Effects of several phosphodiesterase-inhibitors on guinea-pig myocardium

  • Michael Korth
Article

Summary

  1. 1.

    The inotropic effects of (±)-isoprenaline and several phosphodiesterase (PDE)-inhibitors were studied in isometrically contracting guinea-pig papillary muscles driven at a rate of 0.2 Hz. The maximal positive inotropic effect of isoprenaline (ΔFc=2.2 g;n=7) corresponded to that of 1-methyl, 3-isobutylxanthine (IBMX) and theophylline (ΔFc=2.1 and 2.2 g, respectively;n=7 each). Papaverine produced only a slight increase in contractile force (ΔFc=0.38 g;n=7), which in some preparations was completely absent.

     
  2. 2.

    The positive inotropic effects of IBMX, theophylline, and papaverine were not due to release of noradrenaline from adrenergic nerve endings. Blockade of the β-adrenoceptors with 5×10−6 M (±)-propranolol did not prevent the positive inotropic effect of IMBX.

     
  3. 3.

    The relaxation time,t2, was shortened by isoprenaline (36 ms) more than by IBMX (28 ms) while the time to peak force,t1, was reduced by 12 ms by isoprenaline and by 24 ms by IBMX. Isoprenaline and IBMX abbreviated the total contraction time,t1+t2, to nearly the same extent (48 and 52 ms, respectively). Theopylline and papaverine prolongedt1+t2 by 68 and 30 ms, respectively, due to a lengthening oft2.

     
  4. 4.

    IBMX, theophylline, and papaverine shifted the isoprenaline concentration-effect curve to the left, decreasing the concentration of isoprenaline required to produce a half-maximal increase in the force of contraction from 1×10−8 M to 2×10−9 M for IBMX and papaverine and to 3.2×10−9 M for theophylline. IBMX enhanced the inotropic effect of dibutyryl cyclic AMP by a factor of 7.

     
  5. 5.

    Among several PDE-inhibitors, IBMX was found to mimic the effects of isoprenaline with regard to its maximum inotropic effect and its shortening oft1+t2. Isoprenaline-like effects of theophylline and papaverine were probably masked by the involvement of additional factors discussed in this study.

     

