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Basic Research in Cardiology

, Volume 92, Issue 1, pp 25–34 | Cite as

Modulation of pacemaker activity in sheep cardiac Purkinje fibers by stimulation of β-adrenoceptor subtypes

  • U. Thome
  • F. Berger
  • U. Borchard
  • D. Hafner
Original Contribution
  • 45 Downloads

Abstract

The electrophysiological effects mediated by β1- and β2- in spontaneously active sheep cardiac Purkinje fibers were investigated using the non-selective agonist (−)-isoproterenol (IPN) and the selective agonists (−)-noradrenaline (β1) and procaterol (β2) in the absence and presence of the selective antagonists bisoprolol (β1) and ICI 118,551 (β2).

IPN (0.01 μmol/l) increased the spontaneous rate by 54% and the slope of diastolic depolarization by 68% of the respective control values. Further, IPN increased the action potential duration at −20 mV (APD −20 mV) from 96 to 154 ms, reduced the APD −70 mV by 17% and the duration of the diastole by 39% and slightly hyperpolarized the maximum diastolic potential. These effects were partially inhibited by ICI 118,551 (0.03 μmol/l), diminished by bisoprolol (0.1 μmol/l) and almost completely blocked by the combination of both antagonists. Concentration response curves of IPN were influenced by the selective antagonists as follows: ICI 118,551 (0.03 μmol/l) shifted the curves to the right by 0.2–0.4 log units and increased the slope factor. Bisoprolol (0.1 μmol/l) induced a greater shift to the right by 1.1–1.5 log units. Combination of bisoprolol with ICI 118,551 shifted the curves to the right by 1.5–1.7 log units.

Noradrenaline (0.3 μmol/l) elicited similar actions as IPN. Bisoprolol (0.1 μmol/l) shifted the concentration response curves of noradrenaline to the right by 1.1–1.9 log units. Actions of procaterol (0.1 μmol/l) were weak, attained only 15–35% of the maximal effects of IPN and could be blocked by ICI 118,551 (0.03 μmol/l).

These results show that the increase of pacemaker activity induced by catecholamines in sheep cardiac Purkinje fibers is predominantly mediated by stimulation of β1. However, contribution of β2 mediated effects could be demonstrated.

Key words

Sheep cardiac Purkinje fibers action potentials automaticity β12adrenoceptors-(−) isoproterenol (−)-noradrenaline procaterol bisoprolol ICI 118,551 

