Endothelin-3-dependent pulmonary vasoconstriction in monocrotaline-induced pulmonary arterial hypertension.
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.
Sauvageau
Stéphanie
S
Research Center, Montreal Heart Institute and Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada.
Thorin
Eric
E
Villeneuve
Louis
L
Dupuis
Jocelyn
J
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*
D019334:Endothelin-3; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D016686:Monocrotaline
Chest. 2007 Jan;131(1):101-8
17218562
Dev Dyn. 2005 Jun;233(2):407-17
15768389
J Biol Chem. 1989 Oct 25;264(30):18156-61
2509452
Pulm Pharmacol Ther. 2000;13(3):135-40
10873551
Am J Respir Cell Mol Biol. 1992 Nov;7(5):492-9
1419025
Circ Res. 1993 Nov;73(5):887-97
8403258
J Cardiovasc Pharmacol. 1995;26 Suppl 3:S169-76
8587353
Clin Sci (Lond). 2003 Dec;105(6):647-53
12823096
J Vasc Res. 2007;44(5):375-81
17495482
J Cardiovasc Pharmacol. 1998;31 Suppl 1:S482-5
9595519
Nature. 1990 Dec 20-27;348(6303):732-5
2175397
FEBS Lett. 1998 May 29;428(3):304-8
9654154
Ann Thorac Surg. 1993 Feb;55(2):450-8
8431058
Cell. 1994 Dec 30;79(7):1267-76
8001159
Am J Physiol. 1997 Dec;273(6):H2558-64
9435587
Am J Respir Crit Care Med. 2005 Mar 1;171(5):506-13
15579730
Cell. 1994 Dec 30;79(7):1277-85
8001160
Can J Physiol Pharmacol. 2003 Jun;81(6):542-54
12839266
Biochem Biophys Res Commun. 1990 Jun 15;169(2):809-15
2192712
Circulation. 1998 Jun 2;97(21):2169-74
9626178
Proc Natl Acad Sci U S A. 1989 Apr;86(8):2863-7
2649896
Nature. 1990 Dec 20-27;348(6303):730-2
2175396
J Clin Invest. 1992 Sep;90(3):1023-31
1522210
Eur Respir J. 2008 Feb;31(2):407-15
18238950
J Hepatol. 1995 Dec;23(6):681-8
8750167