Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome

Cacoub, Patrice; Dorent, Richard; Maistre, G.; Nataf, Patrick; Carayon, A.; Piette, Jean Charles; Godeau, P; Cabrol, C; Gandjbakhch, I

doi:10.1016/0002-9149(93)90452-i

Cited by 127 publications

(58 citation statements)

References 7 publications

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“…However, all relevant studies are consistent in showing that the ET-1 levels are significantly increased in cases of pulmonary hypertension. The most dramatic increases in circulating ET-1 levels and ET-1 expression, appear to be associated with primary pulmonary hypertension (Stewart et al, 1991;Cacoub et al, 1993;Giaid et al, 1993;Nootens et al, 1995); although ET-1 levels are also significantly increased in pulmonary hypertension secondary to hypoxia (Stewart et al, 1991;Ferri et al, 1995), congenital heart defects (Yoshibayashi et al, 1991;Cacoub et al, 1993;Vincent et al, 1993), valvular heart disease (Stewart et al, 1991;Chang et al, 1993;Yamamoto et al, 1994;Zhu et al, 1994), chronic heart failure (Cody et al, 1992;Kiowski et al, 1995) and the adult respiratory distress syndrome (Langleben et al, 1993). Plasma ET-1 levels can be increased four fold in some of these studies.…”

Section: Resultsmentioning

confidence: 99%

Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries

McCulloch

Docherty

Morecroft

et al. 1996

British J Pharmacology

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Using wire myography, we have examined the endothelin (ET) receptor subtypes mediating vasoconstriction to ET peptides in human pulmonary resistance arteries (150–200 μm, i.d.). Cumulative concentration‐response curves to ET‐1, sarafotoxin 6c (SX6c) and ET‐3 were constructed in the presence and absence of the selective antagonists FR 139317 (ETA‐selective), BMS 182874 (ETA‐selective) and BQ‐788 (ETB‐selective). All agonists induced concentration‐dependent contractions. However, the response curves to ET‐1 were biphasic in nature. The first component demonstrated a shallow slope up to 1 nM ET‐1. Above 1 nM ET‐1 the response curve was markedly steeper. Maximum responses to ET‐3 and SX6c were the same as those to 1 nM ET‐1 and 30% of those to 0.1 μm ET‐1. The order of potency, taking 0.3 μm as a maximum concentration was SX6c > > ET‐3 > ET‐1 (pEC50 values of: 10.75 ± 0.27, 9.05 ± 0.19, 8.32 ± 0.08 respectively). Taking 1 nM ET‐1 as a maximum, the EC50 for ET‐1 was 10.08 ± 0.13 and therefore ET‐1 was equipotent to ET‐3 and SX6c over the first component of the response curve. Responses to ET‐1 up to 1 nM were resistant to the effects of the ETA receptor antagonists, FR 139317 and BMS 182874 but were inhibited by the ETB receptor antagonist, BQ‐788. Conversely, responses to ET‐1 over 1 nM were inhibited by the ETA receptor antagonists, FR 139317 and BMS 182874 but unaffected by the ETB receptor antagonist, BQ‐788. The results suggest that at concentrations up to 1 nM, responses to ET‐1 are mediated via the ETB receptor, whilst the responses to higher concentrations are mediated by ETA receptors.

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Section: Resultsmentioning

confidence: 99%

Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries

McCulloch

Docherty

Morecroft

et al. 1996

British J Pharmacology

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“…A central aspect of pulmonary vascular remodeling is medial hypertrophy caused by sustained pulmonary vasoconstriction (2-4), excessive pulmonary artery smooth muscle cell (PASMC) proliferation (5), and inhibited PASMC apoptosis (6, 7), resulting in a narrowed vascular lumen and increased PVR. Although its etiology remains unclear, elevated levels of circulating mitogens, dysfunction or down-regulation of receptors and ion channels, upregulation of transporters, and heightened activity of elastases and glycoproteins have been implicated in IPAH (5,6,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Transient receptor potential (TRP) channel genes may encode subunits that form receptor-(ROC) and store-(SOC) operated Ca 2ϩ channels in many cell types, including PASMC and pulmonary artery endothelial cells (PAEC) (28,(30)(31)(32)(33)(34). Ca 2ϩ entry through ROC and SOC increases [Ca 2ϩ ] cyt , allowing for phosphorylation of signal transduction proteins and transcription factors (23,24,(35)(36)(37)(38), that are essential for the progression of the cell cycle (21).…”

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confidence: 99%

“…A central aspect of pulmonary vascular remodeling is medial hypertrophy caused by sustained pulmonary vasoconstriction (2)(3)(4), excessive pulmonary artery smooth muscle cell (PASMC) proliferation (5), and inhibited PASMC apoptosis (6,7), resulting in a narrowed vascular lumen and increased PVR. Although its etiology remains unclear, elevated levels of circulating mitogens, dysfunction or down-regulation of receptors and ion channels, upregulation of transporters, and heightened activity of elastases and glycoproteins have been implicated in IPAH (5,6,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

