COLIN DEENEY, author of the article, responds:

Airway hyper-responsiveness (AHR) is indeed a symptom of asthma and could confound any research. Studies have compared one group taking a beta₂-agonist regularly with a control group. In these studies, the control group may have either been using a beta₂-agonist on an “as needed” basis, not using a beta₂-agonist at all, or using an inhaled corticosteroid.

After a given period, or over a series of periods, AHR was assessed in both groups using a provocative challenge (histamine, methacholine or allergen). The studies cited in the article I wrote found an increase in the response to these challenges in the active groups when compared with the control groups. Hence, the concern that beta₂-agonists may increase AHR.

There have, however, been criticisms of the methodology, statistical analysis and interpretation with some of these papers. Furthermore, other studies have found no evidence of rebound AHR. In these studies the control also consisted of people with asthma and I am unaware of any study which has investigated whether a beta₂-agonist may lead to AHR in people with no asthma. However, Girodet et al¹ studied human and guinea-pig isolated airways in vitro. They found that salbutamol inhibited contractions induced by low concentrations of acetylcholine but potentiated contractions induced by higher concentrations of acetylcholine. In addition, Loss et al² found rebound AHR in guinea pigs (with no asthma) following a low dose of salbutamol, administered via subcutaneous osmotic minipumps. The rebound AHR followed challenge with the cholinergic agonists carbachol and methacholine (but not histamine). The hyper-responsiveness was more marked 24 hours after salbutamol cessation. The investigators suggest that the salbutamol may have therefore afforded some protection against the hyper-responsiveness. Now, if this is also the case in patients, when the beta₂-agonist has waned, patients may perceive they need more due to rebound AHR.

While the debate continues as to the significance and relevance of these papers from a clinical perspective, the possibility that the S-enantiomer may be responsible for rebound AHR is of interest. The literature on beta₂-agonist chirality and AHR suggests that some researchers, at least, have “moved on”. Rightly or wrongly they have accepted the possibility that AHR increases with the S-enantiomer alone and are looking at using the R-enantiomer alone clinically. There may be commercial advantage for them in doing so, of course, even if the debate on rebound AHR remains inconclusive.

One reason that has been put forward as a mechanism for rebound AHR is a crossing of the bronchodilating and bronchoprotective pathways. Loss et al also suggest this or chirality as “attractive possibilities”. Girodet et al propose that rebound hyper-responsiveness is mediated through a mechanism involving calcium channel activation. This was after pre-treatment of isolated airways with the calcium channel antagonist nicardipine suppressed the hyper-response. Furthermore, stimulation of cultured human airway smooth muscle cells with salbutamol amplified intracellular calcium concentration rise induced by acetylcholine.¹ Swystun et al³ found indicators of an early asthmatic response as early as one hour after treatment with salbutamol. They therefore suggest that a combination of allergen exposure and beta₂-agonist may induce both an early and late asthmatic response and this may lead to an increase in AHR. They also queried whether environmental allergen exposure is the reason why some studies have found rebound AHR while others have not. Proponents of Buteyko’s hypothesis suggest that the use of a beta₂-agonist leads to an increase in minute ventilation and that this in turn leads to cooling and drying of the airways, increased allergen and irritant deposition, hypocapnia, and an increase in inflammatory factors, and thus, AHR.

References

1. Girodet PO, Berger P, Martinez B, Marthan R, Advenier C, Molimard M. Paradoxal effect of salbutamol in an in vitro model of bronchoprotection. Fundamental & Clinical Pharmacology 2005;19:179.

2. Loss JR, Hock RS, Farmer SG, Orzechowski R. Racemic salbutamol administration to guinea-pigs selectively augments airway smooth muscle responsiveness to cholinoceptor agonists. Journal of Autonomic Pharmacology 2001;21:211–7.

3. Swystun VA, Gordon JR, Davis EB, Zhang X, Cockcroft DW. Mast cell tryptase release and asthmatic responses to allergen increase with regular use of salbutamol. Journal of Allergy and Clinical Immunology 2000;106:57–64.