Skip to main content
SpringerLink
Log in

β-Adrenoceptor antagonists (non-selective as well as β 1-selectiveβ 2-adrenoceptor density in human lymphocytes

Evidence for a β 2-agonistic component of the partial agonistic activity

  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

In the present study the effects of pindolol [nonselective β-adrenoceptor antagonist with strong partial agonistic activity (PAA)] on β2-adrenoceptor density in lymphocytes (assessed by (-)-[125I]iodocyanopindolol (ICYP) binding) were compared with those of the β1-selective antagonists celiprolol (with PAA) and bisoprolol (no PAA) in normotensive young volunteers to get further insights into the nature of PAA.

  1. 1)

    Administration of pindolol (2×5 mg/day) caused an about 25% decrease in lymphocyte β2-adrenoceptor density after 2 days; during treatment β2-adrenoceptor density declined further (maximum decrease after 7 days: 50%). After withdrawal of pindolol lymphocyte β2-adrenoceptor density recovered very slowly being still after 4 days significantly reduced, although no pindolol was detectable in plasma after 36 h. The K D-values for ICYP, however, did not change during or after pindolol treatment. The decrease in lymphocyte β2-adrenoceptor density induced by pindolol could be completely prevented by simultaneous administration of propranolol (3×40 mg/day) indicating that the PAA of pindolol is the cause of its β-adrenoceptor decreasing effect.

  2. 2)

    Administration of the non-selective β-adrenoceptor antagonist bopindolol (1×2 mg/day) with PAA caused decreases in lymphocyte β2-adrenoceptor density (maximum decrease after 7 days: 40%); concomitantly the 10 μmol/l (-)-isoprenaline evoked increases in the intracellular level of lymphocyte cyclic AMP were attenuated to a similar extent indicating that the β-adrenoceptor antagonist-induced decrease in β-adrenoceptor density is accompanied by a loss in β-adrenoceptor function.

  3. 3)

    Administration of the β1-selective antagonist celiprolol (1×200 mg/day) with PAA produced effects comparable to those of pindolol and bopindolol: during celiprolol treatment lymphocyte β2-adrenoceptor density and 10 μmol/l (-)-isoprenaline evoked cyclic AMP increases decreased significantly (maximum effect after 7 days: 35%). On the other hand, the β1-selective antagonist bisoprolol (1×10 mg/day) without PAA did not affect lymphocyte β2-adrenoceptor density which strongly supports the view that drug-induced changes in lymphocyte β-adrenoceptors are subtype-selective changes in β2-adrenoceptors.

  4. 4)

    The celiprolol evoked reduction in lymphocyte β2-adrenoceptor density and 10 μmol/l (-)-isoprenaline evoked cyclic AMP increases were abolished by simultaneous administration of propranolol (3×40 mg/day), but not by concomitant application of the β1-adrenoceptor antagonist bisoprolol (1×10 mg/day).

  5. 5)

    It is concluded that the PAA of β-adrenoceptor antagonists possesses a β2-agonistic component since all β-adrenoceptor antagonists with relatively strong PAA-irrespective of to whether they are non-selective (pindolol, bopindolol) or β1-selective (celiprolol)-decrease lymphocyte β2-adrenoceptor density. Whether the PAA of β-adrenoceptor antagonists is solely a β2-effect or tissuedependently a β1- or β2-effect, remains to be elucidated

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • 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

    Google Scholar 

  • Borchard U, Hafner D, Hirth C (1985) In vitro studies on the pharmacological properties of diacetolol, the major metabolite of acebutolol in man. Arch Int Pharmacodyn Ther 273:4–17

    Google Scholar 

  • Böyum A (1968) Isolation of mononuclear cells and granulocytes from human blood. Scand J Clin Lab Invest 21:Suppl 97:77–89

    Google Scholar 

  • Brodde O-E, Daul A, Bock KD (1985a) The intrinsic sympathomimetic activity of β-adrenoceptor antagonists is not β-adrenoceptor subtype selective (Abstract). Naunyn-Schmiedeberg's Arch Pharmacol 329 Suppl R 322

    Google Scholar 

  • Brodde O-E, Daul A, Stuka N, O'Hara N, Borchard U (1985b) Effects of β-adrenoceptor antagonist administration on β2-adrenoceptor density in human lymphocytes. The role of the “intrinsic sympathomimetic activity”. Naunyn-Schmiedeberg's Arch Pharmacol 328:417–422

    Google Scholar 

  • Brodde O-E, Engel G, Hoyer D, Bock 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

    Google Scholar 

  • Bryan LJ, Cole JJ, O'Donnell SR, Wanstall JC (1981) A study designed to explore the hypothesis that beta-1 adrenoceptors are “innervated” receptors and beta-2 adrenoceptors are “hormonal” receptors. J Pharmacol Exp Ther 216:395–400

    Google Scholar 

  • Cook N, Richardson A, Barnett DB (1984) Comparison of the β1-selective affinity of prenalterol and corwin demonstrated by radioligand binding. Eur J Pharmacol 98:407–412

    Google Scholar 

  • Freyss-Beguin M, Griffaton G, Lechat P, Picken D, Quennedey MC, Rouot B, Schwarzt J (1983) Comparison of the chronotropic effect and the cyclic AMP accumulation induced by β2-agonist in rat heart cell culture. Br J Pharmacol 78:717–723

    Google Scholar 

  • Galeazzi RL, Pirovino M, Weidmann P (1983) Constant kinetics and constant concentration-effect relationship during long-term β-blockade with pindolol. Clin Pharmacol Ther 33:733–740

    Google Scholar 

  • Gilman AG (1970) A protein binding assay for adenosine 3′,5′-cyclic monophosphate. Proc Natl Acad Sci USA 67:305–312

    Google Scholar 

  • 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

    Google Scholar 

  • Jones CR, White KF, Reid JL (1985) Haemodynamic, metabolic and lymphocyte β2-adrenoceptor changes following chronic β-adrenoceptor antagonism (Abstract). Br J Clin Pharmacol 19:Suppl 534P

  • Juberg EN, Minneman KP, Abel PW (1985) 138-3 binding and functional response in right and left atria of rat heart. Naunyn-Schmiedeberg's Arch Pharmacol 330:193–202

    Google Scholar 

  • Kenakin TP, Beek D (1984) Relative efficacy of prenalterol and pirbuterol for beta-1 adrenoceptors. Measurements of agonist affinity by alteration of receptor number. J Pharmacol Exp Ther 229:340–345

    Google Scholar 

  • Man in't Veld AJ, Schalekamp MADH (1983) Effects of 10 different beta-adrenoceptor antagonists on hemodynamics, plasma renin activity and plasma norepinephrine in hypertension: the key role of vascular resistance changes in relation to partial agonist activity. J Cardiovasc Pharmacol 5: (Suppl 1) S30-S45

    Google Scholar 

  • McDevitt DG (1979) Adrenoceptor blocking drugs: clinical pharmacology and therapeutic use. Drugs 17:267–288

    Google Scholar 

  • Molinoff PB, Aarons RD (1983) Effects of drugs on β-adrenergic receptors on human lymphocytes. J Cardiovasc Pharmacol 5:(Suppl 1) S63-S67

    Google Scholar 

  • Motulsky HJ, Insel PA (1982) Adrenergic receptors in man. Direct identification, physiologic regulation and clinical alterations. N Engl J Med 307:18–29

    Google Scholar 

  • Nahorski SR, Howlett DR, Redgrave R (1979) Loss of β-adrenoceptor binding sites in rat striatum following kainic acid lesions. Eur J Pharmacol 60:249–252

    Google Scholar 

  • Nerme V, Severne Y, Abrahamsson T, Vauquelin G (1985) Endogenous noradrenaline masks beta-adrenergic receptors in rat heart membranes via tight agonist binding. Biochem Pharmacol 34:2917–2922

    Google Scholar 

  • Platzer R, Galeazzi RL, Niederberger W, Rosenthaler J (1984) Simultaneous modeling of bopindolol kinetics and dynamics. Clin Pharmacol Ther 36:5–13

    Google Scholar 

  • Prichard BNC (1978) Beta-adrenergic receptor blockade in hypertension, past, present and future. Br J Clin Pharmacol 5:379–399

    Google Scholar 

  • Prichard BNC, Tomlinson B, Walden RJ, Bhattacharjee P (1983) The β-adrenergic blockade withdrawal phenomenon. J Cardiovasc Pharmacol 5: (Suppl 1) S56-S62

    Google Scholar 

  • Scatchard G (1949) The attraction of proteins for small molecules and ions. Ann NY Acad Sci 51:660–672