Key words

Positive inotropic effect Isometric contraction curve Phosphodiesterase-inhibitors Isoprenaline Guinea-pig papillary muscle 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Beavo, J. A., Rogers, N. L., Crofford, O. R., Hardman, J. G., Sutherland, E. W., Newman, E. V.: Effects of xanthine derivatives on lipolysis and on adenosine 3′,5′-monophosphate phosphodiesterase activity. Mol. Pharmacol.6, 597–603 (1970)Google Scholar
  2. Blinks, J. R., Olson, C. B., Jewell, B. R., Bravený, P.: Influences of caffeine and other methylxanthines on mechanical properties of isolated mammalian heart muscle. Circ. Res.30, 367–392 (1972)Google Scholar
  3. Brady, A. J.: The development of tension in cardiac muscle. In: Pharmacology of cardiac function (O. Krayer, ed.), pp. 15–23. Oxford: Pergamon Press 1964Google Scholar
  4. Butcher, R. W., Sutherland, E. W.: Adenosine 3′,5′-monophosphate in biological materials. I. Purification and properties of cyclic 3′,5′-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3′,5′-phosphate in human urine. J. Biol. Chem.237, 1244–1250 (1962)Google Scholar
  5. De Gubareff, T., Sleator, W.: Effect of caffeine on mammalian atrial muscle and its interaction with adenosine and calcium. J. Pharmacol. Exp. Ther.148, 202–214 (1965)Google Scholar
  6. Endoh, M., Schümann, H. J.: Effects of papaverine on isolated rabbit papillary muscle. Eur. J. Pharmacol.30, 213–220 (1975)Google Scholar
  7. Fuchs, F.: Inhibition of sarcotubular calcium transport by caffeine: species and temperature dependence. Biochim. Biophys. Acta172, 566–570 (1969)Google Scholar
  8. Heitmann, M., Meinertz, T., Schmelzle, B., Scholz, H.: Effects of theophylline on force of contraction and cyclic AMP in isolated guinea pig auricles. Naunyn-Schmiedeberg's Arch. Pharmacol.293, R 24 (1976)Google Scholar
  9. Henry, P. D., Sobel, B. E.: Disparate effects of papaverine on cyclic AMP and contractility. Circulation46 (Suppl. II) 120 (1972)Google Scholar
  10. Holzmann, S., Meinertz, T., Nawrath, H., Scholz, H.: Effects of papaverine on cyclic AMP, calcium uptake and force on contraction in isolated guinea-pig auricles. Res. Comm. Chem. Path. Pharmacol.16, 443–450 (1977)Google Scholar
  11. Kirchberger, M. A., Tada, M., Repke, D. I., Katz, A. M.: Cyclic adenosine 3′,5′-monophosphate-dependent protein kinase stimulation of calcium uptake by canine cardiac microsomes. J. Mol. Cell. Cardiol.4, 673–680 (1972)Google Scholar
  12. Klaus, W., Krebs, R., Seitz, N.: Über die Dissoziation von Funktion und Stoffwechsel des isolierten Meerschweinchenherzens unter Einfluß von Phosphodiesterase-Hemmstoffen. Naunyn-Schmiedebergs Arch. Pharmak.267, 99–113 (1970)Google Scholar
  13. Krop, S.: The influence of “heart stimulants” on the contraction of isolated mammalian cardiac muscle. J. Pharmacol. Exp. Ther.82, 48–62 (1944)Google Scholar
  14. Kukovetz, W. R., Pöch, G.: Zum Mechanismus der Herzwirkung von Methylxanthinen. In: Coffein und andere Methylxanthine (F. Heim, H. P. T. Ammon, eds.), pp. 91–108. Stuttgart-New York: Schattauer 1969Google Scholar
  15. Kukovetz, W. R., Pöch, G.: Inhibition of cyclic-3′,5′-nucleotide phosphodiesterase as a possible mode of action of papaverine and similarly acting drugs. Naunyn-Schmiedebergs Arch. Pharmak.267, 189–194 (1970)Google Scholar
  16. Kukovetz, W. R., Pöch, G., Wurm, A.: Quantitative relations between cyclic AMP levels and contraction as affected by stimulators of adenylate cyclase and inhibitors of phosphodiesterase. In: Advances in cyclic nucleotide research, Vol. 5 (G. I. Drummond, P. Greengard, G. A. Robison, eds.), pp. 395–414. New York: Raven Press 1975Google Scholar
  17. Marcus, M. L., Skelton, C. L., Grauer, L. E., Epstein, S. E.: Effects of theophylline on myocardial mechanics. Am. J. Physiol.222, 1361–1365 (1972)Google Scholar
  18. McNeill, J. H., Brenner, M. J., Muschek, L. D.: Interaction of four methylxanthine compounds and norepinephrine on cardiac phosphorylase activation and cardiac contractility. Recent Adv. Stud. Cardiac Struct. Metab.3, 261–273 (1973)Google Scholar
