The β2-agonist Salbutamol Inhibits Bronchoconstriction and Leukotriene D4Synthesis After Dry Gas Hyperpnea in the Guinea-pig

Abstract

Isocapnic dry gas hyperpnea-induced bronchoconstriction (HIB) in the guinea-pig is mediated by both tachykinin release from airway sensory nerve C-type fiber terminals and secondary synthesis of cysteinyl-leukotrienes, in particular LTD4. Beta (β)2-agonists are potent bronchodilators but potentially could also inhibit the airway response to hyperpnea challenge via effects on the release of LTD4from airway cells in vivo. The purpose of this study was to test the hypothesis that β2agonists attenuate HIB in guinea-pigs, in part, by reduction in LTD4release in vivo. Twenty-six guinea-pigs (400–550 g) were anesthetized with xylazine (7 mg/kg) and pentobarbital (65 mg/kg), tracheotomized and mechanically ventilated with a small animal ventilator using a tidal volume of 3 ml and a breathing frequency of 60 breaths/min. Dry gas (95%O2/5%CO2) with a 4 ml tidal volume and a breathing frequency of 150/min was used for hyperpnea challenge. Challenge with isocapnic dry gas triggered a significant increase in pulmonary resistance (0.3 ± 0.02 vs. 0.57 ± 0.06 cmH2O/ml per s; P=0.017; n=13) and excretion of LTD4in the bile (baseline: 2.43 vs. HIB: 4.66 pmol/h; P=0.04). Salbutamol pretreatment completely blocked the airway response to the challenge (0.3±0.02 vs. 0.3±0.05 cmH2O/ml per s; n=13) and reduced the biliary excretion of LTD4(baseline: 2.42 pmol/h; vs. HIB: 2.40 pmol/h). We conclude that salbutamol inhibited the airway responses to dry gas hyperpnea challenge and LTD4synthesis by the airway cells.