Pulmonary responsiveness to methacholine and disodium hexachloroplatinate (Na2PtCl6) aerosols in cynomolgus monkeys (Macaca fascicularis).
Hyperreactivity of the airways is a common finding in human asthma, and responsiveness to inhaled methacholine aerosols is routinely used for assessing airway irritability. Workers in precious metal refineries demonstrate pulmonary signs suggestive of asthma, presumably related to exposure to soluble platinum salts. In these workers, evidence of physiologic dysfunction precedes immunologic evidence (skin test) of disease, suggesting an initial pharmacologic mechanism. With a primate animal model for the screening of occupational asthmogens, 24 Cynomolgus monkeys were evaluated for their comparative pulmonary responsiveness to inhaled aerosols of methacholine and sodium hexachloroplatinate (Na2PtCl6). Average pulmonary flow resistance (RL), dynamic compliance (CLdyn), maximum expiratory flow volume (MEFV), and respiratory frequency changes were evaluated after bronchoprovocation challenge. Both agents produced dose-dependent increases in RL, dose-dependent decreases in CLdyn and MEFV, and no effect on respiratory rates. Analyses of the correlation between concentration effects of the two agents showed no association between cholinergic airway irritability status and Na2PtCl6-induced bronchoconstriction. Na2PtCl6 bronchoprovocation produced significantly greater flow impairment at lower lung volumes when compared to methacholine concentrations with equipotent effects on RL and CLdyn. These compounds have differential effects on peripheral airway function. The lack of respiratory rate change seen on bronchoprovocation with these compounds, in comparison to the rapid shallow breathing in anesthetized monkeys following irritant or histamine challenge, indicates that neither aerosol stimulated pulmonary irritant receptors.
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001985:Bronchial Provocation Tests; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000633:toxicity; D008170:Lung Compliance / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D008449:Maximal Expiratory Flow-Volume Curves; D016210:Methacholine Chloride; D008688:Methacholine Compounds; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D012119:Respiration / Q000187:drug effects; D012129:Respiratory Function Tests; D012130:Respiratory Hypersensitivity / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology
D008688:Methacholine Compounds; D016210:Methacholine Chloride; D002945:Cisplatin; C038762:disodium hexachloroplatinate