The endothelin system in pulmonary hypertension

Michel, René P.; Langleben, David; Dupuis, Jocelyn

doi:10.1139/y03-008

Cited by 51 publications

(38 citation statements)

References 146 publications

(146 reference statements)

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“…Increased plasma levels of ET-1 were detected in patients with various forms of PAH [1] and in various experimental models [2,3]. The chief action of ET-1 is its ability to modulate pulmonary vascular reactivity.…”

Section: Introductionmentioning

confidence: 99%

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

Sauvageau¹,

Thorin²,

Villeneuve³

et al. 2009

Pulmonary Pharmacology & Therapeutics

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Background and purpose-The endothelin (ET) system is activated in pulmonary arterial hypertension (PAH). The therapeutic value of pharmacological blockade of ET receptors has been demonstrated in various animal models and led to the current approval and continued development of these drugs for the therapy of human PAH. However, we currently incompletely comprehend what local modifications of this system occur as a consequence of PAH, particularly in small resistance arteries, and how this could affect the pharmacological response to ET receptor antagonists with various selectivities for the receptor subtypes. Therefore, the purposes of this study were to evaluate potential modifications of the pharmacology of the ET system in rat pulmonary resistance arteries from monocrotaline (MCT)-induced pulmonary arterial hypertension.Experimental approach-ET-1 levels were quantified by ELISA. PreproET-1, ET A and ET B receptor mRNA expressions were quantified in pulmonary resistance arteries using Q-PCR, while protein expression was evaluated by Western blots. Reactivity to ET-1 of isolated pulmonary resistance arteries was measured in the presence of ET A (A-147627), ET B (A-192621) and dual ET A/B (bosentan) receptor antagonists.Key results-In rats with PAH, plasma ET-1 increased (p < 0.001) while pulmonary levels were reduced (p < 0.05). In PAH arteries, preproET-1 (p < 0.05) and ET B receptor (p < 0.001) gene expressions were reduced, as were ET B receptor protein levels (p < 0.05). ET-1 induced similar vasoconstrictions in both groups. In arteries from sham animals, neither bosentan nor the ET A or the ET B receptor antagonists modified the response. In arteries from PAH rats, however, bosentan and the ET A receptor antagonist potently reduced the maximal contraction, while bosentan also reduced sensitivity (p < 0.01).

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Section: Introductionmentioning

confidence: 99%

“…The endothelin (ET) system is activated in pulmonary arterial hypertension (PAH) [1]. Increased plasma levels of ET-1 were detected in patients with various forms of PAH [1] and in various experimental models [2,3].…”

Section: Introductionmentioning

confidence: 99%

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

Sauvageau¹,

Thorin²,

Villeneuve³

et al. 2009

Pulmonary Pharmacology & Therapeutics

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“…ET-1 effects are mediated by activation of at least two receptor subtypes, ET A and ET B [19]. ET A receptors are located on smooth muscle cells and mediate vasoconstriction and smooth muscle proliferation [19].…”

Section: Discussionmentioning

confidence: 99%

Cirrhosis ameliorates monocrotaline-induced pulmonary hypertension in rats

Pavec

Perros²,

Eddahibi³

et al. 2009

European Respiratory Journal

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Common bile duct ligation (CBDL) induces biliary cirrhosis and pulmonary vasodilatation. We tested whether CBDL ameliorates monocrotaline (MCT)-induced pulmonary hypertension (PH) in rats.Five groups of rats were studied: controls; rats dosed with MCT (60 mg?kg -1 subcutaneously);CBDL; rats dosed with MCT followed by CBDL on day 7; and rats dosed with MCT followed by CBDL (day 7) and L-NAME therapy between days 24 and 28. 28-day survival was 26% in the MCT group and 72% in the MCT+CBDL group. Pulmonary vascular resistance measured on days 21 and 28 increased in the MCT and MCT+CBDL+L-NAME groups, but returned to normal in the MCT+CBDL group on day 28. Pulmonary artery (PA) medial hypertrophy persisted in MCT+CBDL rats. PA inflammation increased in MCT+CBDL rats, with accumulation of both intra-and perivascular macrophages. Exhaled nitric oxide (NO) levels decreased in the MCT group and increased in the MCT+CBDL group, which showed upregulation of inducible NO synthase and normal endothelial NO synthase. Blood endothelin (ET)-1 increased in CBDL, MCT, and MCT+CBDL rats. Levels of ET B receptors increased and ET A receptors decreased in the MCT+CBDL group, whereas the opposite changes occurred in the MCT group. Biliary cirrhosis induces pulmonary vasodilation that ameliorates MCT-induced PH and improves survival. Upregulation of inducible NO synthase and ET B receptor and downregulation of ET A receptor may be involved.

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“…There is also an elevation of ET-1 in tracheal aspirates from these infants (15). High blood ET-1 levels have also been reported in neonatal sepsis (16), perinatal asphyxia (17,18), congenital diaphragmatic hernia (19), persistent pulmonary hypertension of the newborn (13,(20)(21)(22)(23), and acute respiratory distress syndrome (ARDS) in children (24).…”

Section: Introductionmentioning

confidence: 94%

“…ET causes isolated contraction of pulmonary veins, vascular smooth muscle mito-genesis, myocardial cell hypertrophy, positive inotropic and chronotropic effects, bronchoconstriction, mucous secretion, cellular proliferation, and inflammatory reactions (5)(6)(7)(8)(9)(10)(11). ET-1 has a potent pulmonary vasoconstrictor effect (5)(6)(7)(8)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Umbilical cord blood and neonatal endothelin-1 levels in preterm newborns with and without respiratory distress syndrome

Benjamin¹,

Silveira²,

Procianoy³

2005

Braz J Med Biol Res

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Increased pulmonary vascular resistance in preterm newborn infants with respiratory distress syndrome is suggested, and endothelin-1 plays an important role in pulmonary vascular reactivity in newborns. We determined umbilical cord blood and neonatal (second sample) levels of endothelin-1 in 18 preterm newborns with respiratory distress syndrome who had no clinical or echocardiographic diagnosis of pulmonary hypertension and 22 without respiratory distress syndrome (gestational ages: 31.4 ± 1.6 and 29.3 ± 2.3 weeks, respectively). Umbilical cord blood and a second blood sample taken 18 to 40 h after birth were used for endothelin-1 determination by enzyme immunoassay. Median umbilical cord blood endothelin-1 levels were similar in both groups (control: 10.9 and respiratory distress syndrome: 11.4 pg/ mL) and were significantly higher than in the second sample (control: 1.7 pg/mL and respiratory distress syndrome: 3.5 pg/mL, P < 0.001 for both groups). Median endothelin-1 levels in the second sample were significantly higher in children with respiratory distress syndrome than in control infants (P < 0.001). There were significant positive correlations between second sample endothelin-1 and Score for Neonatal Acute Physiology and Perinatal Extension II (r = 0.36, P = 0.02), and duration of mechanical ventilation (r = 0.64, P = 0.02). A slower decline of endothelin-1 from birth to 40 h of life was observed in newborns with respiratory distress syndrome when compared to controls. A significant correlation between neonatal endothelin-1 levels and some illness-severity signs suggests that endothelin-1 plays a role in the natural course of respiratory distress syndrome in preterm newborns.

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The endothelin system in pulmonary hypertension

Cited by 51 publications

References 146 publications

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

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

Cirrhosis ameliorates monocrotaline-induced pulmonary hypertension in rats

Umbilical cord blood and neonatal endothelin-1 levels in preterm newborns with and without respiratory distress syndrome

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