Mechanisms of endothelin-mediated bronchoconstriction in the guinea pig

Intravenous injection of anesthetized ventilated guinea pigs with doses of endothelin ranging from 0.25 to 2.50 micrograms/kg caused dose-dependent decreases in respiratory system conductance and compliance. These effects were maximal 1 min after injection and had disappeared 15 min thereafter. When guinea pigs were pretreated with 3 mg/kg of propranolol or 5 mg/kg of hexamethonium, endothelin-induced bronchoconstriction rose significantly, but when they were pretreated with 3 mg/kg of propranolol plus 3 mg/kg of atropine it remained unchanged. The bronchoconstrictor effects of endothelin were suppressed in guinea pigs pretreated with 0.5 or 2 mg/kg of meclofenamate but remained unchanged in those pretreated with 30 micrograms/kg of nicardipine. Endothelin did not increase either lung permeability, as assessed by 99m technetium diethylenetriamine pentaacetic acid clearance, or airway responsiveness to histamine or 5-hydroxy-tryptamine. Histological studies showed that endothelin induced reversible contraction of airway and pulmonary artery smooth muscles but no inflammatory reactions. These results demonstrate that, in guinea pigs, endothelin 1) induces airway smooth muscle contraction mediated by cyclooxygenase metabolites and modulated by the autonomic nervous system and 2) does not induce airway hyperreactivity or inflammation.