ROLE OF EICOSANOIDS IN HYPERPNEA-INDUCED AIRWAY RESPONSES IN GUINEA-PIGS

Guinea pigs mechanically hyperventilated with dry gas exhibit hyperpne a-induced bronchoconstriction (HIB) and hyperpnea-induced bronchovascu lar hyperpermeability (HIBVH). Tachykinins released from airway C-fibe r neurons are the central mediators of guinea pig HIB but play only a contributory role in HIBVH. Recent studies suggest that eicosanoid med iators can provoke bronchoconstriction and bronchovascular hyperpermea bility, are released by dry gas hyperpnea, and can themselves elicit o r modulate tachykinin release. We therefore hypothesized that eicosano ids may participate in HIB and/or HIBVH. To test these hypotheses, we analyzed respiratory system resistance changes and Evans blue-labeled albumin extravasation into the airways of 60 tracheostomized and mecha nically ventilated guinea pigs. Animals were subjected to 10 min of is ocapnic dry gas hyperpnea or to quiet breathing of humidified gas and received as pretreatment either piroxicam, a cyclooxygenase (CO) inhib itor; A-63162, a 5-lipoxygenase (5-LO) inhibitor; BW-755c, a combined CO and 5-LO inhibitor; ICI-198,615, a leukotriene D-4 receptor antagon ist; or no drug. HIB was substantially (50-80%) reduced by each of the four eicosanoid-modulating drugs. In contrast, HIBVH was reduced only by BW-755c, and this effect occurred only within the extrapulmonary a irways (42% reduction). These data indicate that both CO and 5-LO prod ucts, including leukotriene D-4, participate in the pathogenesis of HI B but that, like tachykinins, they play only a small contributory role in HIBVH. Together with our previous demonstration that sensory neuro peptide release is critical for the occurrence of HIB, we conclude tha t the roles of eicosanoids and tachykinins in guinea pig HIB are inter dependent.