Bronchodilator activity of bitter tastants in human tissue

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 β-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in which relaxation to β-agonists is elicited through the β₂-adrenergic receptor (M.G.B., N.D., M.A.B. and B.J.C., unpublished observations).

Figure 1: Comparison of chloroquine- and isoprenaline-induced relaxation of isolated human airway smooth muscle.

(a,b) Relaxant responses of airway tissue induced by increasing concentrations of isoproterenol or chloroquine in tissues that were precontracted with histamine (a) or carbachol (b). Maximal tissue relaxation was assessed by treatment with papaverine (100 μM). Data shown are from experiments using samples from two separate lung samples and are expressed as the percentage of maximum relaxation to papaverine (100 μm). tension. (c,d) Representative traces from an experiment done on bronchial strips that were pre-contracted with acetylcholine (ACh; 0.1 mM) and then treated with vehicle (c) or 10 μM isoproterenol (d). Maximal tissue relaxation was induced by papaverine (100 μM). See Supplementary Methods for additional details.

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 β₂-adrenergic receptor agonists.

Note: Supplementary information is available on the Nature Medicine website.