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

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 LTD 4 . Beta ( β ) 2 -agonists are potent bronchodilators but potentially could also inhibit the airway response to hyperpnea challenge via effects on the release of LTD 4 from airway cells in vivo. The purpose of this study was to test the hypothesis that β 2 agonists attenuate HIB in guinea-pigs, in part, by reduction in LTD 4 release 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%O 2 /5%CO 2 ) 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 cmH 2 O/ml per s; P=0.017; n=13) and excretion of LTD 4 in 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 cmH 2 O/ml per s; n=13) and reduced the biliary excretion of LTD 4 (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 LTD 4 synthesis by the airway cells.