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References

  1. 1.
    Antoni H, Oberdisse E (1965) Elektrophysiologische Untersuchungen über die Barium-induzierte Schritmacher-Aktivität im isolierten Säugetiermyokard. Pflügers Arch 284: 259–272Google Scholar
  2. 2.
    Borchard U, Hafner D, Schütz D (1986) Frequency regulation in the sinoatrial node: Function β1- and β2-receptors. In: Middeke M, Holzgreve H (eds) Adrenoceptors; New aspects in Hypertension. Springer, Berlin, pp 65–73Google Scholar
  3. 3.
    Bristow MR, Ginsburg R (1986) Beta2 receptors on myocardial cells in human ventricular myocardium. Am J Cardiol 57: 3F-6FGoogle Scholar
  4. 4.
    Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmussen R, Zera P, Menlove R, Shah P, Jamieson S, Stinson EB (1986) Beta1 and beta2-adrenergic receptor subpopulations in non failing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta1-receptor down-regulation in heart failure. Circ Res 59: 297–309Google Scholar
  5. 5.
    Brodde O-E, Karad K, Zerkowski H-R, Rohm N, Reidemeister JC (1983) Coexistence of β1- and β2-adrenoceptors in human right atrium. Direct identification by (±)-[125I]iodocyanopindolol binding. Circ Res 53: 752–758Google Scholar
  6. 6.
    Brodde O-E, O'Hara N, Zerkowski H-R, Rohm N (1984) Human cardiac β-adrenoceptors: Both β1- and β2-adrenoceptors are functionally coupled to the adenylate cyclase in right atrium. J Cardiovasc Pharmacol 6: 1184–1191Google Scholar
  7. 7.
    Brodde O-E, Schüler S, Kretsch R, Brinkmann M, Borst HG, Hetzer R, Reidemeister JChr, Warnecke H, Zerkowski H-R (1986) Regional distribution of beta adrenoceptors in the human heart: coexistence of functional beta1 and beta2 adenoceptors in both atria and ventricles in severe congestive cardiomyopathy. J Cardiovasc Pharmacol 8: 1235–1242Google Scholar
  8. 8.
    Brodde O-E, Zerkowski H-R, Doetsch N, Motomura S, Khamssi M, Michel MC (1989) Myocardial beta-adrenoceptor changes in heart failure: concomitant reduction in beta1 and beta2 adrenoceptor function related to the degree of heart failure in patients with mitral valve disease. J Am Coll Cardiol 14 (2): 323–331Google Scholar
  9. 9.
    Brown JE, McLeod AA, Shand DG (1986) In support of cardiac chronotropic beta2 adrenoceptors. Am J Cardiol 57: 11F-16FGoogle Scholar
  10. 10.
    Buxton BF, Jones CR, Molenaar P, Summers RJ (1987) Characterization and autoradiographic localization of β-adrenoceptor subtypes in human cardiac tissues. Br J Pharmacol 92: 299–310Google Scholar
  11. 11.
    Cerbai E, Masini I, Mugelli A (1990) Electrophysiological characterization of cardiac β2-adrenoceptors in sheep Purkinje fibers. J Mol Cell Cardiol 22: 859–870Google Scholar
  12. 12.
    DiFrancesco D, Ferroni A, Visentin S (1984) Barium-induced blockade of the inward rectifier in calf Purkinje fibers. Pflügers Arch 402: 446–453Google Scholar
  13. 13.
    Dukes ID, Vaughan Williams EM (1984) Effects of selective α1-, α2-, β1-, and β2-adrenoceptor stimulation on potentials and contractions in the rabbit heart. J Physiol (Lond) 355: 523–546Google Scholar
  14. 14.
    Elnatan J, Molenaar P, Rosenfeldt FL, Summers RJ (1994) Autoradiographic localization and quantitation of β1- and β2-adrenoceptors in the human atrioventricular conduction system: a comparison of patients with idiopathic dilated cardiomyopathy and ischemic heart disease. J Mol Cell Cardiol 26: 313–323Google Scholar
  15. 15.
    Gille E, Lemoine H, Ehle B, Kaumann AJ (1985) The affinity of (−)-propranolol for β1- and β2-adrenoceptors of human heart. Differential antagonism of the positive inotropic effects and adenylate cyclase stimulation by (−)-noradrenaline and (−)-adrenaline. Naunyn-Schmiedeberg's Arch Pharmacol 331: 60–70Google Scholar
  16. 16.
    Grabowski W, Lüttgau HC, Schulze JJ (1978) The effects of isoprenaline and a new β-sympathomimetic amine upon spontaneous activity, diastolic depolarization and plateau height in cardiac Purkinje fibers. Br J Pharmacol 63: 427–434Google Scholar
  17. 17.
    Hafner D, Heinen E, Noack E (1977) Mathematical analysis of concentration response relationships. Arzneimittel-Forschung/Drug Research 27 (II) 10: 1871–1873Google Scholar
  18. 18.
    Hedberg A, Mattsson H (1981) Beta adrenoceptor interaction of full and partial agonists in the cat heart and soleus muscle. Pharmacol Exp Ther 219: 798–808Google Scholar
  19. 19.
    Heitz A, Schwartz J, Velly J (1983) β-adrenoceptors of the human myocardium: determination of β1 β2 subtypes by radioligand binding. Br J Pharmacol 80: 711–717Google Scholar
  20. 20.
    Ikezono K, Michel MC, Zerkowski H-R, Beckeringh JJ, Brodde O-E (1987) The role of cyclic AMP in the positive inotropic effect mediated by β1- and β2-adrenoceptors in isolated human right atrium. Naunyn-Schmiedeberg's Arch Pharmacol 335: 561–566Google Scholar
