Abstract
BackgroundCurrent therapy for relieving bronchoconstriction may be ineffective in severe asthma, particularly in the small airways. The aim of this study was to further characterise responses to the recently identified novel bronchodilators rosiglitazone (RGZ) and chloroquine (CQ) under conditions where β-adrenoceptor agonist efficacy was limited or impaired in mouse small airways within lung slices.MethodsRelaxation to RGZ and CQ was assessed following submaximal methacholine (MCh) pre-contraction, in slices treated overnight with either RGZ, CQ or albuterol (ALB) (to induce β-adrenoceptor desensitization), and in slices treated with caffeine/ryanodine in which contraction is associated with increases in Ca2+ sensitivity in the absence of contractile agonist-induced Ca2+ oscillations. Furthermore, the effects of RGZ, CQ, ALB and isoproterenol (ISO) on the initiation and development of methacholine-induced contraction were also compared.ResultsRGZ and CQ, but not ALB or ISO, elicited complete relaxation with increasing MCh pre-contraction and maintained their potency and efficacy following β-adrenoceptor desensitization. RGZ, CQ and ALB maintained efficacy following overnight incubation with RGZ or CQ. Relaxation responses to all dilators were generally maintained but delayed after caffeine/ryanodine. Pre-treatment with RGZ, but not CQ, ALB or ISO, reduced MCh potency.ConclusionsThis study demonstrates the superior effectiveness of RGZ in comparison to CQ and β-adrenoceptor agonists as a dilator of mouse small airways. Further investigation of the mechanisms underlying the relatively greater efficacy of RGZ under these conditions are warranted and should be extended to include studies in human asthmatic airways.
Highlights
There is an unmet need for novel dilators for the treatment of severe asthma, when current therapeutic agents, such as the short acting β-adrenoceptor agonist albuterol (ALB), and long acting β-adrenoceptor agonists in combination with anti-inflammatory glucocorticoids, are ineffective at completely reversing symptoms [1,2].The peroxisome proliferator-activated receptor γ (PPARγ) agonist, rosiglitazone (RGZ) and the bitter taste receptors (TAS2R) agonists, such as chloroquine have both been recently identified as potential novel therapeutics for asthma [3,4,5,6]
* Correspondence: jane.bourke@unimelb.edu.au †Equal contributors Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC 3010, Australia (TAS2R) agonists, such as chloroquine have both been recently identified as potential novel therapeutics for asthma [3,4,5,6]
PPARγ has been implicated in lung disease and the regulation of both inflammation and airway smooth muscle function [5], and its expression is upregulated in airways of asthmatic patients [7]
Summary
The peroxisome proliferator-activated receptor γ (PPARγ) agonist, rosiglitazone (RGZ) and the bitter taste receptors (TAS2R) agonists, such as chloroquine have both been recently identified as potential novel therapeutics for asthma [3,4,5,6]. TAS2R agonists have been shown to elicit relaxation of both large airways, potentially via large conductance Ca2+-activated K+-channels [4], and human and mouse small airways as measured in lung slices [8,9]. The aim of this study was to further characterise responses to the recently identified novel bronchodilators rosiglitazone (RGZ) and chloroquine (CQ) under conditions where β-adrenoceptor agonist efficacy was limited or impaired in mouse small airways within lung slices
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