Importance of Local Production of Endothelin-1 and of the ETBReceptor in the Regulation of Pulmonary Vascular Tone

Dupuis, Jocelyn; Jasmin, Jean-François; Prié, Stéphane; Černáček, Peter

doi:10.1006/pupt.2000.0242

Cited by 52 publications

(37 citation statements)

References 18 publications

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“…Importantly, a reduced pulmonary clearance likely contributes to the observed increase in plasma ET-1, the pulmonary circulation playing a major role in the removal of circulating ET-1, and a reduced pulmonary clearance of this peptide contributes to the hyperendothelinemia observed in both human and animal model of PAH [24][25][26][27]. Our group has previously reported a reduction in ET B -receptor-dependent clearance in the MCT model of PAH [28]. Reduced pulmonary clearance is likely explained by the marked down-regulation of the ET B receptor in this pathological model.…”

Section: Discussionmentioning

confidence: 92%

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: Discussionmentioning

confidence: 92%

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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“…Activation of EDNRB by EDN-1 in normal and some tumor cells leads to the induction of EDN-1 clearance, which then stimulates cellular apoptosis, thus having an anticancer effect (20). However in other tumor types EDNRB enhances cancer progression and was found to be overexpressed, such as in melanoma (21) and oligodendroglioma (22).…”

Section: Endothelin Receptors Type a And Bmentioning

confidence: 99%

Aspects of the endothelin system in colorectal cancer

et al. 2014

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“…Stimulation of the endothelial ET B R can release vasodilators such as nitric oxide (NO) and prostacyclin (prostaglandin I 2 ) [28,29]. Under normal conditions, the endothelial ET B R does not seem to contribute significantly to pulmonary vascular tone [16,30], and removal of the endothelium does not affect ET-1-induced pulmonary arterial vasoreactivity [16]. Under conditions of PH, however, when baseline pulmonary vascular tone is increased, the vasodilatory role of the ET B R can be unmasked by selective ET B R stimulation using a low concentration of ET-1 or by selective ET B R blockade [16,30,31].…”

Section: Effects Of Endothelin In the Lungsmentioning

confidence: 99%

“…Under normal conditions, the endothelial ET B R does not seem to contribute significantly to pulmonary vascular tone [16,30], and removal of the endothelium does not affect ET-1-induced pulmonary arterial vasoreactivity [16]. Under conditions of PH, however, when baseline pulmonary vascular tone is increased, the vasodilatory role of the ET B R can be unmasked by selective ET B R stimulation using a low concentration of ET-1 or by selective ET B R blockade [16,30,31]. With higher agonist concentration, the mild vasodilatory role of the ET B R is lost and overcome by potent sustained vasoconstriction [16].…”

Section: Effects Of Endothelin In the Lungsmentioning

confidence: 99%

Endothelin receptor antagonists in pulmonary arterial hypertension

Dupuis¹,

Hoeper²

2008

Eur Respir J

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The endothelin (ET) system, especially ET-1 and the ET A and ET B receptors, has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Together with prostanoids and phosphodiesterase 5 inhibitors, ET receptor antagonists have become mainstays in the current treatment of PAH.Three substances are currently available for the treatment of PAH. One of these substances, bosentan, blocks both ET A and ET B receptors, whereas the two other compounds, sitaxsentan and ambrisentan, are more selective blockers of the ET A receptor.There is ongoing debate as to whether selective or nonselective ET receptor blockade is advantageous in the setting of PAH, although there is no clear evidence that receptor selectivity is relevant with regard to the clinical effects of these drugs.For the time being, other features, such as safety profiles and the potential for pharmacokinetic interactions with other drugs used in the treatment of PAH, may be more important than selectivity or nonselectivity when selecting treatments for individual patients.

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Importance of Local Production of Endothelin-1 and of the ETBReceptor in the Regulation of Pulmonary Vascular Tone

Cited by 52 publications

References 18 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

Aspects of the endothelin system in colorectal cancer

Endothelin receptor antagonists in pulmonary arterial hypertension

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