Abstract
Although endothelin (ET) contributes to the regulation of pulmonary vascular tone in the normal fetus, little is known about its role in pulmonary hypertension in the perinatal period. To examine the role of the ETB receptor in the normal ovine fetal lung, we studied the hemodynamic effects of ET-3 (a selective ETB receptor agonist) before and after RES-701 (a selective ETB receptor antagonist). RES-701 (10 μg/min for 10 min) did not change basal pulmonary tone and blocked pulmonary vasodilation to ET-3(500 ng/min for 10 min). To examine the effects of experimental perinatal pulmonary hypertension on activity of the ETA and ETB receptors, we studied the hemodynamic effects of ET-3, ET-1 (a nonselective ETA and ETB receptor agonist), and BQ 123 (a selective ETA receptor antagonist) in 12 chronically prepared late gestation fetal lambs after partial ligation of the ductus arteriosus. Serial changes in the pulmonary vascular effects of these agents were measured early (1-3 d) and late (7-10 d) after partial ductus arteriosus ligation. Left lung total pulmonary resistance in the normal late-gestation fetus was 0.62 ± 0.01 mm Hg/ml/min(n = 4). After partial ductus arteriosus ligation, total pulmonary resistance increased to 1.2 ± 0.3 (early; p < 0.05versus normal), and progressively rose to 1.9 ± 0.2 mm Hg/ml/min (late; p < 0.05 versus early). Intrapulmonary infusion of ET-3 (500 ng/min for 10 min) increased pulmonary blood flow from 94 ± 11 to 183 ± 17 mL/min in the normal fetus, but had no effect during late pulmonary hypertension. Infusions of ET-1 (50 ng/min for 30 min) caused transient pulmonary vasodilation followed by vasoconstriction during early pulmonary hypertension. During late pulmonary hypertension, however, infusion of ET-1 caused predominantly vasoconstriction. Pulmonary vasodilation to BQ 123 (100 μg/min for 10 min) was greater during late than early pulmonary hypertension (43 versus 21%; p < 0.05). After 10 d of ductus arteriosus ligation, immunoreactive ET-1 content in whole lung tissue was 3-fold higher in hypertensive (n = 7) than control(n = 10) lungs (p < 0.05). We conclude that the ETB receptor contributes little to regulation of basal vascular tone in the normal ovine fetal lung and that chronic intrauterine pulmonary hypertension causes the loss of ETB-mediated vasodilation, progressive ETA-mediated vasoconstriction, and increased lung ET-1 content. We speculate that diminished ETB receptor-mediated vasodilation in combination with enhanced ETA receptor-mediated vasoconstriction and increased ET-1 production contributes to high pulmonary vascular resistance in perinatal pulmonary hypertension.
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Abbreviations
- ET:
-
endothelin
- PPHN:
-
persistent pulmonary hypertension of the newborn
- Paco2:
-
arterial Pco2
- Pao2:
-
arterial Pco2
- TPR:
-
total pulmonary resistance in the left lung
References
Levin DL, Heymann MA, Kitterman JA, Gregory GA, Phibbs RH, Rudolph AM 1976 Persistent pulmonary hypertension of the newborn infant. J Pediatr 89: 626–630.
Abman SH, Shanley PF, Accurso FJ 1989 Failure of postnatal adaptation of the pulmonary circulation after chronic intrauterine pulmonary hypertension in fetal lambs. J Clin Invest 83: 1849–1858.
Morin FC, 1989 1989 Ligating the ductus arteriosus before birth causes persistent pulmonary hypertension in the newborn lamb. Pediatr Res 25: 245–250.
Murphy JD, Rabinovitch M, Goldstein JD, Reid LM 1981 The structural basis of persistent pulmonary hypertension of the newborn infant. J Pediatr 98: 962–967.
Belik J, Halayko AJ, Rao K, Stephens NL 1993 Fetal ductus arteriosus ligation. Pulmonary vascular smooth muscle biochemical and mechanical changes. Circ Res 72: 588–596.
McQueston JA, Kinsella JP, Ivy DD, McMurtry IF, Abman SH 1995 Chronic pulmonary hypertension in utero impairs endothelium-dependent vasodilation. Am J Physiol 2:H 288: 294
Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T 1988 A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411–415.
