Endothelin-1-Induced Pulmonary Vasoreactivity Is Regulated by ET_A and ET_B Receptor Interactions

Abstract

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 ET_B-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 ET_B-R agonist sarafotoxin 6c (S6c) induced a similar vasoconstriction. ET-1 constriction was reduced by a selective ET_A-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 ET_A-R and ET_B-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 ET_A-R and ET_B-R contribute to ET-1-induced pulmonary vasoconstriction with evidence of interaction between receptors. A mild vasodilator role of the endothelial ET_B-R is evident only at low agonist concentration and when baseline vascular tone is increased.

Change in pharmacological effect of endothelin receptor antagonists in rats with pulmonary hypertension: Role of ETB-receptor expression levels

“…Previous investigators such as Mickley [29] and Adner [30] have previously reported the existence of an interaction between the two receptor subtypes in small mesenteric arteries. We have also recently demonstrated the existence of an interaction between the ET A and ET B receptor to induce the ET-1 vasoconstriction in pulmonary resistance arteries [17]. Whether this inter-play occurs post-receptor or takes place at the receptor level, remains to be determined.…”

“…In pulmonary arteries isolated from sham animals, selective ET A , selective ET B and dual ET A/B (bosentan) receptor antagonists had no significant effect on ET-1-induced response. We have previously demonstrated that at these concentrations, the selective ET A and ET B receptor antagonists had little effect on ET-1-dependent response [17]. It is difficult, however, to reconcile the lack of effect of the dual antagonist bosentan as this antagonist simultaneously blocks both receptors (ET A /ET B ) responsible for ET-1-induced pulmonary vasoconstriction.…”

“…Experiments were conducted on isolated pulmonary arteries and on the basilar artery using a wire myograph as previously described [16,17]. The general contractile capacities of pulmonary arteries from both groups were evaluated with: a high potassium solution (127 mmol l −1 ), a concentration-response curve to ET-1 (0. .…”

“…The general contractile capacities of pulmonary arteries from both groups were evaluated with: a high potassium solution (127 mmol l −1 ), a concentration-response curve to ET-1 (0. . In order to test potential improvement in efficacy of the ET receptor antagonists in PAH, the concentrations of the antagonists were chosen based on concentration-response curves for normal pulmonary resistance arteries [17,18] as these concentrations caused no or minimal effects on the normal response. The basilar arteries were subjected to ET-1-induced vasoconstriction in the absence and presence of the dual antagonist bosentan.…”

Peroxisome Proliferator-Activated Receptor-γ Ameliorates Pulmonary Arterial Hypertension by Inhibiting 5-Hydroxytryptamine 2B Receptor

“…Other than the serotonin system, endothelin-1/endothelin-1 receptors also play an important role in the development of PAH. 50 Bosentan, a dual antagonist for endothelin-1 receptors, is clinically used for PAH. In animal models, bosentan attenuated vascular remodeling or hypertrophy or both.…”