beta2-Adrenoceptor desensitization in human alveolar macrophages induced by inhaled terbutaline in vivo is not counteracted by budesonide.
In vitro studies suggest that glucocorticoids may counteract beta-agonist-induced desensitization of beta-adrenoceptors by actions at the transcriptional level, but the clinical relevance of such findings is not clear. Oral terbutaline treatment decreases beta-adrenoceptor sensitivity in alveolar macrophages in vivo. This effect is not counteracted by inhaled or orally taken steroids. We therefore examined whether inhaled terbutaline elicited a similar effect on beta(2)-adrenoceptor sensitivity in alveolar macrophages, and if co-treatment with an inhaled steroid, budesonide, would prevent such down-regulation. Bronchoalveolar lavage (BAL) and lung function tests, including bronchodilator responses to inhaled terbutaline, were performed before and after 2 weeks of regular inhalation of terbutaline, 0.5 mg three times daily, and budesonide, 400 microg twice daily, or placebo, in 24 healthy volunteers. Four untreated subjects served as controls. A marked, approx. 90%, decrease in isoprenaline-induced cAMP accumulation in alveolar macrophages was found in both treatment groups after 2 weeks, with no difference between placebo and budesonide (P = 0.45). In the untreated control group, cAMP responses to both isoprenaline and prostaglandin E(1) tended to be lower on the second occasion. A limited, non-specific desensitization of adenylate cyclase activity thus contributed to the marked desensitization elicited by terbutaline inhalations. The bronchodilator response to inhaled terbutaline did not change after treatment in any of the three groups (F = 0.9, P = 0.50). In conclusion, inhalation of a beta-agonist induced marked down-regulation of beta(2)-adrenoceptor sensitivity in alveolar macrophages in vivo without influencing the bronchodilator response to a beta(2)-agonist in healthy subjects. Co-treatment with an inhaled steroid failed to counteract the desensitization of alveolar macrophage beta(2)-adrenoceptors.
Department of Respiratory Medicine, Karolinska Hospital, SE-171 76 Stockholm, Sweden.
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Zetterlund
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Hjemdahl
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Larsson
D000287:Administration, Topical; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D000527:Alprostadil / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D001993:Bronchodilator Agents / Q000494:pharmacology; D019819:Budesonide / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000502:physiology; D013726:Terbutaline / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D005938:Glucocorticoids; D018343:Receptors, Adrenergic, beta-2; D019819:Budesonide; D000242:Cyclic AMP; D000527:Alprostadil; D007545:Isoproterenol; D013726:Terbutaline