  19. Meinertz, T., Nawrath, H.: Adrenaline, BD-c-AMP and myocardial45Ca exchange. Comparative studies in rat and guinea-pig auricles. Naunyn-Schmiedeberg's Arch. Pharmacol.279, 313–325 (1973)Google Scholar
  20. Meinertz, T., Nawrath, H., Scholz, H., Winter, K.: Effect of DB-c-AMP on mechanical characteristics of ventricular and atrial preparations of several mammalian species. Naunyn-Schmiedeberg's Arch. Pharmacol.282, 143–153 (1974)Google Scholar
  21. Nathan, D., Beeler, G. W.: Electrophysiologic correlates of the inotropic effects of isoproterenol in canine myocardium. J. Mol. Cell. Cardiol. 7, 1–15 (1975)Google Scholar
  22. Peytreman, A., Nicholson, W. E., Liddle, G. W., Hardman, J. G., Sutherland, E. W.: Effects of methylxanthines on adenosine 3′,5′-monophosphate and corticosterone in the rat adrenal. Endocrinology92, 525–530 (1973)Google Scholar
  23. Posternak, T., Sutherland, E. W., Henion, W. F.: Derivatives of cyclic 3′,5′-adenosine monophosphate. Biochim. Biophys. Acta65, 558–560 (1962)Google Scholar
  24. Pretorius, P. J., Pohl, W. G., Smithen, C. S., Inesi, G.: Structural and functional characterization of dog heart microsomes. Circ. Res.25, 487–499 (1969)Google Scholar
  25. Rall, T. W., West, T. C.: Potentiation of cardiac inotropic responses to norepinephrine by theophylline. J. Pharmacol. Exp. Ther.139, 269–274 (1963)Google Scholar
  26. Reiter, M.: Die Wertbestimmung inotrop wirkender Arzneimittel am isolierten Papillarmuskel. Arzneimittel-Forsch.17, 1249–1253 (1967)Google Scholar
  27. Reiter, M.: Differences in the inotropic cardiac effects of noradrenaline and dihydro-ouabain. Naunyn-Schmiederg's Arch. Pharmacol.175, 243–250 (1972)Google Scholar
  28. 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
  29. Schneider, J. A., Brooker, G., Sperelakis, N.: Papaverine blockade of an inward slow Ca++-current in guinea-pig heart. J. Mol. Cell. Cardiol.7, 867–876 (1975)Google Scholar
  30. Scholz, H.: Über den Mechanismus der positiv inotropen Wirkung von Theophyllin am Warmblüterherzen. II. Wirkung von Theophyllin auf Aufnahme und Abgabe von45Ca. Naunyn-Schmiedebergs Arch. Pharmak.271, 396–409 (1971)Google Scholar
  31. Scholz, H., Reuter, H.: Effect of theophylline on membrane currents in mammalian cardiac muscle. Naunyn-Schmiedeberg's Arch. Pharmacol.293, R 19 (1976)Google Scholar
  32. Scholz, H., de Yazikof, E.: Über den Mechanismus der positiv inotropen Wirkung von Theophyllin am Warmblüterherzen. I. Einfluß der extracellulären Ca-, Na- and K-Konzentration und von Reserpin. Naunyn-Schmiedebergs Arch. Pharmak.271, 374–395 (1971)Google Scholar
  33. Skelton, C. L., Karch, F. E., Hougen, T. J., Marcus, M. L., Epstein, S. E.: Potentiation of the inotropic effects of norepinephrine and dibutyryl cyclic AMP by theophylline. J. Mol. Cell Cardiol.3, 243–253 (1971)Google Scholar
  34. Sonnenblick, E. H.: Active state in heart muscle. Its delayed onset and modification by inotropic agents. J. Gen. Physiol.50, 661–676 (1967)Google Scholar
  35. Sutherland, E. W., Robison, G. A., Batcher, R. W.: Some aspects of the biological role of adenosine 3′,5′-monophosphate (cyclic AMP). Circulation37, 279–306 (1968)Google Scholar
  36. Terasaki, W. L., Brooker, G.: Cardiac adenosine 3′:5′-monophosphate. Free and bound forms in the isolated rat atrium. J. Biol. Chem.252, 1041–1050 (1977)Google Scholar
  37. Tsien, R. W.: Adrenaline-like effects of intracellular iontophoresis of cyclic AMP in cardiac Purkinje fibres. Nature New Biol.245, 120–122 (1973)Google Scholar
  38. Tsien, R. W., Weingart, R.: Inotropic effect of cyclic AMP in calf ventricular muscle studied by a cut end method. J. Physiol. (Lond.)260, 117–141 (1976)Google Scholar
  39. Weber, A., Herz, R.: The relationship between caffeine contracture of intact muscle and the effect of caffeine on reticulum. J. Gen. Physiol.52, 750–759 (1968)Google Scholar

Copyright information

© Springer-Verlag 1978

Authors and Affiliations

  • Michael Korth
    • 1
  1. 1.Institut für Pharmakologie und Toxikologie der Technischen Universität MünchenMünchen 40Germany

Personalised recommendations