Mechanism of endothelin-induced asthma

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Inhalation of aerosol of endothelin-1 induced dyspneal behavior in conscious guinea pigs pretreated with histamine or methacholine inhalation, while inhalation of endothelin-1 per se could not provoke dyspneal behavior in the animals. The dyspneal response was not affected either by nifedipine, a calcium channel blocker or by diphenhydramine, an antihistamine drug. Interestingly, the dyspneal response was potently inhibited by indomethasin, a cycolooxigenase inhibitor. In contrast, it has been shown that contraction of guinea pig tracheal strips induced by endothelin-1 was strongly inhibited by nifedipine in vitro. It has been also shown that both types of endothlein receptors (ETA and ETB) are present in lung tissues.Injection of endothelin-1, or 4-Ala-endothelin-1 (a ETB receptor specific agonist) caused elevation of body temperature in conscious rabbits. The pyrogenic action by endothelin-1 was also inhibited by indomethacin.Together with these observations the dyspneal response by endothelin appears to be induced by producing cyclooxigenase metabolites through selective stimuation of ETB receptor. We have clarified two novel roles of endothelin in vivo ; ie., dyspneal response and pyrogenic action, both of which are mediated by cyclooxigenase metabolites.