Effect of Novel Mixed ETA/ETBAntagonists on Responses to ET-1 in Human Small Muscular Pulmonary Arteries

MacLean, Margaret R.; Docherty, Cheryl C.; McCulloch, Kirsty; Morecroft, Ian

doi:10.1006/pupt.1998.0129

Cited by 15 publications

(11 citation statements)

References 2 publications

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“…In the human pulmonary artery, the ET A receptors have been found to predominate in arteries from 0.5 to Ͼ8 mm in diameter, although the number of ET B receptors increases with decreasing arterial diameter (3). These data correlate well with contraction assays showing that ET-1-induced contraction of rat proximal arteries is dependent on ET A receptors, whereas in human and rat distal arteries of 150-250 m in diameter, ET B is responsible (27,28). The present study indicates that both receptors are present on normal sheep PLVSMC and that both receptors regulate expression of ppET-1.…”

Section: Discussionsupporting

confidence: 66%

Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells

Chen

Balyakina

Lawrence³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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-We examined the hypothesis that the potent vasoconstrictor endothelin (ET)-1 regulates both its own production and production of the vasodilator prostaglandins PGE 2 and prostacyclin in sheep peripheral lung vascular smooth muscle cells (PLVSMC). Confluent layers of PLVSMC were exposed to 10 nM ET-1; expression of the prepro (pp)-ET-1, cyclooxygenase (COX)-1, and COX-2 genes was examined by RT-PCR and Western analysis. Intracellular levels of ET-1 were measured by ELISA with and without addition of the protein synthesis inhibitor brefeldin A (50 g/ml). Prostaglandin levels were measured by gas chromatography-mass spectrometry. Through use of ET A and ETB antagonists (BQ-610 and BQ-788, respectively), the contribution of the ET receptors to COX-1 and -2 expression and ppET-1 gene expression was examined. The contribution of phosphorylated p38 and p44/42 MAPK on COX-1 and COX-2 expression was also examined with MAPK inhibitors (p38, SB-203580 and p44/ 42, PD-98056). ET-1 resulted in transient increases in ppET-1, COX-1, and COX-2 gene and protein expression and release of 6-keto-PGF1␣ and PGE2 (P Ͻ 0.05). Both internalization of ET-1 and synthesis of new peptide contributed to an increase in intracellular ET-1 (P Ͻ 0.05). Although increased ppET-1 was regulated by both ETA and ETB, COX-2 expression was upregulated only by ETA; COX-1 expression was unaffected by either antagonist. ET-1 treatment resulted in transient phosphorylation of p38 and p44/42 MAPK; inhibitors of these MAPKs suppressed expression of COX-2 but not COX-1. Our data indicate that local production of ET-1 regulates COX-2 by activation of the ETA receptor and phosphorylation of p38 and p44/42 MAPK in PLVSMC.prostacyclin; prostaglandin E2; endothelin receptors

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Section: Discussionsupporting

confidence: 66%

Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells

Chen

Balyakina

Lawrence³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Initial efforts have focused on ETA selective antagonism, because ETB located on ECs is also known to stimulate NO-mediated vasodilation [56,57] and to participate in endothelin clearance [58,59]. However, more recent studies using isolated human small pulmonary arteries have suggested that a combined blockade of both ETA and the ETB is necessary to achieve optimal inhibition of vasoconstriction [60-62]. This may be due to the fact that activation of smooth muscle ETB receptors contributes to the proliferation of pulmonary SMCs [28] coupled with the fact that increased expression of the ETB receptor has been found in the pulmonary arteries of patients with severe PH [34].…”

Section: Discussionmentioning

confidence: 99%

Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonaryhypertension

Rafikova

Rafikov

Kumar

et al. 2013

Free Radical Biology and Medicine

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Pulmonary arterial hypertension (PH) is a fatal disease marked by excessive pulmonary vascular cell proliferation. Patients with idiopathic PH express endothelin-1 (ET-1) at high levels in their lungs. As the activation of both types of ET-1 receptor (ETA and ETB) leads to increased generation of superoxide and hydrogen peroxide, this may contribute to the severe oxidative stress found in PH patients. As a number of pathways may induce oxidative stress, the particular role of ET-1 remains unclear. The aim of this study was to determine whether inhibition of ET-1 signaling could reduce pulmonary oxidative stress and attenuate the progression of disease in rats with occlusive-angioproliferative PH induced by a single dose of SU5416 (200 mg/kg) and subsequent exposure to hypoxia for 21 days. Using this regimen, animals developed severe PH as evidenced by a progressive increase in right-ventricle (RV) peak systolic pressure (RVPSP), severe RV hypertrophy, and pulmonary endothelial and smooth muscle cell proliferation, resulting in plexiform vasculopathy. PH rats also had increased oxidative stress, correlating with endothelial nitric oxide synthase uncoupling and NADPH oxidase activation, leading to enhanced protein nitration and increases in markers of vascular remodeling. Treatment with the combined ET receptor antagonist bosentan (250 mg/kg/day; day 10 to 21) prevented further increase in RVPSP and RV hypertrophy, decreased ETA/ETB protein levels, reduced oxidative stress and protein nitration, and resulted in marked attenuation of pulmonary vascular cell proliferation. We conclude that inhibition of ET-1 signaling significantly attenuates the oxidative and nitrosative stress associated with PH and prevents its progression.

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“…In isolated resistance human pulmonary arteries, responses to ET-1 are modulated by both the ET A and ET B receptors (McCulloch et al 1996) and are therefore best inhibited by nonselective antagonists MacLean et al 1998). The systemic pressor effects of circulating ET-1 are attenuated by its removal by the pulmonary circulation and by the release of prostacyclin and NO through the endothelial ET B receptor (de Nucci et al 1988).…”

Section: Biology Of the Et System In The Pulmonary Circulationmentioning

confidence: 99%

The endothelin system in pulmonary hypertension

Michel

Langleben²,

Dupuis³

2003

Can. J. Physiol. Pharmacol.

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Pulmonary hypertension (PH) may result from numerous clinical entities affecting the pulmonary circulation primarily or secondarily. It is recognized that vascular endothelial dysfunction contributes to the development and perpetuation of PH by creating an imbalance between vasodilating and antiproliferative forces and between vasoconstrictive and proliferative forces. In that context, endothelin-1 (ET-1) overproduction was rapidly targeted as a plausible contributor to the pathogenesis of PH. The lung is recognized as the major site for ET production and clearance. In all animal models of PH studied, circulating plasma ET-1 levels are elevated, accompanied by an increase in lung tissue expression of the peptide. The use of selective ETA and dual ETA-ETB receptor antagonists in these models both in prevention and in therapeutic studies have confirmed the contribution of ET-1 to the rise in pulmonary vascular tone, pulmonary medial hypertrophy, and right ventricular hypertrophy. This is found consistently in models affecting the pulmonary circulation primarily or producing PH secondarily. Recent clinical trials in patients with pulmonary arterial hypertension have confirmed the therapeutic effectiveness of ET-receptor antagonists in humans. We offer a systematic review of the pathogenic role of the ET system in the development of PH as well as the rationale behind the preclinical and ongoing clinical trials with this new class of agents.

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Effect of Novel Mixed ETA/ETBAntagonists on Responses to ET-1 in Human Small Muscular Pulmonary Arteries

Cited by 15 publications

References 2 publications

Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells

Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells

Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonaryhypertension

The endothelin system in pulmonary hypertension

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