Response to salbutamol in patients with mild asthma treated with nadolol

To the Editors:

β-blockers (inverse agonists) have an exactly opposite effect to β₂-adrenoceptor (β₂-ADR) agonists and are currently contraindicated in asthma. This results from the fact that the acute administration of these drugs can produce bronchoconstriction by blocking the bronchodilating effects of endogenous adrenaline, or by inactivating constitutively active β₂-ADRs, and can worsen asthma symptoms 1. In fact, published accounts have shown that acute β-blocker use can, but will not always, precipitate airway constriction in patients with asthma 2. Nevertheless, there are compelling uses of β-blockers in asthmatics, such as in heart failure and after myocardial infarction. The effect of chronic administration of β-blockers in asthma has remained unknown until recently, when studies on a murine model of asthma showed that, while acute (single-dose) administration of β-blockers increased airway hyperresponsiveness (AHR), their chronic (28-day) administration had an opposite effect and decreased AHR 3. Furthermore, recent data demonstrate that chronic β-blocker treatment produces broad anti-inflammatory effects, and especially dramatic effects on airway epithelium and mucous metaplasia 4, 5. More recently, our group has further confirmed the pivotal role that β₂-ADR has on mucous metaplasia using a β₂-ADR null mouse 6. Based on these findings in the murine asthma model, we investigated the role of chronic administration of nadolol (a non-selective β₁- and β₂-blocker) on airway hyperresponsiveness in an open-label study of 10 subjects with mild asthma 7. We demonstrated that nadolol produced a dose-dependent increase in the PC₂₀ (provocative dose causing a 20% fall in forced expiratory volume in 1 s (FEV₁)) methacholine when administered over 11 weeks. However, a concern that remained is whether these subjects treated with nadolol can still respond to short-acting β₂-ADR agonists for rescue of bronchospasm 8. In fact, one concern is that nadolol “may block bronchodilation produced by endogenous or exogenous catecholamine stimulation of β₂ receptors” (Corgard® product insert; King Pharmaceuticals, Inc., Bristol, TN, USA).

We have now completed our second open-label study of chronic nadolol in subjects with mild asthma who are not on controller therapy (n = 10) (table 1). Both studies were approved by the Baylor College of Medicine Institutional Review Board (Houston, TX, USA) and informed consent was obtained from all subjects. Starting at a daily dose of 1.25 mg and ending at a maximum daily dose of 40 mg, nadolol dose was escalated on a biweekly basis based on predetermined safety, lung function, asthma control and haemodynamic parameters. Subjects were treated for a total of 13 weeks with nadolol (≥3 weeks on their final tolerated dose). Seven out of the 10 subjects were able to be escalated to 40 mg, one tolerated a 10-mg daily dose and one tolerated a 5-mg daily dose. One subject was excluded from the study because of an asthma exacerbation early in the study while on a dose of 1.25 mg. As demonstrated in our first study 8, we were able to show a significant effect on airway hyperresponsiveness with chronic nadolol dosing (fig. 1) with geometric mean±sem PC₂₀ at baseline and at final visit of 1.04±1.54 and 3.61±1.52, respectively, and a doubling dose change±sem of 1.79±0.44 (p = 0.004). No significant changes in lung function were observed (FEV₁ % predicted at baseline and final visit: 91.8±3.4 and 87.1±4.4, respectively; p = 0.165). To address the effect of nadolol on the bronchodilator response to short-acting β₂-ADR agonists, we evaluated the bronchodilator response after administering salbutamol by nebulisation (2.5 mg) immediately following methacholine challenge performed at the final visit in subjects from both studies (n = 18). Spirometry was performed 20 min following salbutamol administration. As shown in figure 2, salbutamol was able to reverse methacholine-induced bronchoconstriction in all subjects who were on chronic treatment with nadolol.

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Figure 1–

The effect of chronic treatment with nadolol on the PC₂₀ (provocative dose causing a 20% fall in forced expiratory volume in 1 s) metacholine in subjects with mild asthma. Data are shown for baseline visit and final visit. Final nadolol doses used for subjects based on dose-escalation are shown. Geometric mean±sem are shown (□ and whiskers, respectively). •: 40 mg nadolol (n = 7); ▪: 10 mg nadolol (n = 1); ▴: 5 mg nadolol (n = 1). Comparisons between V0 and V10 values were performed using paired t-tests. *: p<0.05.

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Figure 2–

Response to salbutamol (2.5 mg by nebulisation) administered after metacholine challenge at final visit in subjects with mild asthma treated with nadolol from both studies (n = 18). Forced expiratory volume in 1 s (FEV₁) % predicted values pre- and post-challenge and values 20 min following salbutamol administration (recovery) are shown. Mean values for each time period with 95% CI are also shown (□ and whiskers, respectively).

Our study has several limitations. We studied steroid-naïve patients with mild asthma. In patients with severe disease and inflammation, it is unknown whether chronic nadolol treatment would also show a preserved response to β2-ADR agonists. In addition, it is not known whether the observed effects may be seen with the use of lower doses of salbutamol. While we believe that our findings can be explained by the high degree of inverse agonism of nadolol, future work needs to explore this further and compare these effects using β-blockers with different levels of inverse agonism.

In summary, we demonstrated that in subjects with mild asthma, chronic dosing with an inverse agonist, nadolol, is accompanied by attenuation of airway hyperresponsivess, and administration of salbutamol is able to reverse methacholine-induced bronchoconstriction in these subjects. These findings suggest that β₂-ADRs may not be completely blocked with chronic nadolol dosing, and are supportive of the data from patients with hypertension and anxiety, which suggested that the use of the β-blocker propranolol in these populations was associated with increased β₂-ADR bronchodilating function contrary to that which would be expected 9, 10. The significance of our findings, if confirmed in larger controlled trials, may provide a paradigm shift in the chronic management of asthma and in the way we view the pathology of asthma.

• ©2010 ERS