PROSTANOIDS COUNTERBALANCE THE BRONCHOCONSTRICTOR ACTIVITY OF ENDOTHELIN-1 IN PIGS

In 12 anaesthetized spontaneously breathing pigs divided into two grou ps of six animals we evaluated the respiratory and haemodynamic respon ses to endothelin-1 (ET-1) administered by aerosol (200 pmol.kg(-1) in 1 mi of saline solution). In the first group (control group), the res ponses to ET-1 were evaluated before and after the blocking of endogen ous nitric oxide (NO) by N-G-nitro-L-arginine methyl ester (L-NAME 5 m g.kg(-1), i.v.). In the second group (indomethacin-pretreated group), the experimental protocol was similar to that of the control group, bu t the responses were evaluated after the blocking of endogenous prosta noids by indomethacin (3 mg.kg(-1), i.v.). Results show that in the co ntrol group ET-1 administered before and after L-NAME did not change c ompliance (Crs) or resistances (Rrs) of the respiratory system. In ind omethacin-pretreated pigs, ET-1 significantly increased Rrs and decrea sed Crs. This constrictor effect appearing only during the block of ar achidonic acid metabolites showed that ET-1 activity can be counterbal anced by a release of dilator prostanoids. In this group after L-NAME pretreatment ET-1 did not alter the mechanical properties of the respi ratory system, suggesting an involvement of other bronchodilator mecha nisms. In the control group, aerosol administered ET-1 increased mean systemic (MAP) and pulmonary (MPAP) arterial pressures, while when ET- 1 was administered after L-NAME pretreatment, MPAP decreased. In the i ndomethacin-pretreated group, the peptide did not modify MAP, but caus ed an early decrease in MPAP when administered after L-NAME. Therefore , our results show that ET-1 caused a bronchoconstrictor effect only i n indomethacin-pretreated pigs and suggest that the intrinsic constric tor activity of the peptide can be modulated especially by the release of dilator prostanoids.