Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1988 Jul;94(3):685–692. doi: 10.1111/j.1476-5381.1988.tb11576.x

Selective regulation of beta 1- and beta 2-adrenoceptors in the human heart by chronic beta-adrenoceptor antagonist treatment.

M C Michel 1, A Pingsmann 1, J J Beckeringh 1, H R Zerkowski 1, N Doetsch 1, O E Brodde 1
PMCID: PMC1854050  PMID: 2902891

Abstract

1. In 44 patients undergoing coronary artery bypass grafting, the effect of chronic administration of the beta-adrenoceptor antagonists sotalol, propranolol, pindolol, metoprolol and atenolol on beta-adrenoceptor density in right atria (containing 70% beta 1- and 30% beta 2-adrenoceptors) and in lymphocytes (having only beta 2-adrenoceptors) was studied. 2. beta-Adrenoceptor density in right atrial membranes and in intact lymphocytes was assessed by (-)-[125I]-iodocyanopindolol (ICYP) binding; the relative amount of right atrial beta 1- and beta 2-adrenoceptors was determined by inhibition of ICYP binding by the selective beta 2-adrenoceptor antagonist ICI 118,551 and analysis of the resulting competition curves by the iterative curve fitting programme LIGAND. 3. With the exception of pindolol, all beta-adrenoceptor antagonists increased right atrial beta-adrenoceptor density compared to that observed in atria from patients not treated with beta-adrenoceptor antagonists. 4. All beta-adrenoceptor antagonists increased right atrial beta 1-adrenoceptor density; on the other hand, only sotalol and propranolol also increased right atrial beta 2-adrenoceptor density, whereas metoprolol and atenolol did not affect it and pindolol decreased it. 5. Similarly, in corresponding lymphocytes, only sotalol or propranolol increased beta 2-adrenoceptor density, while metoprolol and atenolol did not affect it and pindolol decreased it. 6. It is concluded that beta-adrenoceptor antagonists subtype-selectively regulate cardiac and lymphocyte beta-adrenoceptor subtypes. The selective increase in cardiac beta 1-adrenoceptor density evoked by metoprolol and atenolol may be one of the reasons for the beneficial effects observed in patients with end-stage congestive cardiomyopathy following intermittent treatment with low doses of selective beta 1-adrenoceptor antagonists.

