title: Endothelin-3-dependent pulmonary vasoconstriction in monocrotaline-induced pulmonary arterial hypertension.
abstract: Blockade of the endothelin (ET) system is beneficial in pulmonary arterial hypertension (PAH). The contribution of ET-3 and its interactions with ET receptors have never been evaluated in the monocrotaline (MCT)-induced model of PAH. Vasoreactivity of pulmonary arteries was investigated; ET-3 localization was determined by confocal imaging and gene expression of prepro-ET-3 quantified using RT-PCR. ET-3 plasma levels tended to increase in PAH. ET-3 localized in the media of pulmonary arteries, where gene expression of prepro-ET-3 was reduced in PAH. ET-3 induced similar pulmonary vasoconstrictions in sham and PAH rats. In sham rats, the ET(A) antagonist A-147627 (10nmol/l) significantly reduced the maximal response to ET-3 (E(max) 77+/-1 to 46+/-2%, mean+/-S.E.M., P<0.001), while the ET(B) antagonist A-192621 (1mumol/l) reduced the sensitivity (EC(50) 21+/-7 to 59+/-16nmol/l, P<0.05) without affecting E(max). The combination of both antagonists completely abolished ET-3-induced pulmonary vasoconstriction. In PAH, the ET(A) antagonist further reduced the maximal response to ET-3 and shifted the EC(50) (E(max) 23+/-2%, P<0.001, EC(50) 104+/-24nmol/l, P<0.05), while the ET(B) antagonist only shifted the EC(50) (123+/-36nmol/l, P<0.05) without affecting the E(max). In PAH, dual ET receptor inhibition did not further reduce constriction compared to selective ET(A) inhibition. ET-3 significantly contributes to pulmonary vasoconstriction by activating the ET(B) at low concentration, and the ET(A) at high concentration. The increased inhibitory effect of the ET(A) antagonist in PAH suggests that the contribution of ET(B) to ET-3-induced vasoconstriction is reduced. Although ET-3 is a potent pulmonary vasoconstrictor in PAH, its potential pathophysiologic contribution remains uncertain.
authors.affiliation: Research Center, Montreal Heart Institute and Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Sauvageau
authors.forename: Eric
authors.initials: E
authors.lastname: Thorin
authors.forename: Louis
authors.initials: L
authors.lastname: Villeneuve
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Dupuis
mesh_terms: D000818:Animals; D019334:Endothelin-3 / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply; D008297:Male; D018613:Microscopy, Confocal; D016686:Monocrotaline; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000502:physiology; D044023:Receptor, Endothelin B / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D019334:Endothelin-3; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D016686:Monocrotaline
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