ManitobaWinnipegCanada
  2. 2.Department of Pharmacology, School of MedicineUniversity of RyukyusNahaJapan

Personalised recommendations