Is There Loss of a Protective Muscarinic Receptor Mechanism in Asthma: Materials and Methods
Fifteen nonsmoker subjects (ten men and five women) without a recent history of upper respiratory tract infection were included in the study. Six subjects had a history of mild asthma; their ages ranged from 25 to 52 years (mean 37). The remaining nine subjects had no personal or family history of atopy. Their ages ranged from 22 to 38 years (mean 30). The asthmatic subjects were asymptomatic at the time of the study, and had not received inhaled beta agonists for at least 12 hours prior to each test. The protocol was approved by the institutional ethics and research committees. Informed consent was obtained from each subject.
Baseline pulmonary function tests consisted of spirometry and measurements of airway resistance and functional residual capacity (FRC) by body plethysmography. Specific airway conductance (SGaw) was calculated by dividing the reciprocal of airway resistance by the thoracic gas volume at which airway resistance was measured.
Both methacholine and histamine provocation tests were performed in an identical manner. Agonists were delivered to the lungs through a DeVilbiss No nebulizer by a modified technique of Chai et al. H The nebulizer was attached to a dosimeter, which consisted of a breath-activated solenoid valve and a source of compressed air (20 psi). The solenoid valve was set to remain open for 0.6 s during inhalation to allow the compressed air to flow through the nebulizer, dispersing an average of 0.023 ml of the solution with each breath. The aerosolized material was delivered from FRC position through the course of a submaximal inspiratory effort. After obtaining the baseline measurements of specific airway conductance, the subjects inhaled five breaths of saline diluent, and the measurements were repeated after a 2-min interval. Dose response curves for each agent were then established by having the subjects take five inhalations from each of the increasing concentrations of the agonist, at intervals of 5 min. The first concentration was 0.075 mg/ml, while the concentrations of subsequent doses increased in an alternating two-fold manner. For both agonists, the test was stopped when the SGaw had fallen by at least 50 percent from the post-diluent value or the maximal concentration of Mean±SE; % predicted in parentheses; KV = residual volume in liters; TLC = total lung capacity in liters; FRC = functional residual capacity in liters; FVC = forced vital capacity in liters; FEVj=forced expiratory volume in 1 second in liters; Raw=airway resistance in cm H20/IVs; SGaw = specific airway conductance, L*s.
5 mg/ml had been reached. The SGaw was then plotted against the cumulative agonist dose, expressed in breath units. One breath unit was defined as one inhalation of a 1 mg/ml concentration of the agonist. The results were expressed as the cumulative provocative dose of the agonist causing a fall in the SGaw by 50 percent (PDgo). At the end of each experiment day, the subjects took two inhalations of albuterol to reverse the bronchoconstriction. Wfe used SGaw as an indicator of airway narrowing during bronchial provocation to avoid the potential problems associated with deep inspiration and also because methacholine may cause changes in SGaw and minimal changes in forced expired volume in one second (FEVJ.