Full text

PDF

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aarons R. D., Molinoff P. B. Changes in the density of beta adrenergic receptors in rat lymphocytes, heart and lung after chronic treatment with propranolol. J Pharmacol Exp Ther. 1982 May;221(2):439–443. [PubMed] [Google Scholar]
  2. Aarons R. D., Nies A. S., Gal J., Hegstrand L. R., Molinoff P. B. Elevation of beta-adrenergic receptor density in human lymphocytes after propranolol administration. J Clin Invest. 1980 May;65(5):949–957. doi: 10.1172/JCI109781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bilski A. J., Halliday S. E., Fitzgerald J. D., Wale J. L. The pharmacology of a beta 2-selective adrenoceptor antagonist (ICI 118,551). J Cardiovasc Pharmacol. 1983 May-Jun;5(3):430–437. doi: 10.1097/00005344-198305000-00013. [DOI] [PubMed] [Google Scholar]
  4. Bristow M. R., Ginsburg R., Minobe W., Cubicciotti R. S., Sageman W. S., Lurie K., Billingham M. E., Harrison D. C., Stinson E. B. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982 Jul 22;307(4):205–211. doi: 10.1056/NEJM198207223070401. [DOI] [PubMed] [Google Scholar]
  5. Bristow M. R., Ginsburg R., Umans V., Fowler M., Minobe W., Rasmussen R., Zera P., Menlove R., Shah P., Jamieson S. Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. Circ Res. 1986 Sep;59(3):297–309. doi: 10.1161/01.res.59.3.297. [DOI] [PubMed] [Google Scholar]
  6. Bristow M. R., Kantrowitz N. E., Ginsburg R., Fowler M. B. Beta-adrenergic function in heart muscle disease and heart failure. J Mol Cell Cardiol. 1985 Jul;17 (Suppl 2):41–52. doi: 10.1016/0022-2828(85)90007-0. [DOI] [PubMed] [Google Scholar]
  7. Brodde O. E. Bisoprolol (EMD 33512), a highly selective beta 1-adrenoceptor antagonist: in vitro and in vivo studies. J Cardiovasc Pharmacol. 1986;8 (Suppl 11):S29–S35. doi: 10.1097/00005344-198511001-00005. [DOI] [PubMed] [Google Scholar]
  8. Brodde O. E., Brinkmann M., Schemuth R., O'Hara N., Daul A. Terbutaline-induced desensitization of human lymphocyte beta 2-adrenoceptors. Accelerated restoration of beta-adrenoceptor responsiveness by prednisone and ketotifen. J Clin Invest. 1985 Sep;76(3):1096–1101. doi: 10.1172/JCI112063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brodde O. E., Daul A., Stuka N., O'Hara N., Borchard U. Effects of beta-adrenoceptor antagonist administration on beta 2-adrenoceptor density in human lymphocytes. The role of the "intrinsic sympathomimetic activity". Naunyn Schmiedebergs Arch Pharmacol. 1985 Feb;328(4):417–422. doi: 10.1007/BF00692910. [DOI] [PubMed] [Google Scholar]
  10. Brodde O. E., Daul A., Wellstein A., Palm D., Michel M. C., Beckeringh J. J. Differentiation of beta 1- and beta 2-adrenoceptor-mediated effects in humans. Am J Physiol. 1988 Feb;254(2 Pt 2):H199–H206. doi: 10.1152/ajpheart.1988.254.2.H199. [DOI] [PubMed] [Google Scholar]
  11. Brodde O. E., Schemuth R., Brinkmann M., Wang X. L., Daul A., Borchard U. Beta-adrenoceptor antagonists (non-selective as well as beta 1-selective) with partial agonistic activity decrease beta 2-adrenoceptor density in human lymphocytes. Evidence for a beta 2-agonistic component of the partial agonistic activity. Naunyn Schmiedebergs Arch Pharmacol. 1986 Jun;333(2):130–138. doi: 10.1007/BF00506515. [DOI] [PubMed] [Google Scholar]
  12. Brodde O. E., Schüler S., Kretsch R., Brinkmann M., Borst H. G., Hetzer R., Reidemeister J. C., Warnecke H., Zerkowski H. R. Regional distribution of beta-adrenoceptors in the human heart: coexistence of functional beta 1- and beta 2-adrenoceptors in both atria and ventricles in severe congestive cardiomyopathy. J Cardiovasc Pharmacol. 1986 Nov-Dec;8(6):1235–1242. doi: 10.1097/00005344-198611000-00021. [DOI] [PubMed] [Google Scholar]
  13. Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
  14. CHIDSEY C. A., HARRISON D. C., BRAUNWALD E. Augmentation of the plasma nor-epinephrine response to exercise in patients with congestive heart failure. N Engl J Med. 1962 Sep 27;267:650–654. doi: 10.1056/NEJM196209272671305. [DOI] [PubMed] [Google Scholar]
  15. Cohn J. N., Levine T. B., Olivari M. T., Garberg V., Lura D., Francis G. S., Simon A. B., Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984 Sep 27;311(13):819–823. doi: 10.1056/NEJM198409273111303. [DOI] [PubMed] [Google Scholar]
  16. Fowler M. B., Bristow M. R. Rationale for beta-adrenergic blocking drugs in cardiomyopathy. Am J Cardiol. 1985 Apr 26;55(10):120D–124D. doi: 10.1016/0002-9149(85)91066-5. [DOI] [PubMed] [Google Scholar]
