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.
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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.
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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.
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3.
Alprenolol treatment (4×100 mg/day) led to a rapid fall in PRA, but did not significantly affect β2-adrenoceptor density.
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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.
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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
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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
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DOI: https://doi.org/10.1007/BF00692910