Coceani F, Kelsey L 1991 Endothelin-1 release from lamb ductus arteriosus: relevance to postnatal closure of the vessel. Can J Physiol Pharmacol 69: 218–221.
Miyauchi T, Yorikane R, Sakai S, Sakurai T, Okada M, Nishikibe M, Yano M, Yamaguchi I, Sugishita Y, Goto K 1993 Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension. Circ Res 73: 887–897.
Bonvallet ST, Zamora MR, Hasunuma K, Sato K, Hanasato N, Anderson D, Sato K, Stelzner TJ 1994 BQ123, an ETA-receptor antagonist, attenuates hypoxic pulmonary hypertension in rats. Am J Physiol 266:H1327–H1331.
MacCumber MW, Ross CA, Glaser BM, Snyder SH 1989 Endothelin: visualization of mRNAs by in situ hybridization provides evidence for local action. Proc Natl Acad Sci USA 86: 7285–7289.
Nakamura T, Kasai K, Konuma S, Emoto T, Banba N, Ishikawa M, Shimoda S 1990 Immunoreactive endothelin concentrations in maternal and fetal blood. Life Sci 46: 1045–1050.
Ivy DD, Kinsella JP, Abman SH 1994 Physiologic characterization of endothelin A and B receptor activity in the ovine fetal pulmonary circulation. J Clin Invest 93: 2141–2148.
Wang Y, Coceani F 1992 Isolated pulmonary resistance vessels from fetal lambs. Contractile behavior and responses to indomethacin and endothelin-1. Circ Res 71: 320–330.
Rosenberg AA, Kennaugh J, Koppenhafer SL, Loomis M, Chatfield BA, Abman SH 1993 Elevated immunoreactive endothelin-1 levels in newborn infants with persistent pulmonary hypertension. J Pediatr 123: 109–114.
Masaki T, Vane JR, Vanhoutte PM 1994 International Union of Pharmacology nomenclature of endothelin receptors. Pharmacol Rev 46: 137–142.
Wang Y, Coe Y, Toyoda O, Coceani F 1995 Involvement of endothelin-1 in hypoxic pulmonary vasoconstriction in the lamb. J Physiol 482: 421–434.
Emori T, Hirata Y, Marumo F 1990 Specific receptors for endothelin-3 in cultured bovine endothelial cells and its cellular mechanism of action. FEBS Lett 263: 261–264.
Fukuda N, Soma M, Izumi Y, Minato M, Watanabe Y, Watanabe M, Hatano M 1991 Low doses of endothelin-3 elicit endothelium dependent vasodilation which accompanies with elevation of cyclic GMP. Jpn Circ J 55: 617–622.
Morishita Y, Chiba S, Tsukuda E, Tanaka T, Ogawa T, Yamasaki M, Yoshida M, Kawamoto I, Matsuda Y 1994 RES-701-1, a novel and selective endothelin type B receptor antagonist produced by Streptomyces sp. RE-701. I. Characterization of producing strain, fermentation, isolation, physicochemical and biological properties. J Antibiot 47:269-275. J Antibiot 47: 269–275.
Ihara M, Ishikawa K, Fukuroda T, Saeki T, Funabashi K, Fukami T, Suda H, Yano M 1992 In vitro biological profile of a highly potent novel endothelin (ET) antagonist BQ-123 selective for the ETA receptor. J Cardiovasc Pharmacol 20( suppl 12): S11–S14.
Chatfield BA, McMurtry IF, Hall SL, Abman SH 1991 Hemodynamic effects of endothelin-1 on ovine fetal pulmonary circulation. Am J Physiol 261:R182–R187.
Li H, Elton TS, Chen YF, Oparil S 1994 Increased endothelin receptor gene expression in hypoxic rat lung. Am J Physiol 266:L553–L560.
Yorikane R, Miyauchi T, Sakai S, Sakurai T, Yamaguchi I, Sugishita Y, Goto K 1993 Altered expression of ETB-receptor mRNA in the lung of rats with pulmonary hypertension. J Cardiovasc Pharmacol 22( suppl 8): S336–S338.
