Prostanoids counterbalance the bronchoconstrictor activity of endothelin-1 in pigs

Abstract

In 12 anaesthetized spontaneously breathing pigs divided into two groups of six animals we evaluated the respiratory and haemodynamic responses to endothelin-1 (ET-1) administered by aerosol (200 pmol.kg −1 in 1 ml of saline solution). In the first group (control group), the responses to ET-1 were evaluated before and after the blocking of endogenous nitric oxide (NO) by N G-nitro-L-arginine methyl ester (L-NAME 5 mg.kg −1, i.v.). In the second group (indomethacin-pretreated group), the experimental protocol was similar to that of the control group, but the responses were evaluated after the blocking of endogenous prostanoids by indomethacin (3 mg.kg −1, i.v.). Results show that in the control group ET-1 administered before and after L-NAME did not change compliance (Crs) or resistances (Rrs) of the respiratory system. In indomethacin-pretreated pigs, ET-1 significantly increased Rrs and decreased Crs. This constrictor effect appearing only during the block of arachidonic acid metabolites showed that ET-1 activity can be counterbalanced by a release of dilator prostanoids. In this group after L-NAME pretreatment ET-1 did not alter the mechanical properties of the respiratory system, suggesting an involvement of other bronchodilator mechanisms. 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 indomethacin-pretreated group, the peptide did not modify MAP, but caused an early decrease in MPAP when administered after L-NAME. Therefore, our results show that ET-1 caused a bronchoconstrictor effect only in indomethacin-pretreated pigs and suggest that the intrinsic constrictor activity of the peptide can be modulated especially by the release of dilator prostanoids.