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confidence: 99%

Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension

Fantozzi

Remillard

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

395

366

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Pulmonary vascular medial hypertrophy caused by excessive pulmonary artery smooth muscle cell (PASMC) proliferation is a major cause for the elevated pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH). Increased Ca 2؉ influx is an important stimulus for PASMC proliferation. Transient receptor potential (TRP) channel genes encode Ca 2؉ channels that are responsible for Ca 2؉ entry during cell proliferation. Normal human PASMC expressed multiple canonical TRP (TRPC) isoforms; TRPC6 was highly expressed and TRPC3 was minimally expressed. The protein expression of TRPC6 in normal PASMC closely correlated with the expression of Ki67, suggesting that TRPC6 expression is involved in the transition of PASMC from quiescent phase to mitosis. In lung tissues and PASMC from IPAH patients, the mRNA and protein expression of TRPC3 and -6 were much higher than in those from normotensive or secondary pulmonary hypertension patients. Inhibition of TRPC6 expression with TRPC6 small interfering RNA markedly attenuated IPAH-PASMC proliferation. These results demonstrate that expression of TRPC channels correlates with the progression of the cell cycle in PASMC. TRPC channel overexpression may be partially responsible for the increased PASMC proliferation and pulmonary vascular medial hypertrophy in IPAH patients.I diopathic pulmonary arterial hypertension (IPAH) is a fatal disease that causes right heart failure and death. The elevated pulmonary vascular resistance (PVR) and arterial pressure in IPAH patients result mainly from pulmonary vasoconstriction, vascular remodeling, and in situ thrombosis (1). A central aspect of pulmonary vascular remodeling is medial hypertrophy caused by sustained pulmonary vasoconstriction (2-4), excessive pulmonary artery smooth muscle cell (PASMC) proliferation (5), and inhibited PASMC apoptosis (6, 7), resulting in a narrowed vascular lumen and increased PVR. Although its etiology remains unclear, elevated levels of circulating mitogens, dysfunction or down-regulation of receptors and ion channels, upregulation of transporters, and heightened activity of elastases and glycoproteins have been implicated in IPAH (5,6,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Transient receptor potential (TRP) channel genes may encode subunits that form receptor-(ROC) and store-(SOC) operated Ca 2ϩ channels in many cell types, including PASMC and pulmonary artery endothelial cells (PAEC) (28,(30)(31)(32)(33)(34). Ca 2ϩ entry through ROC and SOC increases [Ca 2ϩ ] cyt , allowing for phosphorylation of signal transduction proteins and transcription factors (23,24,(35)(36)(37)(38), that are essential for the progression of the cell cycle (21). High levels of [Ca 2ϩ ] cyt and sufficient levels of Ca 2ϩ in the SR are required for vascular smooth muscle cell proliferation (22,25,39). Because they regulate SR and cytoplasmic Ca 2ϩ , CCE and SOC may play significant roles in regulating cell proliferation (28,29). This study tested the hypothesis that canonical TRP (TRPC...

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“…Endothelin (ET)-1 is a potent vasoconstrictor and mitogen. 2 Patients with PPH present with increased circulating ET-1 and increased lung tissue expression of the endothelin system 3,4 and are improved by the endothelin receptor antagonist bosentan. 5 Progress in pathophysiological understanding of PPH, or pulmonary arterial hypertension (PAH) defined as PPH with identifiable associated conditions, 6 has been limited until now by the absence of a satisfactory experimental animal model.…”

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confidence: 99%

Bosentan for the Prevention of Overcirculation-Induced Experimental Pulmonary Arterial Hypertension

et al. 2003

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Background-The dual endothelin-receptor antagonist bosentan has been reported to improve pulmonary arterial hypertension, but the role of endothelins in the pathogenesis of the condition remains uncertain. We investigated the roles of endothelin-1 (ET-1), nitric oxide (NO), vascular endothelial growth factor (VEGF), and tenascin in overcirculation-induced pulmonary hypertension in piglets, as a model of early pulmonary arterial hypertension, with or without bosentan therapy. Methods and Results-Thirty 3-week-old piglets were randomized to placebo or to bosentan 15 mg/kg BID after the anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by cardiac and pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative PCR. Chronic systemic-to-pulmonary shunting increased circulating plasma ET-1, pulmonary mRNA for ET-1, ET B receptor, inducible NO synthase, VEGF, and pulmonary ET-1 and VEGF proteins. There were increases in myocardial mRNA for ET A receptor and VEGF and in myocardial VEGF protein. Pulmonary and myocardial tissue mRNA for tenascin did not change. Normalized-flow pulmonary artery pressure increased from 20 (2) to 33 (1) mm Hg [mean (SEM)], arteriolar medial thickness increased on average by 83%, and these changes were completely prevented by bosentan therapy. Right ventricular end-systolic elastance increased in proportion to pulmonary arterial elastance with or without bosentan. Conclusions-Experimental overcirculation-induced pulmonary arterial hypertension appears to be causally related to an activation of the pulmonary ET-1 system and as such is completely prevented by the dual endothelin receptor antagonist bosentan. (Circulation. 2003;107:1329-1335.)

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Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome

Cited by 127 publications

References 7 publications

Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries

Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries

Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension

Bosentan for the Prevention of Overcirculation-Induced Experimental Pulmonary Arterial Hypertension

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Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome

Cited by 127 publications

References 7 publications

EndothelinB receptor‐mediated contraction in human pulmonary resistance arteries

EndothelinB receptor‐mediated contraction in human pulmonary resistance arteries

Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension

Bosentan for the Prevention of Overcirculation-Induced Experimental Pulmonary Arterial Hypertension

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Product

Resources

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Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries

Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries