Über den Einfluß von Mangan-Ionen auf die positiv inotrope Wirkung von Adrenalin, Theophyllin und Digitoxigenin an isolierten Meerschweinchenvorhöfen

  • T. Meinertz
  • H. Scholz


Ca-Einstrom und Mangan Adrenalin Theophyllin Digitoxigenin Isolierter Meerschweinchenvorhof 


The influence of bivalent manganese ions (Mn++ ) on the positive inotropic effect of adrenaline, theophylline, and digitoxigenin was studied in isolated, electrically driven left guinea-pig auricles in phosphate-free Tyrode’s solutions with different extracellular calcium concentrations ([Ca] e ; 0.45; 1.8; 7.2 mM).

Mn++ (0.1–50 mM) exerted a dose-dependent negative inotropic effect which was dependent on [Ca] e : Raising [Ca] e decreased the inhibitory action of Mn++ . The negative inotropic effect of Mn++ was exclusively due to a decrease in the rate of tension development; the time to peak tension and the duration of contraction remained unchanged.

In a solution containing 0.45 mM Ca, pretreatment with 0.1 mM Mn++ significantly diminished the positive inotropic effect of adrenaline (10−9–10−5 g/ml) and theophylline (5× 10−6–10−3 g/ml), but did not influence the effect of digitoxigenin (2 × 10−7–2 × 10−6 g/ml). The depression of the positive inotropic effect of adrenaline and theophylline with higher concentrations of Mn++ (0.35–2.25 mM, producing a negative inotropic effect of about 50%) was influenced by the [Ca] e . The effect of Mn++ was most evident at 0.45 mM Ca, less pronounced (but significant) at 1.8 mM Ca and was not observed at 7.2 mM Ca. With the same concentrations of Mn++ , however, the positive inotropic effect of digitoxigenin was only slightly decreased at 0.45 mM Ca, was not changed at 1.8 mM Ca and was increased at 7.2 mM Ca.

As Mn++ selectively blocks the inward movement of Ca ions across the membrane of the myocardial cell during depolarisation, it is tentatively concluded from these experiments that the positive inotropic effect of adrenaline and theophylline may be due at least partially to an increase of the Ca influx during the excitation process, whereas the positive inotropic effect of digitoxigenin seems to be independent of this mechanism.


Ca-Influx and Manganese Adrenaline Theophylline Digitoxigenin Isolated Guinea-Pig Auricle 


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  1. Ariens, E.J., A.M. Simonis, and J.M. van Rossum: Drug-receptor interaction. Interaction of one or more drugs with different receptor systems. In: Molecular Pharmacology, pp. 287–393. Ed.: E.J. Ariens. New York-London: Academic Press 1964.Google Scholar
  2. Axelsson, J., and S. Thesleff: Activation of the contractile mechanism in striated muscle. Acta physiol. scand. 44, 55–66 (1958).PubMedCrossRefGoogle Scholar
  3. Bianchi, C.P.: Kinetics of radiocaffeine uptake and release in frog sartorius. J. Pharmacol. exp. Ther. 138, 41–47 (1962).PubMedGoogle Scholar
  4. Carsten, M.E., and W.F.H.M. Mommaerts: The accumulation of calcium ions by sarcotubular vesicles. J. gen. Physiol. 48, 183–197 (1965).CrossRefGoogle Scholar
  5. Ebashi, S., and M. Endo: Calcium ion and muscle contraction. In: Progr. Biophys. Mol.Biol. 18, 123–183. Ed.: J.A.V. Butler and D. Noble. Oxford-New York: Pergamon Press 1968.Google Scholar
  6. Govier, W. C, and W.C. Holland: The relationship between atrial contractions and the effect of oubain on contractile strength and calcium exchange in rabbit atria. J. Pharmacol. exp. Ther. 148, 284–289 (1965).PubMedGoogle Scholar
  7. Grossman, A., and R.F. Furchgott: The effects of external calcium concentration on the distribution and exchange of calcium in resting and beating guinea-pig auricles. J. Pharmacol. exp. Ther. 143, 107–119 (1964a).PubMedGoogle Scholar
  8. — The effects of frequency of stimulation and calcium concentration on Ca45 exchange and contractility on the isolated guinea-pig auricle. J. Pharmacol. exp. Ther. 143, 120–130 (1964b).PubMedGoogle Scholar
  9. — The effect of various drugs on calcium exchange in the isolated guinea-pig left auricle. J. Pharmacol. exp. Ther. 145, 162–172 (1964c).PubMedGoogle Scholar
  10. Gubareff, T. de, and W. Sleator, Jr.: Effects of caffeine on mammalian atrial muscle, and its interaction with adenosine and calcium. J. Pharmacol. exp. Ther. 148, 202–214 (1965).Google Scholar
  11. Herz, R., and A. Weber: Caffeine inhibition of Ca uptake by muscle reticulum. Fed. Proc. 24, 208 (1965).Google Scholar
  12. Jenny, E.: Physikalisch-chemische und enzymatische Untersuchungen von Kalbsherzmyosin. Helv. physiol. pharmacol. Acta 23, 357–373 (1965).Google Scholar
  13. Jork, K., G. Kuschinsky u. H. Reuter: Der Einfluß der extracellulären Calciumkonzentration auf die Wirkung von Noradrenalin, β-Adrenolytica und Chinidin an isolierten Meerschweinchenvorhöfen. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 258, 59–68 (1967).CrossRefGoogle Scholar
  14. Katz, A.M., D.I. Repke, and B.R. Cohen: Control of the activity of highly purified cardiac actomyosin by Ca2+, Na+ and K+. Circulat. Res. 19, 1062–1070 (1966).PubMedCrossRefGoogle Scholar
  15. Kaufmann, R., u. A. Fleckenstein: Ca++ -kompetitive elektromechanische Entkoppelung durch Ni++ -und Co++ -Ionen am Warmblütermyokard. Pflügers Arch. ges. Physiol. 282, 290–297 (1965).CrossRefGoogle Scholar
  16. Klaus, W., u. G. Kuschinsky: Über die Wirkung von Digitoxigenin auf den cellulären Calcium-Umsatz im Herzmuskelgewebe. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 244, 237–253 (1962).CrossRefGoogle Scholar
  17. — Neuere Aspekte über den Wirkungsmechanismus der Herzglykoside. Z. naturwiss.-med. Grundlagenforschung 2, 43–117 (1964).Google Scholar
  18. — Comments on the role of cellular calcium in digitalis action. In: Factors influencing myocardial contractility, pp. 533–540. Ed.: R.D. Tanz, F. Kavaler, and J. Roberts. New York: Academic Press 1967.Google Scholar
