Endothelin receptors mediating contraction of rat and human pulmonary resistance arteries: effect of chronic hypoxia in the rat

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

doi:10.1038/sj.bjp.0701785

Cited by 72 publications

(60 citation statements)

References 37 publications

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“…There is experimental evidence that both ET A and ET B receptors modulate ET-1 responses in small muscular pulmonary arteries of humans, and that combining blockade of both receptor subtypes can block ET-1-induced pulmonary vasoconstriction. 25 Nevertheless, ET A selective antagonists have been effective in improving cardiovascular function and structure in numerous experimental animal studies, suggesting therapeutic efficacy with ET A receptor blockade alone. It has been demonstrated that ET B receptor blockade alone impairs pulmonary clearance of ET-1 and reduces nitric oxide-mediated vasodilation.…”

Section: Et Receptor Blockade For Cardiovascular Diseasementioning

confidence: 99%

Endothelin Receptor Blockers in Cardiovascular Disease

Rich¹,

McLaughlin²

2003

Circulation

199

126

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Abstract-The endothelin (ET) system is comprised of 4 active ETs, with ET-1 being the predominant isoform in the cardiovascular system. Because of the potent vasoconstricting and mitogenic effects of ET-1 and its involvement in various cardiovascular diseases, blockade of the ET receptor has received considerable attention. ET receptor antagonism has been demonstrated to be beneficial in patients with pulmonary hypertension. The nonselective ET receptor antagonist bosentan improves exercise capacity and increases time to clinical worsening in patients with pulmonary arterial hypertension. Key Words: endothelin Ⅲ heart failure Ⅲ pulmonary heart disease T he endothelin (ET) system, like other vascular regulatory systems, consists of a parent peptide that undergoes enzymatic activation and exerts its biologic effects by modulating specific receptors. Of the 4 active ETs (ET 1 through 4), ET-1 is the predominant isoform in the cardiovascular system, which is generated through the cleavage of prepro ET-1 to big ET-1 and then to ET-1 by the action of ET-converting enzymes. ET-1 is found in endothelial cells and is released toward the vascular smooth muscle consistent with a paracrine role, but it is also produced by smooth muscle cells and cardiomyocytes. 1,2 ET-1 has vasoconstrictive and mitogenic effects, stimulates the production of growth factors such as vascular endothelial growth factor and basic fibroblast growth factor, and potentiates the effects of transforming growth factor-␤ and platelet-derived growth factor. 3-7 Chronic ET-1 stimulation can result in myocardial fibrosis and hypertrophy and vascular fibrosis with extracellular matrix proliferation. 8 In the lung, ET-1 is abundantly expressed in the pulmonary vasculature and appears to play an important role in the regulation of pulmonary vascular tone. 9 ET-1 is also produced in leukocytes where it influences the production of a wide range of cytokines in the inflammatory response. 10 ET is regulated in an autocrine fashion by physiochemical factors such as blood flow, pulsatile stretch, sheer stress, and pH. 11-13 Acute hypoxia leads to selective stimulation of the ET-1 gene and ET synthesis in the pulmonary vasculature. 14 ET-1 biosynthesis is also stimulated by low-density lipoprotein cholesterol and glucose, and thrombin. 15,16 Endogenous inhibitors of ET-1 synthesis include nitric oxide, prostacyclin, atrial natriuretic peptides, and estrogens. [17][18][19][20] ET-1 exerts its major vascular effects through activation of 2 distinct G protein coupled ET A and ET B receptors. ET A receptors are found in the medial smooth muscle layers of the blood vessels, and atrial and ventricular myocardium. 21 When stimulated, the ET A receptors induce vasoconstriction and cellular proliferation by increasing intracellular calcium.ET B receptors are localized on endothelial cells and, to some extent, smooth muscle cells and macrophages. 22 The activation of ET B receptors stimulates the release of nitric oxide and prostacyclin and prevents apoptosis. 23 Normally, t...

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Section: Et Receptor Blockade For Cardiovascular Diseasementioning

confidence: 99%

Endothelin Receptor Blockers in Cardiovascular Disease

Rich¹,

McLaughlin²

2003

Circulation

199

126

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“…12 In contrast, ET B receptors are present on both ECs and VSMCs in the rat and human pulmonary circulations. 13 Stimulation of endothelial ET B receptors causes vasodilation through release of NO and prostacyclin and also functions to remove ET-1 from the circulation. 14,15 Stimulation of ET B receptors on smooth muscle causes vasoconstriction in the rat lung.…”

