Summary
Abrupt withdrawal of β-adrenoceptor antagonists may lead to “rebound-effects”. To study the mechanism underlying this phenomenon, the effects of the nonselective β-adrenoceptor antagonists propranolol [no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and mepindolol (strong ISA) on lymphocyte β2-adrenoceptor density — assessed by (±)-[125I]-iodocyanopindolol (ICYP) binding — and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23–35 years.
-
1.
Propranolol treatment (4×40 mg/day) increased the density of β2-adrenoceptors by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment β2-adrenoceptor density remained elevated. After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. β2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of ICYP to β2-adrenoceptors was not changed during or after treatment.
-
2.
Mepindolol treatment (2×5 mg/day) caused a 30% decrease of β2-adrenoceptor density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas β2-adrenoceptor density was still after 4 days significantly diminished. TheK D-values for ICYP, however, were not changed. During and after treatment heart rate was not affected.
-
3.
Alprenolol treatment (4×100 mg/day) led to a rapid fall in PRA, but did not significantly affect β2-adrenoceptor density.
-
4.
It is concluded, that the ISA may play an important role in modulating β2-adrenoceptor density and hence tissue responsiveness to β-adrenoceptor stimulation. Propranolol (no ISA) caused increase in β2-adrenoceptor density still persisting after withdrawal, which might explain the “propranolol rebound-effect”. Since β-adrenoceptor antagonists with ISA did not increase, but rather decrease β2-adrenoceptor density, such “rebound-effects” may not occur after rapid cessation of drug treatment.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aarons RD, Molinoff, PB (1982) Changes in the density of beta adrenergic receptors in rat lymphocytes, heart and lung after chronic treatment with propranolol. J Pharmacol Exp Ther 221:439–443
Aarons, RD, Nies, AS, Gal J, Hegstrand LR, Molinoff, PB (1980) Elevation of β-adrenergic receptor density in human lymphocytes after propranolol administration. J Clin Invest 65:949–957
Böyum A (1968) Isolation of mononuclear cells and granulocytes from human blood. Scand J Clin Lab Invest 21:Suppl. 97:77–89
Brodde O-E, Engel G, Hoyer D, Block KD, Weber F (1981) The β-adrenergic receptor in human lymphocytes: Subclassification by the use of a new radio-ligand, (±)-125iodocyanopindolol. Life Sci 29:2189–2198
Brodde O-E, Karad, K, Zerkowski H-R, Rohm N, Reidemeister J Chr (1983a) Coexistence of β1- and β2-adrenoceptors in human right atrium. Direct identification by (±)-125iodocyanopindolol binding. Circ Res 53:752–758
Brodde O-E, Kuhlhoff, F, Arroyo J, Prywarra A (1983b) No evidence for temperature-dependent changes in the pharmacological specificity of β1- and β2-adrenoceptors in rabbit lung membranes. Naunyn-Schmiedeberg's Arch Pharmacol 322: 20–28
Daul A, Anlauf M, Stuka N, Bock KD (1984) The role of intrinsic activity of β-adrenoceptor antagonists in modulating the density of β2-adrenoceptors in human lymphocytes (Abstract). Naunyn-Schmiedeberg's Arch Pharmacol 325:Suppl R264
Giudicelli Y, Lacasa D, Agli B, Leneveu A (1984) Comparison of changes in the characteristics of β-adrenoceptors and responsiveness of human circulating lymphocytes during chronic and after chronic administration of pindolol and propranolol. Eur J Clin Pharmacol 26:7–12
Hoffman BB, Lefkowitz RJ (1980) Radioligand binding studies of adrenergic receptors: New insights into molecular and physiological regulation. Annu Rev Pharmacol Toxicol 20:581–608
Molinoff PB, Aarons RD (1983) Effects of drugs on β-adrenergic receptors on human lymphocytes. J Cardiovasc Pharmacol 5: (Suppl. 1) S63-S67
Motulsky HJ, Insel PA (1982) Adrenergic receptors in man. Direct identification, physiologic regulation and clinical alterations. N Engl J Med 307:18–29
Prichard BNC, Tomlinson B, Walden RJ, Bhattacharjee P (1983) The β-adrenergic blockade withdrawal phenomenon. J Cardiovasc Pharmacol 5:(Suppl. 1) S56-S62
Scatchard G (1949) The attraction of proteins for small molecules and ions. Ann N Y Acad Sci 51:660–672
Scriabine A (1979) Adrenoceptor blocking drugs in hypertension. Annu Rev Pharmacol Toxicol 19:269–284
Walden RJ, Bhattacharjee P, Tomlinson B, Cashin J, Graham BR, Prichard BNC (1982) The effect of intrinsic sympathomimetic activity on β-receptor responsiveness after β-adrenoceptor blockade withdrawal. Br J Clin Pharmacol 13:(Suppl. 2) 359S-364S
Wood AJJ, Feldman R, Nadeau J (1982) Physiological regulation of beta-receptors in man. Clin Exp Hypertension A4:807–817
Zohar J, Bannel J, Drummer D, Fisch R, Epstein RP, Belmaker RH (1983) The response of lymphocyte β-adrenergic receptors to chronic propranolol treatment in depressed patients, schizophrenic patients, and normal controls. Biol Psychiatr 18:553–560
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Brodde, OE., Daul, A., Stuka, N. et al. Effects ofβ-adrenoceptor antagonist administration on β2-adrenoceptors density in human lymphocytes. Naunyn-Schmiedeberg's Arch. Pharmacol. 328, 417–422 (1985). https://doi.org/10.1007/BF00692910
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00692910