  21. 21.
    Imoto Y, Ehara T, Matsuura H (1987) Voltage- and time-dependent block of ik1 underlying Ba2+-induced ventricular automaticity. Am J Physiol 252 (Heart Circ Physiol 21): H325-H333Google Scholar
  22. 22.
    Janse MJ, Capelle FJL van, Morsink H, Kléber AG, Wilms-Schopman F, Cardinal R, Naumann D'Alnoncourt CN, Durrer D (1980) Flow of “injury” current and patterns of excitation during early ventricular arrhythmias in acute regional myocardial ischemia in isolated porcine and canine hearts. Evidence for two different arrhythmogenic mechanisms. Circ Res 47: 151–165Google Scholar
  23. 23.
    Kaumann AJ (1970) Adrenergic receptors in heart muscle: Relation among factors influencing the sensitivity of the cat papillary muscle to catecholamines. J Pharmacol Exp Ther 173: 383–398Google Scholar
  24. 24.
    Kaumann AJ, Lemoine H (1985) Direct labelling of myocardial β1. Comparison of binding affinity of3H-(−)-bisoprolol with its blocking potency. Naunyn-Schmiedeberg's Arch Pharmacol 331: 27–39Google Scholar
  25. 25.
    Kaumann AJ, Lemoine H (1987) 33-16 positive inotropic effect of adrenaline in human ventricular myocardium. Quantitative discrepancies with binding and adenylate cyclase stimulation. Naunyn-Schmiedeberg's Arch Pharmacol 335: 403–411Google Scholar
  26. 26.
    Lands AM, Arnold A, McAuliff JP, Luduena FP, Brown TG (1967) Differentiation of receptor systems activated by sympathomimetic amines. Nature 214: 597–598Google Scholar
  27. 27.
    Lands AM, Luduena FP, Buzzo HJ (1967) Differentiation of receptors responsive to isoproterenol. Life Sci 6: 2241–2249Google Scholar
  28. 28.
    Lemoine H, Ehle B, Kaumann AJ (1985) Direct labelling of β1-adrenoceptors. Comparison of binding potency of3H-ICI 118.551 and blocking potency of ICI 118,551. Naunyn-Schmiedeberg's Arch Pharmacol 331: 40–51Google Scholar
  29. 29.
    Michel MC, Pingsmann A, Beckeringh JJ, Zerkowski H-R, Doetsch N, Brodde O-E (1988) Selective regulation of β1- and β2-adrenoceptors in the human heart by chronic β-adrenoceptor antagonist treatment. Br J Pharmacol 94: 685–692Google Scholar
  30. 30.
    Molenaar P, Summers RJ (1987) Characterization of beta-1 and beta-2 adrenoceptors in guinea-pig atrium: Functional and receptor binding studies. J Pharmacol Exp Ther 241 (3): 1041–1047Google Scholar
  31. 31.
    Molenaar P, Russell FD, Shimada T, Summers RJ (1990) Densitometric analysis of β1- and β2-adrenoceptors in guinea-pig atrioventricular conduction system. J Mol Cell Cardiol 22: 483–485Google Scholar
  32. 32.
    Motomura S, Zerkowski H-R, Daul A, Brodde O-E (1990) On the physiologic role of beta-2 adrenoceptors in the human heart: In vitro and in vivo studies. Am Heart J 119 (3): 608–619Google Scholar
  33. 33.
    Mugelli A, Amerini S, De Bonfioli Cavalcabo P, Cerbai E, Visentin S (1987) Electrophysiological effects mediated by the stimulation of cardiac β2-adrenoceptors with tulobuterol. Cardiovasc Drugs Ther 1: 101–107Google Scholar
  34. 34.
    Rappen-Cremer E, Borchard U, Hafner D, Berger F (1989) H1-receptor reserves in guinea-pig left atria, trachea and pig coronary artery as identified by phenoxybenzamine. Agents Actions 28: 219–223Google Scholar
  35. 35.
    Terris S, Wasserstrom JA, Fozzard HA (1986) Depolarizing effects of catecholamines in quiescent sheep cardiac Purkinje fibers. Am J Physiol 251 (Heart Circ Physiol 20): H1056-H1061Google Scholar
  36. 36.
    Thome U, Borchard U, Berger F, Hafner D (1990) Histamine- and β-receptor subtypes in sheep cardiac purkinje fibers (Abstract). Naunyn-Schmiedeberg's Arch Pharmacol 342, Suppl: 164Google Scholar
  37. 37.
    Yamashita S, Takai M, Yabuuchi Y (1978) Actions of procaterol (OPC-2009), a new β2-adrenoceptor stimulant, on pulmonary resistance, contractions of the soleus muscle, and cardiovascular system of the anaesthetized cat. J Pharm Pharmacol 30: 273–279Google Scholar
  38. 38.
    Yanagisawa T, Ishii K, Hashimoto H, Taira N (1989) Differential coupling to positive inotropic response of cyclic AMP produced by stimulation of β1- and β2-adrenergic receptors. J Cardiovasc Pharmacol 13: 64–75Google Scholar
  39. 39.
    Zerkowski H-R, Ikezono K, Rohm N, Reidemeister JC, Brodde O-E (1986) Human myocardial β-adrenoceptors: demonstration of both β1- and β2-adrenoceptors mediating contractile responses to β-agonists on the isolated right atrium. Naunyn-Schmiedeberg's Arch Pharmacol 332: 142–147Google Scholar

Copyright information

© Steinkopff Verlag 1997

Authors and Affiliations

  • U. Thome
    • 1
  • F. Berger
    • 1
  • U. Borchard
    • 1
  • D. Hafner
    • 1
  1. 1.Institut für PharmakologieHeinrich-Heine-Universität DüsseldorfDüsseldorfGermany

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