Effects of Acute and Chronic Administration of ß-Adrenoceptor
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Effects of acute and chronic administration of -adrenoceptor ligands on airway function in a murine model of asthma Zsuzsanna Callaerts-Vegh*†, Kenda L. J. Evans*†‡, Noornabi Dudekula*, Donald Cuba*, Brian J. Knoll*, Patrick F. K. Callaerts§, Heather Giles‡, Felix R. Shardonofsky¶ʈ, and Richard A. Bond* *Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 521 Science and Research Building 2, Houston, TX 77204-5037; §Department of Biology and Biochemistry, 369 Science and Research Building 2, Houston, TX 77204-5001; ‡Encysive Pharmaceuticals, 7000 Fannin 20th Floor, Houston, TX 77030; and ¶Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, 6621 Fannin, Suite CCC1040.00, Houston, TX 77030-2399 Communicated by James W. Black, The James Black Foundation, London, United Kingdom, February 10, 2004 (received for review October 9, 2003) The clinical effects of treatment with -adrenoceptor (-AR) ago- of antigen-induced early asthmatic reaction. On the other hand, nists and antagonists in heart failure vary with duration of therapy, chronic administration of -AR agonists in asthmatic individuals as do the effects of -AR agonists in asthma. Therefore, we may cause clinically detrimental effects, including an enhanced hypothesized that chronic effects of ‘‘-blockers’’ in asthma may degree of unspecific airway responsiveness (8) and airway in- differ from those observed acutely. We tested this hypothesis in an flammation (9, 10), loss of bronchoprotection, and ultimately, antigen (ovalbumin)-driven murine model of asthma. Airway re- increased risk of death. In this connection, epidemiological sistance responses (Raw) to the muscarinic agonist methacholine studies have demonstrated a positive correlation between the were measured by using the forced oscillation technique. In com- chronic use of short-acting -AR agonists and asthma mortality  parison with nontreated asthmatic mice, we observed that: (i) The (11, 12). Recently, a large trial with the long-acting 2-AR -AR antagonists nadolol or carvedilol, given as a single i.v. agonist, salmeterol, was stopped because of increased death injection (acute treatment) 15 min before methacholine, increased rates and serious ‘‘asthma related’’ events among the African- methacholine-elicited peak Raw values by 33.7% and 67.7% (P < American subgroup on long-term salmeterol (13). Taken to- 0.05), respectively; when either drug was administered for 28 days gether, these data suggest the possibility that the administration  (chronic treatment), the peak Raw values were decreased by 43% of -AR ligands in asthmatic patients might cause either bene- (P < 0.05) and 22.9% (P < 0.05), respectively. (ii) Chronic treatment ficial or detrimental effects depending on duration of therapy, in with nadolol or carvedilol significantly increased -AR densities in a fashion similar to that observed in CHF. lung membranes by 719% and 828%, respectively. (iii) Alprenolol, Presently, the administration of -blockers is contraindicated a -blocker with partial agonist properties at -ARs, behaved as a in asthmatics (14) because of the observation that single-dose  -AR agonist, and acutely reduced peak Raw value by 75.7% (P < administration of nonselective -blockers may cause airway 0.05); chronically, it did not alter Raw.(iv) Salbutamol, a -AR partial narrowing in asthmatic patients, presumably because of sympa- agonist, acutely decreased peak Raw by 41.1%; chronically, it did thetic modulation of airway smooth muscle tone. Interestingly, not alter R .(v) None of the -blockers produced significant results from a metaanalysis suggest that the use of cardioselective aw   changes in eosinophil number recovered in bronchoalveolar la- -blockers (those with preference for the 1-AR subtype) ap- vage. These results suggest that -AR agonists and -blockers with pears to be safe in patients with chronic airway obstruction (15). inverse agonist properties may exert reciprocating effects on Presumably, this is due to the lack of antagonist effect at the  cellular signaling dependent on duration of administration. predominant subtype in the lung, the 2-AR. However, the effects of long-term administration of nonselective -blockers to -blockers ͉ sympathomimetics ͉ airway resistance ͉ inverse agonist asthmatic subjects or in animal models of asthma have never been examined, perhaps because of the implicit assumption that   the long-term effects of these drugs are similar to those produced harmacological modulation of -adrenoreceptor ( -AR) during short-term administration (16, 17). Pfunction with drugs classified as -AR antagonists and   Based on the observation that the clinical effects of -AR inverse agonists (‘‘ -blockers’’) accomplishes important thera- ligand treatments in heart failure vary dramatically with duration peutic objectives in diverse disease processes such as hyperten- of therapy, we hypothesized that the long-term effects of sion, angina, congestive heart failure (CHF), and glaucoma. -blockers in asthma may be different from those observed Recently, there has been a major paradigm shift in the treatment during short-term treatment. We tested this hypothesis in an of CHF as a result of the observation that duration of treatment antigen-driven murine model of asthma. We found that the in this syndrome determines whether the therapeutic effects of -blockers nadolol and carvedilol, administered for 28 days, -AR ligands are beneficial or detrimental. In heart failure,  decreased significantly the maximal airway constrictor response -AR agonists produce short-term hemodynamic improve- to cholinergic stimulation and increased significantly -AR ments, whereas they have been found to increase mortality rates densities in lung tissue. The degree of inhibition produced by 28  ءء when administered chronically ( , 2, 3). Conversely, -blockers, days of nadolol treatment was similar to that obtained with a a class of drugs previously contraindicated in heart failure,  single dose of the 2-AR agonist, salbutamol. These results produce symptomatic worsening at the onset of therapy, yet some members of this class improve both hemodynamics and mortality with chronic use (4–6). Abbreviations: AR, airway responsiveness; -AR, -adrenoceptor; BALF, bronchoalveolar Although asthma and CHF are disease processes that appear lavage fluid; CHF, congestive heart failure. unrelated, both are influenced by ligands interacting with †Z.C.-V. and K.L.J.E. contributed equally to this work. -ARs. In asthmatic patients, acute administration of -AR ʈTo whom correspondence should be addressed. E-mail: [email protected]. agonists typically produces bronchodilation (7) and bronchopro- **Dies, F., Krell, M. J., Whitlow, P., Liang, C.-S., Goldenberg, I., Applefeld, M. M. & Gilbert, tection, i.e., attenuation of the airway narrowing elicited by E. M. (1986) Circulation 74, Suppl. II, 38 (abstr.). constrictor agonists or exercise and prevention of the occurrence © 2004 by The National Academy of Sciences of the USA 4948–4953 ͉ PNAS ͉ April 6, 2004 ͉ vol. 101 ͉ no. 14 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0400452101 Downloaded by guest on September 26, 2021 suggest that -AR agonists and certain -blockers may exert studied in close temporal relationship with mice receiving acute reciprocating effects on cellular signaling that depend on the -blocker treatments than in those obtained in nontreated duration of treatment. asthmatic mice studied concomitantly with mice on chronic -blocker therapy. Methods Animals. Balb͞cJ mice aged 6 weeks (The Jackson Laboratory) Airway Smooth Muscle Activation. To induce airway constriction, a were housed under specific pathogen-free conditions and fed a solution containing 150 g⅐mlϪ1 of acetyl--methylcholine chlo- chicken ovalbumin-free diet. The Animal Research Ethics Boards ride (methacholine) (Sigma) was infused i.v. at constant rates, of both the University of Houston and Baylor College of Medicine using a syringe infusion pump (Raze Scientific Instruments, approved all experiments reported in this investigation. Stanford, CT). The methacholine infusion was started at 0.008 ml⅐minϪ1, and its rate was doubled stepwise up to a maximum of Experimental Design. The effects of administration of the -block- 0.136 ml⅐minϪ1. Each methacholine dose was administered until ers carvedilol (GlaxoSmithKline, King of Prussia, PA), nadolol a plateau was reached, during which data were sampled at 1-min  (Sigma), alprenolol (Sigma), and of salbutamol (Sigma), a 2-AR intervals for 3–5 min and then averaged. partial agonist, were examined in a murine model of human asthma (18). The results obtained in drug-treated animals were compared Determination of -AR Density by Radioligand Binding. Plasma with those obtained in vehicle-treated counterparts in experiments membranes were prepared from homogenized lung tissue as performed in close temporal relationship. described (26). -AR density was determined by incubation with increasing concentrations (5–7,500 pmol) of (Ϫ)3-[125I]- Antigen Sensitization and Challenge Protocols. Mice were systemi- iodocyanopindolol (Amersham Pharmacia). Propranolol (100 cally sensitized with ovalbumin adsorbed to aluminum hydroxide M) (Sigma) was used to determine nonspecific binding. All and respiratory challenged with the same antigen (18). A group of experiments were performed in triplicate. ovalbumin-sensitized saline-challenged mice served as controls for systemic sensitization and respiratory challenges with ovalbumin.