Reversal of Acute β-Blocker Induced Bronchoconstriction

Asthma was originally thought to be associated with an intrinsic defect of β2- adrenoceptor function tipping the balance towards parasympathetic bronchoconstriction. While β2-agonists are highly effective for the acute relief of bronchoconstriction, their chronic use is accompanied by an adaptive reduction in β2ADR numbers and associated desensitisation of response, resulting in increased exacerbations and rare cases of death. Conversely the chronic use of β blockers have been shown in murine models to reduce airway inflammation and mucous metaplasia. Recent work in humans has further demonstrated a potential benefit of β blockers in asthmatics by demonstrating a significant improvement in airway hyperresponsiveness to bronchial challenge1.

Despite this early evidence supporting chronic use of β blockers in asthma, there is concern in 2 major regards: their potential to cause acute bronchoconstriction (irrespective of long-term benefit) and the possibility that they could block the reliever action of β-agonists.

Sub-sensitivity of β-adrenoceptors occurs following treatment with long-acting β-agonists. Previous work in our department has shown that high dose steroids can re-establish the β-adrenoceptor function following such down-regulation2. It therefore seems plausible that a similar response may occur following β-blockade (reversing β-blockade and re-establishing β-agonist sensitivity).

The investigators wish to gather evidence for the best methods to treat β-blocked patients in the short term. The investigators therefore wish to examine the effects of acute-β blockade with low dose propranolol on mild-to-moderate asthmatics. The investigators wish to simulate airway stress and rescue in acutely β-blocked patients. For safety purposes the investigators have chosen propranolol due to its short half-life of 3 to 5 hours. Importantly the ability to achieve airway reversibility and recovery following acute β-blockade will influence the long term viability of chronic β blockers use in the management of asthma.

Inclusion criteria

• Ability to obtain Informed consent.
• Mild to Moderate Asthmatics taking ≤1000μg BDP per day or equivalent.
• Histamine PC10
• Ability to perform spirometry, IOS, bronchial challenge and all domiciliary measurements.
• Withhold LABAs, montelukast and theophyllines for 1 week prior to study.
• FEV1 >80% predicted with diurnal FEV1 variation <20% post wash out.

Exclusion criteria

• Uncontrolled symptoms of asthma.
• Resting BP<110 systolic or HR<60.
• Pregnancy or lactation.
• Known or suspected sensitivity to IMP.
• Inability to comply with protocol.
• Any degree of heart block.
• Rate limiting medication including β blockers, rate limiting Calcium Channel Blockers and Amiodarone.
• Any other clinically significant medical condition that may either endanger the health or safety of the participant, or jeopardise the protocol.