Stelzner TJ, O'Brien RF, Yanagisawa M, Sakurai T, Sato K, Webb S, Zamora M, McMurtry IF, Fisher JH 1992 Increased lung endothelin-1 production in rats with idiopathic pulmonary hypertension. Am J Physiol 262:L614–L620.
Li H, Chen SJ, Chen YF, Meng QC, Durand J, Oparil S, Elton TS 1994 Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. J Appl Physiol 77: 1451–1459.
Cassin S, Kristova V, Davis T, Kadowitz P, Gause G 1991 Tone-dependent responses to endothelin in the isolated perfused fetal sheep pulmonary circulation in situ. J Appl Physiol 70: 1228–1234.
Jones OWI, Abman SH 1994 Systemic and pulmonary hemodynamic effects of big endothelin-1 and phosphoramidon in the ovine fetus. Am J Physiol 266: R929–R955
Wong J, Vanderford PA, Fineman JR, Chang R, Soifer SJ 1993 Endothelin-1 produces pulmonary vasodilation in the intact newborn lamb. Am J Physiol 265:H1318–H1325.
Wong J, Fineman JR, Heymann MA 1994 The role of endothelin and endothelin receptor subtypes in regulation of fetal pulmonary vascular tone. Pediatr Res 35: 664–670.
Belik J 1994 Myogenic response in large pulmonary arteries and its ontogenesis. Pediatr Res 36: 34–40.
Belik J 1995 The myogenic response of arterial vessels is increased in fetal pulmonary hypertension. Pediatr Res 37: 196–201.
Cornfield DN, Chatfield BA, McQueston JA, McMurtry IF, Abman SH 1992 Effects of birth-related stimuli on L-arginine-dependent pulmonary vasodilation in ovine fetus. Am J Physiol 262:H1474–H1481.
Fineman JR, Wong J, Morin FCr, Wild LM, Soifer SJ 1994 Chronic nitric oxide inhibition in utero produces persistent pulmonary hypertension in newborn lambs. J Clin Invest 93: 2675–2683.
Kourembanas S, McQuillan LP, Leung GK, Faller DV 1993 Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest 92: 99–104.
Zamora MA, Dempsey EC, Walchak SJ, Stelzner TJ 1993 BQ123, an ETA receptor antagonist, inhibits endothelin-1-mediated proliferation of human pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol 9: 429–433.
Hasunuma K, Rodman DM, O'Brien RF, McMurtry IF 1990 Endothelin 1 causes pulmonary vasodilation in rats. Am J Physiol 259:H48–H54.
D'Orleans-Juste P, Telemaque S, Claing A, Ihara M, Yano M 1992 Human big-endothelin-1 and endothelin-1 release prostacyclin via the activation of ET1 receptors in the rat perfused lung. Br J Pharmacol 105: 773–775.
Eddahibi S, Raffestin B, Braquet P, Chabrier PE, Adnot S 1991 Pulmonary vascular reactivity to endothelin-1 in normal and chronically pulmonary hypertensive rats. J Cardiovasc Pharmacol 17( suppl 7): S358–S361.
Fukuroda T, Fujikawa T, Ozaki S, Ishikawa K, Yano M, Nishikibe M 1994 Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun 199: 1461–1465.
Cacoub P, Dorent R, Maistre G, Nataf P, Carayon A, Piette C, Godeau P, Cabrol C, Gandjbakhch I 1993 Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome. Am J Cardiol 71: 448–450.
Allen SW, Chatfield BA, Koppenhafer SA, Schaffer MS, Wolfe RR, Abman SH 1993 Circulating immunoreactive endothelin-1 in children with pulmonary hypertension. Association with acute hypoxic pulmonary vasoreactivity. Am Rev Respir Dis 148: 519–522.
Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ 1993 Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 328: 1732–1739.
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This work was supported in part by National Institutes of Health Grants H241012 and 46481, the March of Dimes Birth Defects Foundation, the American Heart Association of Colorado (CF-035-93), and the Bugher Physician-Scientist Training Program.
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Ivy, D., Ziegler, J., Dubus, M. et al. Chronic Intrauterine Pulmonary Hypertension Alters Endothelin Receptor Activity in the Ovine Fetal Lung. Pediatr Res 39, 435–442 (1996). https://doi.org/10.1203/00006450-199603000-00010
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DOI: https://doi.org/10.1203/00006450-199603000-00010
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