Separation of bronchoconstriction from increased ventilatory drive in a nonhuman primate model of chronic allergic asthma

Abstract

The relationship between allergen-induced ventilatory drive and bronchoconstriction was investigated in dust mite-sensitive cynomolgus macaques periodically exposed to low doses of aerosolized antigen for up to 5.5 yr. Initially, the animals responded to aerosolized dust mite allergen at a concentration of 350 arbitrary units (AU)/ml with simultaneous increases in lung resistance (RL) and respiratory rate (RR). With time, RL and RR became differentially sensitive to allergen provocation. At the end of the study period, aerosolized allergen at a concentration of 15 AU/ml doubled RR without increasing RL. When mechanically ventilated to maintain tidal volume, higher concentrations of allergen could be delivered, and RL increased. Inhaled disodium cromoglycate and intravenous diphenhydramine attenuated the increase in RR, indicating that allergen-induced release of histamine and activation of H(1) receptors mediated the response. Inhaled beta-adrenergic agonists attenuated the RR response to dust mite and to direct histamine provocation. These results demonstrate that chronic periodic allergen challenge increases the allergic sensitivity of histamine-dependent reflexes controlling ventilatory drive. Activation of these reflexes is independent of overt bronchoconstriction, but can be inhibited by beta-adrenergic agonists, indicating that beta-adrenergic agonists exert their effect independent of bronchodilation.