Bronchodilator activity of bitter tastants in human tissue

Abstract

776 volume 17 | number 7 | july 2011 nature medicine To the Editor: We read with interest the article by Deshpande et al.1 on bitter taste receptors (TAS2Rs) in the lungs and the expression of TAS2Rs on human airway smooth muscle (ASM). The authors describe experiments in which TAS2R agonists, such as chloroquine, evoked relaxation of mouse tracheal rings that was threefold greater in magnitude than that elicited by b-adrenergic receptor agonists1 (the current gold-standard bronchodilator therapy for asthma and chronic obstructive pulmonary disease2). We sought to investigate the uncharacteristically weak bronchodilator activity of isoproterenol in human tissue. After repeating key experiments from the paper by Deshpande et al.1 in our laboratories in the UK and in the laboratories of our collaborator in the US (B.J.C.), we obtained data that is consistent with a body of literature3 and clinical practice that suggests that isoproterenol is a potent and efficacious relaxant of human airway smooth muscle, eliciting a relaxation 4 log fold (10,000×) more potent than chloroquine, although both agents had similar efficacy (Fig. 1a,b). This difference in potency was apparent when we precontracted the human airway smooth muscle to 60–80% of the maximum attainable contraction with either 10 μM histamine (Fig. 1a) or 1 μM carbachol (Fig. 1b). We obtained comparable results in studies using airway smooth muscle preparations from guinea pigs, a species in which relaxation to b-agonists is elicited through the b2-adrenergic receptor (M.G.B., N.D., M.A.B. and B.J.C., unpublished observations). Several explanations could be proffered as to why there is a discrepancy between our results and those obtained by Deshpande et al.1 When performing in vitro tissue bath experiments to investigate the relaxant properties of agonists on ASM, standard practice is to precontract the tissue to establish a baseline level of bronchoconstrictor tone. The tone induced would normally be submaximal to avoid functional antagonism of the potential relaxant response4. However, the concentration of acetylcholine used by Deshpande et al.1 (0.1 mM) is supramaximal, which could functionally antagonize the relaxant response to isoproterenol, thereby making it appear smaller than expected. When we repeated these experiments under conditions of supramaximal tension (0.1 mM ACh), we also found that the relaxation to isoproterenol was compromised (60% of the maximal relaxation evoked by papaverine instead of 100%; Fig. 1c,d). We should emphasize that we do not question the author’s conclusions that airway smooth muscle from humans and mice express bitter taste receptors. This is potentially a physiologically important observation. We would respectfully suggest, however, that our data and the published literature cast doubt on the claim that TAS2R agonists are more effective bronchodilators than currently prescribed b2-adrenergic receptor agonists. Note: Supplementary information is available on the Nature Medicine website.