Pharmacological modulation of the bronchopulmonary action of the vasoactive peptide, endothelin, administered by aerosol in the guinea-pig

Administration by aerosol for 1 min of solutions of endothelin (ENDO; 1, 5 or 10 micrograms/ml) to anaesthetized and ventilated guinea-pigs induced a dose-dependent bronchopulmonary response (BR) which was maximal within 4 to 5 min. In contrast, no significant change of the mean arterial blood pressure was observed. Pretreatment of guinea-pigs with propranolol (1 mg/kg, i.v.), mepyramine (1 mg/kg, i.v.), nifedipine (50 mg/kg, i.p.) or verapamil (0.3 mg/kg, i.v.) did not significantly affect the BR induced by an aerosol of a solution of 10 micrograms/ml ENDO. In contrast, BR was significantly reduced when the animals were pretreated with the cyclooxygenase inhibitor, indomethacin (10 mg/kg, i.v.) or the platelet-activating factor (PAF) receptor antagonist, BN 52021 (10 mg/kg, i.v.). These results indicate that aerosolized ENDO induces a BR via the generation of secondary mediators such as cyclooxygenase products and PAF in a process which is unaffected by the blockers of the voltage-dependent calcium channels.