Regulation of beta2-adrenoceptors by steroid hormones in asthma

Tan, Kia Soong (1998) Regulation of beta2-adrenoceptors by steroid hormones in asthma. MD thesis, University of Glasgow.

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Abstract

Previous studies have demonstrated the facilitatory effects of corticosteroids on the beta2-adrenoceptor (beta2-AR). Tolerance or subsensitivity with regular beta2-agonist use is of concern m asthma therapy. As corticosteroids and beta2-agonists are often prescribed together, the aim of these studies was to investigate their mteraction on beta2-AR function. Our initial study showed that despite taking inhaled corticosteroids, asthma patients developed bronchodilator and systemic beta2-AR subsensitivity following regular formoterol use. Administration of systemic corticosteroid rapidly restored beta2-AR responsiveness. This reversibility did not appear to be related to beta2-AR polymorphism. However, the development of formoterol-induced bronchodilator subsensidvity was influenced by beta2-AR polymorphism, with glycine 16 homozygous patients developing greater desensitisation than those homozygous for arginine 16. We further demonstrated that inhaled corticosteroids failed to prevent the development of tolerance to the bronchoprotective effects of formoterol against methacholine and AMP, irrespective of formoterol dose and dosing frequency. beta2-AR polymorphism did not appear to influence the development of bronchoprotective tolerance, in contrast to bronchodilator tolerance. Unlike systemic corticosteroid, high-dose inhaled corticosteroid, in single and repeated doses, showed no significant facilitatory effect on lymphocyte beta2-AR parameters. In contrast, we demonstrated that low-dose systemic corticosteroid protected against the development of beta2-AR subsensitivity induced by regular formoterol treatment. Female sex steroid hormones also influence beta2-AR function. Indeed, abnormal beta2-AR regulation has been postulated as a cause of premenstrual asthma. We found that normal cyclical regulation of beta2-AR function was lost in female asthmatic patients. In addition, there was greater airway hyperresponsiveness to AMP during the premenstrual period compared to the follicular phase. Our studies showed that exogenous progesterone, but not oestradiol, had facilitatory effects on lymphocyte beta2- AR function m normal females. In contrast, exogenous progesterone had a 'paradoxical' down-regulating and desensitising effect on beta2-AR function in female asthmatic patients. Unlike those with natural menstrual cycles, female asthmatics taking the oral contraceptive pill had attenuated cyclical changes in airway hyperresponsiveness and diurnal peak flow rates. We therefore conclude that corticosteroids have significant facilitatory effects on beta2- AR function m asthma. Our findings also suggest that there may be abnormal hormonal regulation of beta2-AR in female asthma patients. Further studies examining the facilitatory effects of inhaled corticosteroid on beta2-AR function m asthma are indicated. Research into the role of exogenous sex hormones on beta2-AR function m premenstrual asthma, pregnancy and the menopause is also necessary.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: Brian Lipworth
Keywords: Pharmacology
Date of Award: 1998
Depositing User: Enlighten Team
Unique ID: glathesis:1998-72531
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 11 Jun 2019 11:06
Last Modified: 11 Jun 2019 11:06
URI: http://theses.gla.ac.uk/id/eprint/72531

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