In vivo evaluation of airway and pulmonary tissue response to inhaled methacholine in the rat.

The current study was designed to assess the methacholine dose-response behaviour of the airways and pulmonary parenchyma with the aid of alveolar capsules. The experiments were performed in eight adult female Wistar rats (155-250 g). The animals were anaesthetized with sodium pentobarbital (30 mg kg-1 i.p.) and mechanically ventilated. Measurements of tracheal (ptr) and alveolar (pA) pressures and the pressure change across the airway (p(aw)) were performed prior to and after exposing rats to aerosols generated from sequentially increasing concentrations of methacholine chloride solution (2, 4, 8, 16, 32, 64 and 128 mg ml-1) through the breathing circuit. Baseline p(aw) and pA mean (+/- SD) values (6.44 +/- 2.06 and 8.25 +/- 3.44 cmH2O, respectively) were not statistically different (P = 0.220). The increases in ptr and pA were significant during the dose-response study (P = 0.001), whereas p(aw) was not increased. The increase in pA was significantly higher than that of p(aw) (P less than 0.001). The relationship between the mean (+/- SE) values of ptr and pA could be well described by a straight line (r = 0.990, P less than 0.001). There were also significant correlations based on regression equations between ptr and p(aw) (r = 0.947, P less than 0.001) and pA and p(aw) (r = 0.913, P = 0.004). These findings suggest that the pulmonary tissue of rats is a major component responsible for the increase in lung impedance observed after methacholine challenge. In addition, airway and pulmonary parenchyma pressure changes were correlated, suggesting that both lung regions have a similar sensitivity to the agonist. Our results indicate that the response of peripheral tissues should be considered during bronchial challenge protocols in rats.

Pulmonary aerosol actions of LY188695 (KB2413), a new potent H1-receptor antagonist.

The new potent H1 receptor antagonist, LY188695 (KB2413), was delivered to guinea pigs as a pulmonary aerosol and its ability to inhibit histamine-induced airway obstruction examined. Aerosol LY188695 was more effective than inhaled chlorpheniramine or clemastine in reducing the pulmonary gas trapping produced by histamine challenge. Lung antihistamine effects occurred within minutes of a brief, low concentration aerosol exposure and persisted for at least 1 hour. LY188695 aerosol treatment did not produce significant inhibition of methacholine-induced gas trapping. Although systemic antihistamine effects occurred 50 minutes after LY188695 inhalation, aerosol administration produced an enhanced local (i.e., lung) action compared to intravenous delivery.

Increased metachromatic cells and lymphocytes in bronchoalveolar lavage fluid of dogs with airway hyperreactivity.

Bronchoalveolar lavage (BAL) was performed in 11 basenji greyhound (BG) dogs, which showed persistent airway hyperreactivity to methacholine and citric acid aerosols, and in 15 non-BG dogs, which were significantly less reactive to these challenges. Five of the BG dogs had never received any aerosols prior to BAL, and 3 of the non-BG dogs were allergic to Ascaris suum. No dog received aerosols for 2 wk prior to BAL. Fluid recovered was centrifuged, and aliquots were taken for histamine content and cell identification. Total cell numbers were similar in BG and non-BG dogs. The BG dogs had increased percentages of lymphocytes and metachromatic cells in BAL fluid compared with those in non-BG dogs. Lymphocytes averaged 35.5 +/- 2.3% (mean +/- SEM) and 17.2 +/- 1.2% (p less than 0.005) in BG and non-BG dogs, respectively. The BG dogs that had received previous aerosol challenge and the BG dogs never challenged had 6.2 +/- 0.4% (mean +/- SEM) and 4.6 +/- 0.6% metachromatic cells in BAL. Nonallergic non-BG dogs had 0.91 +/- 0.2% and allergic non-BG dogs had 2.6 +/- 0.5% metachromatic cells in BAL (p less than 0.05 from BG). Total histamine closely correlated with numbers of metachromatic cells in BAL (r = 0.86). Forty-nine percent fewer mast cells were detected in cell preparations fixed in formalin than in cell preparations fixed in basic lead acetate. Electron micrographs revealed 2 mast cell types on the basis of structural characteristics of the granules.(ABSTRACT TRUNCATED AT 250 WORDS)

Methacholine: a 7-day inhalation toxicity study with primates.

The acute and sub-acute inhalation toxicity of methacholine to cynomolgus monkeys was assessed by exposure of animals to an aerosol of a 2% solution of the material in sterile saline. The acute response was characterized by a decrease in tidal volume, increase in respiratory rate, a fall in dynamic compliance and an increased pulmonary resistance. Onset of the acute response was rapid, reached a peak after 2-3 min of exposure and recovery appeared to be complete after 30 min following termination of an exposure. The sub-acute inhalation toxicity of methacholine was assessed by single daily aerosol exposure of primates to graded doses of the compound for 7 days. Pre- and post-exposure measurements of haematology and blood biochemistry, urinalysis, blood gas analysis and ECG showed no changes which could be attributed to exposure to methacholine. Nor were treatment-related histopathological changes observed in exposed animals. Distinct changes were seen in the mechanical characteristics of the lungs of exposed animals. Pulmonary resistances, measured on the day following final exposure, were increased in all animals exposed to the methacholine aerosol. During 9 weeks following the last of the daily exposures, increased pulmonary resistance values persisted in the animals retained for this period, although there was some indication of a gradual return to pre-exposure resistance values.