  19. — Zur Wirkung von Herzglykosiden auf den Elektrolytstoffwechsel. In: Herzinsuffizienz, S. 546–549. Ed.: H. Reindell, J. Keul u. E. Doll. Stuttgart: Thieme 1968.Google Scholar
  20. Kukovetz, W.R., and G. Pöch: The action of imidazol on the effects of methylxanthines and catecholamines on cardiac contraction and phosphorylase activity. J. Pharmacol. exp. Ther. 156, 514–521 (1967).PubMedGoogle Scholar
  21. Kuschinsky, G., u. E. Muscholl: Die Wirkung von Theophyllin, Coffein und Theobromin auf Kontraktionskraft, Erregbarkeit, Refraktärzeit und Spontan-frequenz des isolierten Herzmuskels der Katze. Naunyn-Schmiedebergs Arch, exp. Path. Pharmak. 229, 348–359 (1956).CrossRefGoogle Scholar
  22. Langer, G.A.: Ion fluxes in cardiac excitation and contraction and their relation to myocardial contractility. Physiol. Rev. 48, 708–757 (1968).PubMedGoogle Scholar
  23. — Kinetic studies of calcium distribution in ventricular muscle of the dog. Circulat. Res. 15, 393–405 (1964).PubMedCrossRefGoogle Scholar
  24. —, and A.J. Brady: Calcium flux in the mammalian ventricular myocardium. J. gen. Physiol. 46, 703–719 (1963).PubMedCentralPubMedCrossRefGoogle Scholar
  25. Lindmar, R., u. E. Muscholl: Die Wirkung von Pharmaka auf die Elimination von Noradrenalin aus der Perfusionsflüssigkeit und die Noradrenalinaufnahme in das isolierte Herz. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 247, 469–492 (1964).CrossRefGoogle Scholar
  26. Lüllmann, H., and W. Holland: Influence of ouabain on an exchangeable calcium fraction, contractile force, and resting tension of guinea-pig atria. J. Pharmacol. exp. Ther. 137, 186–192 (1962).PubMedGoogle Scholar
  27. Lüttgau, H.C.: Nerven-und Muskel-Elektrophysiologie. Fortschr. Zool. 17, 272 bis 312 (1965).Google Scholar
  28. —, and H. Oetliker: The action of caffeine on the activation of the contractile mechanism. J. Physiol. (Lond.) 194, 51–73 (1968).Google Scholar
  29. Mascher, D., and K. Peper: Two components of inward current in myocardial muscle fibers. Pflügers Arch. 307, 190–203 (1969).PubMedCrossRefGoogle Scholar
  30. Meinertz, T., u. H. Scholz: Über den Einfluß von Mn++ -Ionen auf die positiv inotrope Wirkung einiger Pharmaka an isolierten Meerschweinchenvorhöfen. Naunyn-Schmiedebergs Arch. Pharmak. 264, 281–282 (1969).CrossRefGoogle Scholar
  31. Nayler, W.G.: Effect of caffeine on cardiac contractile activity and radiocalcium movement. Amer. J. Physiol. 204, 969–974 (1963).PubMedGoogle Scholar
  32. — Calcium exchange in cardiac muscle: a basic mechanism of drug action. Amer. Heart J. 73, 379–394 (1967).PubMedCrossRefGoogle Scholar
  33. —, and J.R. Hasker: Effect of caffeine on calcium in subcellular fractions of cardiac muscle. Amer. J. Physiol. 211, 950–954 (1966).PubMedGoogle Scholar
  34. Niedergerke, R.: Movements of Ca in beating ventricles of the frog heart. J. Physiol. (Lond.) 167, 551–580 (1963).Google Scholar
  35. Pöch, G., u. W.R. Kukovetz: Über den Einfluß von Serotoninantagonisten auf die Herzwirkung von Theophyllin. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 246, 46–47 (1963).CrossRefGoogle Scholar
  36. Price, J.M., and W.G. Nayler: Effect of hypothermia on the response of isolated rat myocardium to xanthine derivates. Arch. int. Pharmacodyn. 166, 390–397 (1967).PubMedGoogle Scholar
  37. — J. Swann, and W.G. Nayler: Effect of isoproterenol on contractions and phosphorylase activity of normo-and hypothermic cardiac muscle. Arch. int. Pharmacodyn. 168, 296–303 (1967).PubMedGoogle Scholar
  38. Rall, T.W., and T.C. West: The potentiation of cardiac inotropic responses to norepinephrine by theophylline. J. Pharmacol. exp. Ther. 139, 269–274 (1963).PubMedGoogle Scholar
