ENDOTHELIN-1 AND BRONCHIAL HYPERRESPONSIVENESS IN THE RABBIT

Endothelins (ETs) are a family of peptide mediators that have a number of biological properties, including the ability to act as potent bron choconstrictors of isolated human airways. Moreover, elevated concentr ations of ET-1 in the bronchoalveolar lavage fluid from patients with symptomatic asthma have also been detected. We investigated the possib le contribution of ET-1 in the development of bronchial hyperresponsiv eness and the role of inflammatory cell accumulation in rabbit lungs. Our data show that ET-1 challenge to rabbits does not modify basal lun g function but results in an increased airway responsiveness to inhale d histamine. Endothelin-treated rabbits were 3-fold (P<0.01) more resp onsive to inhaled histamine when compared with vehicle-treated rabbits . This hyperresponsiveness was not associated with an alteration in ei ther total or differential inflammatory cell numbers as assessed by br onchoalveolar lavage (BAL). Pre-treatment with capsaicin (80 mg/kg s.c .) did not alter basal lung function or basal responsiveness to inhale d histamine. While capsaicin had no significant effect on the acute br onchoconstriction induced by endothelin-l, this dose was sufficient to significantly inhibit the increase in airway responsiveness to inhale d histamine, achieved 24 h following endothelin-l challenge. These res ults indicate that ET-1 may play a role in the development of bronchia l hyperresponsiveness to inhaled histamine and that the maintenance of this state is unrelated to a detectable alteration in cellular infilt ration within the airway lumen, but probably via the involvement of ca psaicin-sensitive nerves.