The interaction of endothelin receptor responses in the isolated perfused rat lung

To gain more insight into the complex pulmonary interactions of endothelins (ET), we studied airway and vascular responses to endothelins in isolated perfused rat lungs in the presence of the novel ETB-receptor antagonist BQ788. In particular we focused on airway responses and on prostacyclin release. The effectiveness of BQ788 in our system was shown by its ability to concentration-dependently prevent vasoconstriction (IC50 0.1μM), bronchoconstriction (IC50 0.1μM) and prostacyclin production (IC50<0.1μM) induced by the ETB-receptor agonist IRL1620 (1nmol). Airway responses to ET-1: ET-1-induced bronchoconstriction was aggravated by BQ123 (1 or 8μM), while BQ788 pretreatment (1 or 8μM) showed no significant effect. Simultaneous treatment with 8μM BQ123 and BQ788 attenuated the ET-1-induced bronchoconstriction. Vascular responses to ET-1: ET-1 (1nmol)-induced vasoconstriction was potentiated by BQ788 (1 or 8μM), but attenuated by the ETA-receptor antagonist BQ123 (1μM). In the presence of BQ788 diminished amounts of the stable prostacyclin metabolite 6-keto-PGF1α were detected in the perfusate. Simultaneous treatment with 8μM BQ123 and BQ788 completely prevented the ET-1-induced vasoconstriction. Conclusions: Both ETA- and ETB-receptors contribute to ET-1-induced vasoconstriction and bronchoconstriction. The ET-1-induced vasoconstriction is attenuated by stimulation of ETB-receptors, a response that is partly mediated by prostacyclin. Due to the mutual interactions between ETA- and ETB-receptors, simultaneous inhibition of both receptors is required to prevent the deleterious effects of ET-1 on lung functions.