  39. Reiter, M., u. H.G. Schöber: Die positive inotrope Adrenalinwirkung auf den Meerschweinchen-Papillarmuskel bei Variation der äußeren Calcium-und Natriumkonzentration. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 250, 9–20 (1965).Google Scholar
  40. Reuter, H.: Über die Wirkung von Adrenalin auf den cellulären Ca-Umsatz des Meerschweinchenvorhofs. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 251, 401–412 (1965).Google Scholar
  41. — Strom-Spannungsbeziehungen von Purkinje-Fasern bei verschiedenen extra-cellulären Calcium-Konzentrationen und unter Adrenalineinwirkung. Pflügers Arch. ges. Physiol. 287, 357–367 (1966).CrossRefGoogle Scholar
  42. Reuter, H.: The dependence of slow inward current in Purkinje fibres on the extracellular calcium-concentration. J. Physiol. (Lond.) 192, 479–492 (1967).Google Scholar
  43. —, and G.W. Beeler: Calcium current and activation of contraction in ventricular myocardial fibers. Science 163, 399–401 (1969).PubMedCrossRefGoogle Scholar
  44. —, u. H. Scholz: Über den Einfluß der extracellulären Ca-Konzentration auf Membranpotential und Kontraktion isolierter Herzpräparate bei graduierter Depolarisation. Pflügers Arch. ges. Physiol. 300, 87–107 (1968).CrossRefGoogle Scholar
  45. —, u. U. Wollert: Über die Wirkung verschiedener sympathomimetischer Amine auf Kontraktionskraft und 45Ca-Aufnahme isolierter Meerschweinchenvorhöfe. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 258, 288–296 (1967).CrossRefGoogle Scholar
  46. Rougier, O., G. Vassort, D. Garnier, Y.-M. Gargouël et E. Coraboeuf: Données nouvelles concernant le rôle des ions Na++ et Ca++ sur les propriétés électro-physiologiques des membranes cardiaques; existence d’un canal lent. C.R. Acad. Sci. (Paris) 266, 802–805 (1968).Google Scholar
  47. Sabatini-Smith, S., and W.C. Holland: Influence of manganese and ouabain on the rate of action of calcium on atrial contractions. Amer. J. Physiol. 216, 244–248 (1969).PubMedGoogle Scholar
  48. Sandow, A.: Excitation-contraction coupling in skeletal muscle. Pharmacol. Rev. 17, 265–320 (1965).PubMedGoogle Scholar
  49. Scholz, H.: Ca-abhängige Membranpotentialänderungen am Herzen und ihre Bedeutung für die elektro-mechanische Kopplung. Versuche mit Tetrodotoxin in Na-haltigen Lösungen. Naunyn-Schmiedebergs Arch. Pharmak. 265, 187–204 (1969).CrossRefGoogle Scholar
  50. —, u. H. Reuter: Über die Beziehung zwischen Membranpotential und Kontraktion am Herzen unter dem Einfluß von Adrenalin. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 260, 196–197 (1968).CrossRefGoogle Scholar
  51. Snedecor, G.W.: Statistical Methods. Ames, Iowa: The Iowa State College Press 1950.Google Scholar
  52. Strubelt, O.: Der Einfluß von Reserpin, Propranolol, Hexamethonium und der Adrenalektomie auf die chronotropen Wirkungen von Theophyllin und Coffein. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 261, 176–190 (1968).CrossRefGoogle Scholar
  53. Vassort, G., O. Rougier, D. Garnier, M.-P. Sauviat, E. Corabœuf et Y.-M. Gargouël: Effets de l’adrénaline sur les courants entrants transmembranaires au cours de l’activité cardiaque. C.R. Acad. Sci. (Paris) 267, 1762–1765 (1968).Google Scholar
  54. Weber, A., R. Herz, and I. Reiss: The nature of the cardiac relaxing factor. Bio-chim. biophys. Acta (Amst.) 131, 188–194 (1967).CrossRefGoogle Scholar
  55. Winegrad, S., and A.M. Shanes: Calcium flux and contractility in guinea-pig atria. J. gen. Physiol. 45, 371–394 (1962).PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1969

Authors and Affiliations

  • T. Meinertz
    • 1
  • H. Scholz
    • 1
  1. 1.Pharmakologisches Institut der UniversitätMainzDeutschland

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