Reply: Adverse Effects of Long-Acting Beta-Agonists on Airway Hyperresponsiveness

Abstract

From the Authors: In their letter, Lipworth and colleagues raise an interesting point and we welcome their suggestion that our work in murine asthma models may help understand a clinically important point (1). We fully concur with the idea that a patient’s β2-adrenoceptor (β2AR) genotype may increase their susceptibility to adverse effects of β2AR agonists. Lipworth and colleagues suggest our data are consistent with their finding that individuals with the arginine-16 polymorphism have enhanced airway hyperresponsiveness following exposure to the high-efficacy β2AR agonist formoterol (but not the low-efficacy agonist salmeterol) (1); they also raise concerns with the recently developed high-efficacy ultra-long-acting β2AR agonists, like indacaterol and vilanterol. Lipworth and colleagues conclude by suggesting that the likely explanation for this observation is that the arginine-16 polymorphism enhances the higher rates of desensitization and down-regulation that have been shown to be produced by high-efficacy β2AR agonists (2). We fully concur that this pharmacological principle, of a significant correlation between ligand efficacy and desensitization and down-regulation, is the Occam’s razor explanation for the clinical findings and must be ruled out before introducing complex alternatives. However, we wish to point out that in wider studies, the uniqueness of formoterol over salmeterol in producing adverse effects has not been observed, and the FDA guidelines have labeled them with identical precautions and warnings. A more inclusive, albeit more speculative, explanation may be that the arginine-16 polymorphism results in preferential trafficking of the formoterol occupied β2AR to an alternate pathway than the canonical Gs-cAMP-PKA signaling. In asthma we suggest β2AR signaling via β-arrestin is the alternate pathway promoting airway hyperresponsiveness and inflammation (3, 4). Preferential pathway activation resulting from a specific ligand (ligand bias) is well documented as an ability of the ligand to form a binary complex with the receptor producing a conformation that results in biased pathway activation (4). Here we simply suggest that a structural change in the other component of the binary complex, the receptor, is now responsible for conferring the bias. Finally, we would like to add that there is an intrinsic weakness to the desensitization/down-regulation hypothesis. While it is true that high-efficacy ligands produce greater loss of receptor function and number in comparison to low-efficacy ligands that produce minimal alterations in receptor function and numbers, it is also true that high-efficacy ligands require less occupied receptors to produce their effects. Thus, from a receptor theory point of view, these effects tend to cancel each other out, and that is why both strategies have been employed and rationalized by different pharmaceutical companies.