  17. Francis G. S., Cohn J. N. The autonomic nervous system in congestive heart failure. Annu Rev Med. 1986;37:235–247. doi: 10.1146/annurev.me.37.020186.001315. [DOI] [PubMed] [Google Scholar]
  18. Francis G. S., Goldsmith S. R., Ziesche S. M., Cohn J. N. Response of plasma norepinephrine and epinephrine to dynamic exercise in patients with congestive heart failure. Am J Cardiol. 1982 Apr 1;49(5):1152–1156. doi: 10.1016/0002-9149(82)90039-x. [DOI] [PubMed] [Google Scholar]
  19. Gille E., Lemoine H., Ehle B., Kaumann A. J. The affinity of (-)-propranolol for beta 1- and beta 2-adrenoceptors of human heart. Differential antagonism of the positive inotropic effects and adenylate cyclase stimulation by (-)-noradrenaline and (-)-adrenaline. Naunyn Schmiedebergs Arch Pharmacol. 1985 Oct;331(1):60–70. doi: 10.1007/BF00498852. [DOI] [PubMed] [Google Scholar]
  20. Giudicelli Y., Lacasa D., Agli B., Leneveu A. Comparison of changes in the characteristics of beta-adrenoceptors and responsiveness of human circulating lymphocytes during and after chronic administration of pindolol and propranolol. Eur J Clin Pharmacol. 1984;26(1):7–12. doi: 10.1007/BF00546700. [DOI] [PubMed] [Google Scholar]
  21. Harden T. K. Agonist-induced desensitization of the beta-adrenergic receptor-linked adenylate cyclase. Pharmacol Rev. 1983 Mar;35(1):5–32. [PubMed] [Google Scholar]
  22. Hedberg A., Gerber J. G., Nies A. S., Wolfe B. B., Molinoff P. B. Effects of pindolol and propranolol on beta adrenergic receptors on human lymphocytes. J Pharmacol Exp Ther. 1986 Oct;239(1):117–123. [PubMed] [Google Scholar]
  23. Kaumann A. J., Lemoine H. Beta 2-adrenoceptor-mediated positive inotropic effect of adrenaline in human ventricular myocardium. Quantitative discrepancies with binding and adenylate cyclase stimulation. Naunyn Schmiedebergs Arch Pharmacol. 1987 Apr;335(4):403–411. doi: 10.1007/BF00165555. [DOI] [PubMed] [Google Scholar]
  24. Lands A. M., Arnold A., McAuliff J. P., Luduena F. P., Brown T. G., Jr Differentiation of receptor systems activated by sympathomimetic amines. Nature. 1967 May 6;214(5088):597–598. doi: 10.1038/214597a0. [DOI] [PubMed] [Google Scholar]
  25. McPherson G. A. Analysis of radioligand binding experiments. A collection of computer programs for the IBM PC. J Pharmacol Methods. 1985 Nov;14(3):213–228. doi: 10.1016/0160-5402(85)90034-8. [DOI] [PubMed] [Google Scholar]
  26. Neve K. A., Barrett D. A., Molinoff P. B. Selective regulation of beta-1 and beta-2 adrenergic receptors by atypical agonists. J Pharmacol Exp Ther. 1985 Dec;235(3):657–664. [PubMed] [Google Scholar]
  27. Snavely M. D., Motulsky H. J., Moustafa E., Mahan L. C., Insel P. A. beta-Adrenergic receptor subtypes in the rat renal cortex. Selective regulation of beta 1-adrenergic receptors by pheochromocytoma. Circ Res. 1982 Oct;51(4):504–513. doi: 10.1161/01.res.51.4.504. [DOI] [PubMed] [Google Scholar]
  28. Stiles G. L., Caron M. G., Lefkowitz R. J. Beta-adrenergic receptors: biochemical mechanisms of physiological regulation. Physiol Rev. 1984 Apr;64(2):661–743. doi: 10.1152/physrev.1984.64.2.661. [DOI] [PubMed] [Google Scholar]
  29. Thomas J. A., Marks B. H. Plasma norepinephrine in congestive heart failure. Am J Cardiol. 1978 Feb;41(2):233–243. doi: 10.1016/0002-9149(78)90162-5. [DOI] [PubMed] [Google Scholar]
  30. Tsujimoto G., Manger W. M., Hoffman B. B. Desensitization of beta-adrenergic receptors by pheochromocytoma. Endocrinology. 1984 Apr;114(4):1272–1278. doi: 10.1210/endo-114-4-1272. [DOI] [PubMed] [Google Scholar]
  31. Whyte K., Jones C. R., Howie C. A., Deighton N., Sumner D. J., Reid J. L. Haemodynamic, metabolic, and lymphocyte beta 2-adrenoceptor changes following chronic beta-adrenoceptor antagonism. Eur J Clin Pharmacol. 1987;32(3):237–243. doi: 10.1007/BF00607569. [DOI] [PubMed] [Google Scholar]
  32. Wood A. J., Feldman R., Nadeau J. Physiological regulation of beta-receptors in man. Clin Exp Hypertens A. 1982;4(4-5):807–817. doi: 10.3109/10641968209061614. [DOI] [PubMed] [Google Scholar]
  33. Zerkowski H. R., Ikezono K., Rohm N., Reidemeister J. C., Brodde O. E. Human myocardial beta-adrenoceptors: demonstration of both beta 1- and beta 2-adrenoceptors mediating contractile responses to beta-agonists on the isolated right atrium. Naunyn Schmiedebergs Arch Pharmacol. 1986 Feb;332(2):142–147. doi: 10.1007/BF00511404. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES