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β-Adrenoceptor regulation and functional responses in the guinea-pig following chronic administration of the long-acting β2-adrenoceptor agonist formoterol

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Abstract

Formoterol is a long acting β2-adrenoceptor agonist designed for the alleviation of the symptoms of asthma. This study examined the effects of 14 day administration of formoterol (200 μg/kg/day i.p.) on β1- and β2-adrenoceptors in guinea-pig cardiac and lung tissue. Quantitative autoradiography was used to measure changes in receptor density and organ bath studies determined alterations in functional response.

Formoterol treatment produced marked reductions of between 43% and 77% in β2-adrenoceptor density in all regions of the heart (atrioventricular node, bundle of His, right and left bundle branches, interventricular and interatrial septa, right and left atria, ventricles and apex) and lung (bronchial and vascular smooth muscle and parenchyma) (P < 0.01, n = 6). β1-Adrenoceptor density remained unchanged in all cardiac and lung regions. In functional studies (−)-isoprenaline was 4 fold less potent at causing relaxation of carbachol (1 μM) precontracted tracheal smooth muscle (pD2: control 8.49 ± 0.03, formoterol 7.91 ± 0.10, P < 0.001, n = 4), but formoterol treatment did not change the ability of (−)-isoprenaline to elicit a maximum response. The pKB values for ICI 118,551, 7.33 ± 0.08 in the control and 7.20 ± 0.01 in formoterol treated animals, were between those expected for β1- and β2-adrenoceptors suggesting involvement of both subtypes in the response. In spontaneously beating right atria and electrically paced left atria, tissues in which responses are largely mediated by β1-adrenoceptors, there was no significant change in responses to (−)isoprenaline (right atria pD2: control 8.45 ± 0.02; formoterol 8.42 ± 0.11; P = 0.77, n = 4) (left atria pD2: control 8.25 ± 0.03; formoterol 8.47 ± 0.08; P = 0.09, n = 4). In the presence of CGP 20712A (100 nM) the pKB values did not change with formoterol treatment (left atria: control 9.59 ± 0.12, formoterol 9.66 ± 0.12; P = 0.70, n = 4) (right atria: control 8.93 ± 0.11, formoterol 9.11 ± 0.07; P = 0.25, n = 4).

The doses and route of administration of formoterol used in this study differs from those used clinically. However, this study demonstrates that chrome formoterol administration produces selective down-regulation of β2-adrenoceptors in the lung and heart. The changes in the lung are accompanied by a shift to the right in the concentration-response curve to β-agonist stimulation with no change in the maximum response.

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References

  • Barnes PJ (1986) Neural control of human airways in health and disease. Am Rev Respir Dis 134:1289–1314

    Google Scholar 

  • Barnes PJ (1989) A new approach to the treatment of asthma. N Engl J Med 321:1517–1527

    Google Scholar 

  • Barnes PJ, Nadel JA, Skoogh B-E, Roberts JM (1983) Characterization of beta-adrenoceptor subtypes in canine smooth muscle by radioligand binding and physiological responses. J Pharmacol Exp Ther 225:456–461

    Google Scholar 

  • Barnes PJ, Jacobs MM, Roberts JM (1984) Gluocorticoids preferably increase fetal alveolar beta-receptors: autoradiographic evidence. Pediatr Res 18:1191–1194

    Google Scholar 

  • Bilski AJ, Halliday SE, Fitzgerald JD, Wade JC (1983) The pharmacology of a β2-selective adrenoceptor antagonist (ICI 118,551). J Cardiovasc Pharmacol 5:430–437

    Google Scholar 

  • Boushey HA, Holtzman MJ, Sheller JR, Nadel JA (1980) Bronchial hyperreactivity. Am Rev Respir Dis 121:389–413

    Google Scholar 

  • Böhm M, Gengenbach S, Hauck RW, Sunder-Plassmann L, Erdmann E (1991) Beta-adrenergic receptors and m-cholinergic receptors in human lung: Findings following in vivo and in vitro exposure to the β-adrenergic receptor agonist, terbutaline. Chest 100:1246–1253

    Google Scholar 

  • Brodde OE, Brinkmarm M, Schemuth R, O'Hara N, Daul A (1985) Terbutaline-induced desensitization of human lymphocyte β2-adrenoceptors. J Clin Invest 76:1096–1101

    Google Scholar 

  • Brodde OE, Petrasch S, Bauch HJ, Daul A, Gnadt M, Oefler, D, Michel MC (1992) Terbutaline-induced desensitization of β2-adrenoceptor in vivo function in humans: Attenuation by ketotifen. J Cardiovasc Pharmacol 20:434–439

    Google Scholar 

  • Carstairs JR, Nimmo AJ, Barnes PJ (1984) Autoradiographic localisation of β-adrenoceptors in human lung. Eur J Pharmacol 103:189–190

    Google Scholar 

  • Carstairs JR, Nimmo AJ, Barnes PJ (1985) Auto radiographic visualization of beta-adrenoceptor subtypes in human lung. Am Rev Respir Dis 132:541–547

    Google Scholar 

  • Carswell H, Nahorski SR (1983) β-Adrenoceptor heterogeneity in guinea-pig airways: comparison of functional and receptor labelling studies. Br J Pharmacol 79:965–971

    Google Scholar 

  • Conolly ME, Davies DS, Dollery CT, George DF (1971) Resistance to β-adrenoceptor stimulants (a possible explanation for the rise in asthma deaths). Br J Pharmacol 43:389–402

    Google Scholar 

  • Decker N, Quennedey MC, Rouot B, Schwartz J, Velly J (1982) Effects of N-aralkyl substitution of β-agonists on α- and β-adrenoceptor subtypes: pharmacological studies and binding assays. J Pharm Pharmacol 34:107–112

    Google Scholar 

  • De Monchey JR, Kauffman HE, Venge P, Koëter GH, Jansen HM, Sluiter HJ, De Vries K (1985) Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions. Am Rev Respir Dis 131:373–376

    Google Scholar 

  • Dooley DJ, Bittiger H, Reyman NC (1986) CGP 20712A: a useful tool for quantitating β1- and β2-adrenoceptors. Eur J Pharmacol 130:137–140

    Google Scholar 

  • Dunnill MS (1960) The pathology of asthma with special reference to changes in the bronchial mucosa. J Clin Pathol 13:27–33

    Google Scholar 

  • Elfellah MS, Reid JL (1990) Regulation of β-adrenoceptors in the guinea-pig left ventricle and skeletal muscle following chronic agonist treatment. Eur J Pharmacol 182:387–392

    Google Scholar 

  • Emmerson J, Mackay D (1979) The zig-zag tracheal strip. J Pharm Pharmacol 31:798

    Google Scholar 

  • Engels F, Carstairs JR, Barnes PJ, Nijkamp FP (1989) Autoradiographic localization of changes in pulmonary β-adrenoceptors in an animal model of atopy. Eur J Pharmacol 164:139–146

    Google Scholar 

  • Faulds D, Hollingshead LM, Goa KL (1991) Formoterol: A review of its pharmacological properties and therapeutic potential in reversible obstructive airways disease. Drugs 42:115–137

    Google Scholar 

  • Furchgott RF (1972) The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory. In: Blashko H, Muscholl E (eds) Handbook of experimental pharmacology, vol 33. Springer, New York, Berlin Heidelberg, pp 283–335

    Google Scholar 

  • Furchgott RF, Wakade TD, Sorace RA, Stollak JS (1975) Occurrence of both β1 and β2 receptors in guinea-pig tracheal smooth muscle, and variation of the β12 ratio in different animals [Abstract]. Fed Proc 34:794

    Google Scholar 

  • Galant SP, Duriseti L, Underwood S, Insel PA (1978) Decreased beta-adrenergic receptors on polymorphonuclear leukocytes after adrenergic therapy. N Engl J Med 299:933–936

    Google Scholar 

  • Gatto C, Johnson MG, Seybold V, Kulik TJ, Lock JE, Johnson DE (1984) Distribution and quantitative developmental changes in guinea-pig pulmonary β-receptors. J Appl Physiol 57: 1901–1907

    Google Scholar 

  • Gatto C, Green TP, Johnson MG, Marchessault RP, Seybold V, Johnson DE (1987) Localization of quantitative changes in pulmonary beta-receptors in ovalbumin-sensitized guinea-pigs. Am Rev Respir Dis 136:150–154

    Google Scholar 

  • Goldie RG, Papadimitriou JM, Paterson JW, Rigby PJ, Spina D (1986a) Autoradiographic localization of β-adrenoceptors in pig lung using [125I]-iodocyanopinodolol. Br J Pharmacol 88:621–628

    Google Scholar 

  • Goldie RG, Spina D, Henry PJ, Lulich KM, Paterson JW (1986b) In vitro responsiveness of human asthmatic bronchus to carbachol, histamine β-adrenoceptor agonists and theophylline. Br J Clin Pharmacol 22:669–676

    Google Scholar 

  • Goldie RG, Spina D, Rigby PJ, Paterson JW (1986c) Autoradiographic localisation of ascorbic acid-dependent binding sites for [125I]iodocyanopindolol in guinea-pig trachea. Eur J Pharmacol 124:179–182

    Google Scholar 

  • Harvey JE, Tattersfield AE (1982) Airway response to salbutamol: effect of regular salbutamol inhalations in normal, atopic, and asthmatic subjects. Thorax 37:280–287

    Google Scholar 

  • Henry PJ, Rigby PJ, Goldie RG (1990) Distribution of β1- and β2-adrenoceptors in mouse trachea and lung: a quantitative autoradiographic study. Br J Pharmacol 99:136–144

    Google Scholar 

  • Ida H (1976) Cardiorespiratory activities of 3-formylamino-4-hydroxy-α —(N-1-methyl-2-p-methoxyphenethylaminomethyl)benzylalcohol-hemifumarate (BD 40A) and some other β-adrenoceptor stimulants in conscious guinea-pigs. Arzneim Forsch 26:1337–1340

    Google Scholar 

  • Jeppsson AB, Lofdahl CG, Waldeck B, Widmark E (1989) On the predictive value of experiments in vitro in the evaluation of the effect duration of bronchodilator drugs for local administration. Pul Pharmacol 2:81–85

    Google Scholar 

  • Kawakami Y (1984) Evaluation of therapeutic effects of formoterol, a β-adrenoceptor stimulating bronchodilator, on bronchial asthma - a multicentre double-blind single-dose study. Clin Evaluation 12:697–727

    Google Scholar 

  • Kawakami Y, Noguchi E, Takahashi T, Shida T, Ito K (1983) Clinical trial of formoterol (BD 40A) on bronchial asthma. Yakuri to Chiryo. 11:3923–3934

    Google Scholar 

  • Kompa AR, Molenaar P, Summers RJ (1992) Regulation of guineapig cardiac β-adrenoceptor subtypes after (−)-adrenaline and (−)-noradrenaline treatment. Mol Neuropharmacol 1:203–210

    Google Scholar 

  • Lew R, Summers RJ (1985) Autoradiographic localization of β-adrenoceptor subtypes in guinea-pig kidney. Br J Pharmacol 85:341–348

    Google Scholar 

  • Löfdahl CG, Chung KF (1991) Long acting β2-adrenoceptor agonists: a new perspective in the treatment of asthma. Eur Respir J 4:218–226

    Google Scholar 

  • Löfdahl CG, Svedmyr N (1989) Formoterol fumarate, a new β2-adrenoceptor agonist. Allergy 44:264–271

    Google Scholar 

  • Lulich KM, Goldie RG, Paterson JW (1988) Beta-adrenoceptor function in asthmatic bronchial smooth muscle. Gen Pharmacol 19:307–311

    Google Scholar 

  • Maesen FPV, Smeets JJ, Gubbelmans HLL, Zweers PGMA (1990a) Bronchodilator effect of inhaled formoterol vs salbutamol over 12 hours. Chest 97:590–594

    Google Scholar 

  • Maesen FPV, Smeets JJ, Gubbelmans HLL, Zweers PGMA (1990b) Formoterol in the treatment of nocturnal asthma. Chest 98:866–870

    Google Scholar 

  • McAlpine LG, Thomson NC (1990) Prophylaxis of exercise-induced asthma with inhaled formoterol, a long acting β2-adrenergic agonist. Respir Med 84:293–295

    Google Scholar 

  • McPherson GA, Malta E, Molenaar P, Raper C (1984) The affinity and efficacy of the selective β1-adrenoceptor stimulant R0363 at β1- and β2-adrenoceptor sites. Br J Pharmacol 82:897–904

    Google Scholar 

  • Metzger WJ, Zavala D, Richerson HB, Moseley P, Iwamota P, Monick M, Sjoerdsma K, Hunninghake GW (1987) Local allergen challenge and bronchoalveolar lavage of allergic asthmatic lungs. Description of the model and local airway inflammation. Am Rev Respir Dis 135:433–440

    Google Scholar 

  • 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 241:1041–1047

    Google Scholar 

  • Molenaar P, Canale E, Summers RJ (1987) Autoradiographic localization of beta-1 and beta-2 adrenoceptors in guinea-pig atrium and regions of the conducting region. J Pharmacol Exp Ther 241:1048–1064

    Google Scholar 

  • Molenaar P, Russell FD, Shimada T, Summers RJ (1990a) Densitometric analysis of β1- and β2-adrenoceptors in guinea-pig atrioventricular conducting system. J Mol Cell Cardiol 22: 483–495

    Google Scholar 

  • Molenaar P, Smolich JJ, Russell FD, McMartin LR, Summers RJ (1990b) Differential regulation of beta-1 and beta-2 adrenoceptors in gunea-pig atrioventricular conducting system after chronic (−)-isoproterenol infusion. J Pharmacol Exp Ther 255:393–400