    Google Scholar 

  • Schiess W, Welzel D, Gugler R (1984) Double-blind comparison of once-daily bopindolol, pindolol and atenolol in essential hypertension. Eur J Clin Pharmacol 27:529–534

    Google Scholar 

  • Schliep H-J, Harting J (1984) 138-4 of bisoprolol, a new β-adrenoceptor antagonist, in anesthetized dogs and guinea pigs. J Cardiovasc Pharmacol 6:1156–1160

    Google Scholar 

  • Schwabe U, Ebert R (1972) Different effects of lipolytic hormones and phosphodiesterase inhibitors on cyclic 3′,5′-AMP levels in isolated fat cells. Naunyn-Schmiedeberg's Arch Pharmacol 274:287–298

    Google Scholar 

  • Scriabine A (1979) β-Adrenoceptor blocking drugs in hypertension. Annu Rev Pharmacol Toxicol 19:269–284

    Google Scholar 

  • Smith RD, Wolf PS (1984) Celiprolol. In: Scriabine A (ed) New drugs annual: Cardiovascular drugs, vol 2. Raven Press, New York, pp 19–35

    Google Scholar 

  • Stiles GL, Caron MG, Lefkowitz RJ (1984) β-Adrenergic receptors: biochemical mechanisms of physiological regulation. Physiol Rev 64:661–743

    Google Scholar 

  • Szecsi E, Kohlschütter S, Schiess W, Lang E (1982) Abrupt withdrawal of pindolol or metoprolol after chronic therapy. Br J Clin Pharmacol 13:Suppl 2, 353S-357S

    Google Scholar 

  • Van Baak MA, Struyker Boudier AJ, Smits JFM (1985). Antihypertensive mechanisms of beta-adrenoceptor blockade: a review. Clin Exp Hypertension A 7:1–72

    Google Scholar 

  • Vanhees L, Fagard R, Hespel P, Lijnen P, Amery A (1985) Renin release: β1- or β2-receptro mediated? N Engl J Med 312:123–124

    Google Scholar 

  • Van Inwegen RG, Khandwala A, Weinryb I, Pruss TP, Neiss E, Sutherland CA (1984). Effects of celiprolol (REV 5320), a new cardioselective beta-adrenoceptor antagonist, on in vitro adenylate cyclase, alpha-and beta-adrenergic receptor binding and lipolysis. Arch Int Pharmacodyn Ther 272:40–55

    Google Scholar 

  • 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, 259S-364S

    Google Scholar 

  • Wang XL, Brinkmann M, Brodde O-E (1985) Selective labelling of β1-adrenoceptor in rabbit lung membranes by (-)-3H-bisoprolol. Eur J Pharmacol 114:157–165

    Google Scholar 

  • Weber F, Brodde O-E, Anlauf M, Bock KD (1983) Subclassification of human beta-adrenergic receptors mediating renin release. Clin Exp Hypertension A 5:225–238

    Google Scholar 

  • Wilson C, Lincoln C (1984) β-Adrenoceptor subtypes in human, rat, guinea-pig and rabbit atria. J Cardiovasc Pharmacol 6:1216–1221

    Google Scholar 

  • Wood AJJ, Feldman R, Nadeau J (1982) Physiological regulation of beta-receptors in man. Clin Exp Hypertension A 4:807–817

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Biochemical Research Laboratory, Medizinische Klinik und Poliklinik, Division of Renal and Hypertensive Diseases, University of Essen, Hufelandstrasse 55, D-4300, Essen, Federal Republic of Germany

    Otto-Erich Brodde, Robert Schemuth, Matthias Brinkmann, Xiao Liang Wang & Anton Daul

  2. Institute of Pharmacology, University of Düsseldorf, D-4000, Düsseldorf, Federal Republic of Germany

    Ulrich Borchard

Authors
  1. Otto-Erich Brodde
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Schemuth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthias Brinkmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiao Liang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anton Daul
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ulrich Borchard
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brodde, OE., Schemuth, R., Brinkmann, M. et al. β-Adrenoceptor antagonists (non-selective as well as β 1-selectiveβ 2-adrenoceptor density in human lymphocytes. Naunyn-Schmiedeberg's Arch. Pharmacol. 333, 130–138 (1986). https://doi.org/10.1007/BF00506515

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00506515

Key words

Search

Navigation