Endothelin-1-induced pulmonary vasoreactivity is regulated by ETA and ETB receptor interactions

Background: Roles of endothelin ( ET) receptors ( R) and of the endothelium on ET-1-induced pulmonary vasoreactivity are subjects of debate. This stems from endothelial ETB-R that can release both vasodilators and vasoconstrictors. The aim of this study was to evaluate the roles of the endothelium and of ET-Rs on ET-1-induced pulmonary vasoreactivity. Methods: Pharmacological experiments were performed in isolated rat lungs and in pulmonary resistance arteries. Results: In isolated lungs, ET-1 and the selective ETB-R agonist sarafotoxin 6c (S6c) induced a similar vasoconstriction. ET-1 constriction was reduced by a selective ETA-R antagonist; however, the selective ET B - R antagonist had no significant effect. In preconstricted lungs, ET B - R stimulation caused mild vasodilation at low concentrations but severe vasoconstriction at higher concentrations. In isolated arteries, responses to ET-1 and S6c were not different and unaffected by removal of endothelium. Interestingly, concentrations of ETA -R and ETB-R antagonists that only mildly reduced ET-1 vasoconstriction when used alone, prevented maximal constriction and greatly reduced vascular sensitivity to ET-1 when used in combination. Conclusion: In rat lungs, both ETA-R and ETB-R contribute to ET- 1-induced pulmonary vasoconstriction with evidence of interaction between receptors. A mild vasodilator role of the endothelial ETB-R is evident only at low agonist concentration and when baseline vascular tone is increased.