    Google Scholar 

  • Molenaar P, Kompa AR, Roberts SJ, Pak HS, Summers RJ (1992) Localization of (−)-[125I]cyanopindolol binding in guinea-pig heart: characteristics of non-β-adrenoceptor related binding in cardiac pacemaker and conducting regions. Neurosci Lett 136:118–122

    Google Scholar 

  • Murphree SS, Saffitz JE (1988) Delineation of the distribution of β-adrenergic receptor subtypes in canine myocardium. Circ Res 63:117–125

    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 

  • Neve KA, McGongile P, Molinoff PB (1986) Quantitative analysis of the selectivity of radioligands for subtypes of beta-adrenergic receptors. J Pharmacol Exp Ther 238:46–53

    Google Scholar 

  • O'Donnell SR, Wanstall JC (1979) The importance of choice of agonist in studies designed to predict β2: β1 adrenoceptor selectivity of antagonists from pA2 values on guinea-pig trachea and atria. Naunyn Schmiedeberg's Arch Pharmacol 308:183–190

    Google Scholar 

  • Raaijmakers JAM, Van Rozen AJ, Terpstra GK, Wassink GA, Kreukniet J (1985) Autonomic receptor deficiencies in the pathogenesis of chronic obstructive lung disease. Prog Respir Res 19:152–158

    Google Scholar 

  • Raaijmakers JAM, Beneker C, Dol R, De Ruiter-Bootsma AL (1987) Decreased bronchiolar epithelial β-adrenoceptor densities in patients with chronic obstructive lung disease. Cell Mol Biol 33: 515–518

    Google Scholar 

  • Reed CE (1974) Abnormal automatic mechanisms in asthma. J Allergy Clin Immunol 53:34–41

    Google Scholar 

  • Roets E, Burvenich C (1993) Effect of clenbuterol on β-adrenoceptors and adenylate cyclase activity in the smooth muscle and epithelium of the trachea of calves. Vet Quart 15:180–181

    Google Scholar 

  • Spina D, Rigby PJ, Paterson JW, Goldie RG (1989) Autoradiographic localization of beta-adrenoceptors in asthmatic lung. Am Rev Respir Dis 140:1410–1415

    Google Scholar 

  • Svedmyr N, Larsson SA, Thiringer GK (1976) Development of “resistance” in beta-adrenergic receptors of asthmatic patients. Chest 69:479–483

    Google Scholar 

  • Szentivanyi A (1968) The beta adrenergic theory of the atopic abnormality in bronchial asthma. J Allergy 42:203–232

    Google Scholar 

  • Tashkin DP, Conolly ME, Deutsch RI, Hui KK, Littner M, Scarpace P, Abrass I (1982) Subsensitization of beta-adrenoceptors in airways and lymphocytes of healthy and asthmatic subjects. Am Rev Respir Dis 125:185–193

    Google Scholar 

  • Tattersfield AE, Holgate ST, Harvey JE, Gribbin HR (1983) Is asthma due to partial beta-blockade of airways? Agents Actions [Suppl] 13:265–271

    Google Scholar 

  • Tomioka K, Yamada T, Tachikawa S (1984) Effects of formoterol (BD 40A), a β-adrenoceptor stimulant, on isolated guinea-pig lung parenchymal strips and antigen-induced SRS-A release in rats. Arch Int Pharmacodyn 267:91–102

    Google Scholar 

  • Tsoy AN, Cheltzov VV, Zaseyeva OV, Shilinsh V, Yashina LA (1990) Preventative effect of formoterol aerosol in exercise-induced bronchoconstriction. [Abstract] Eur Respir J [Suppl] 3:235s

  • Weber RW, Smith JA, Nelson HS (1982) Aerosolized terbutaline in asthmatics: development of subsensitivity with long-term administration. J Allergy Clin Immunol 70:417–422

    Google Scholar 

  • Xue QF, Maurer R, Engel G (1983) Selective distribution of beta-and alpha1-adrenoceptors in rat lung visualized by autoradiography. Arch Int Pharmacodyn Ther 266:308–313

    Google Scholar 

  • Young WS, Kuhar MJ (1979) A new method for receptor autoradiography: [3H]-Opioid receptors in rat brain. Brain Res 179:255–270

    Google Scholar 

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Kompa, A.R., Molenaar, P. & Summers, R.J. β-Adrenoceptor regulation and functional responses in the guinea-pig following chronic administration of the long-acting β2-adrenoceptor agonist formoterol. Naunyn-Schmiedeberg's Arch Pharmacol 351, 576–588 (1995). https://doi.org/10.1007/BF00170156

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