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confidence: 99%

Development of Occlusive Neointimal Lesions in Distal Pulmonary Arteries of Endothelin B Receptor–Deficient Rats

et al. 2005

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Background-Human pulmonary arterial hypertension (PAH) is characterized by proliferation of vascular smooth muscle and, in its more severe form, by the development of occlusive neointimal lesions. However, few animal models of pulmonary neointimal proliferation exist, thereby limiting a complete understanding of the pathobiology of PAH. Recent studies of the endothelin (ET) system demonstrate that deficiency of the ET B receptor predisposes adult rats to acute and chronic hypoxic PAH, yet these animals fail to develop neointimal lesions. Herein, we determined and thereafter showed that exposure of ET B receptor-deficient rats to the endothelial toxin monocrotaline (MCT) leads to the development of neointimal lesions that share hallmarks of human PAH. Methods and Results-The pulmonary hemodynamic and morphometric effects of 60 mg/kg MCT in control (MCT ϩ/ϩ ) and ET B receptor-deficient (MCT sl/sl ) rats at 6 weeks of age were assessed. MCT sl/sl rats developed more severe PAH, characterized by elevated pulmonary artery pressure, diminished cardiac output, and right ventricular hypertrophy. In MCT sl/sl rats, morphometric evaluation revealed the presence of neointimal lesions within small distal pulmonary arteries, increased medial wall thickness, and decreased arterial-to-alveolar ratio. In keeping with this, barium angiography revealed diminished distal pulmonary vasculature of MCT sl/sl rat lungs. Cells within neointimal lesions expressed smooth muscle and endothelial cell markers. Moreover, cells within neointimal lesions exhibited increased levels of proliferation and were located in a tissue microenvironment enriched with vascular endothelial growth factor, tenascin-C, and activated matrix metalloproteinase-9, factors already implicated in human PAH. Finally, assessment of steady state mRNA showed that whereas expression of ET B receptors was decreased in MCT sl/sl rat lungs, ET A receptor expression increased. Conclusions-Deficiency

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“…observation is consistent with the previous pharmacological studies utilizing small pulmonary arteries isolated from normal rats in which ETB receptor agonist is more potent to induce vasoconstriction than ET-1. ETA receptor antagonist had little effects on the ET-1-induced vasoconstriction [1,27]. Conversely, ETA receptor antagonists prevented ET-1 induced vasoconstriction utilizing the main rat pulmonary artery [28].…”

Section: Discussionmentioning

confidence: 99%

Discrepant distribution of big endothelin (ET)-1 and ET receptors in the pulmonary artery

et al. 2001

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Since pulmonary vasculature is complex in terms of regional difference in structure and function, it is important to understand the site of endothelin (ET) synthesis and the distribution of the ET system along the axial pathways of pulmonary artery.The expression of big ET-1, ET converting enzyme (ECE) and ETA receptors were examined in rat pulmonary arteries under normal and hypoxic conditions using an immunohistochemical method and Northern blot analysis.In normal conditions, big ET-1 was expressed in the intima and media of pulmonary arteries with a predominant distribution in the distal segments and a preferential localization in the media, while ETA receptors were dominantly expressed in the proximal segments. ECE was constitutively expressed in the intima and media. Following exposure to hypoxia, messenger ribonucleic acid (mRNA) expression of ET-1 and ETA receptors were up-regulated by two-fold and immunoreactivities for big ET-1, ECE, and ETA receptors significantly increased by two to five-fold in the distal segments.Smooth muscle cells are an important source of endothelin-1 in the pulmonary artery. The distribution of big endothelin-1 and endothelin A receptors in pulmonary arteries was discrepant in normal conditions while their expression concomitantly increased in the distal segments in hypoxic conditions. This heterogeneity may play an important role in the regulation of pulmonary vascular tone. Endothelins (ETs) and their receptors are abundantly expressed in the lung and postulated to play an important role in the regulation of pulmonary vascular tone. ET-l, a potent vasoconstrictor and smooth muscle mitogen composed of 21 amino acids, is synthesized from big ET-l by a specific cleavage at Trp 21 -Val 22 by ET converting enzyme (ECE) [l, 2]. The actions of ET-l are mediated by two different receptors, ETA and ETB receptors [1,2]. ETA receptors are found in pulmonary vascular smooth muscle cells and mediate smooth muscle contraction and the proliferation of smooth muscle cells and fibroblasts, while ETB receptors are expressed in endothelial cells (ETB1 receptors) and smooth muscle cells (ETB2 receptors) and cause either relaxation or contraction, respectively [2,3,4]. Since the pulmonary vascular bed is complex in terms of regional differences in both structure and function, it is important to know about localization and distribution of ET-1 and ET receptors. Although it is known that ET-1 is expressed in various cells including endothelial cells, epithelial cells, smooth muscle cells, and tissue macrophages in the lung [2,5,6], there are few studies showing the distribution of ET-1 and ECE expression along the axial pathways of the pulmonary artery.The over-expression of the messenger ribonucleic acid (mRNA) for ET-1, ETA and ETB receptors, and the overproduction of the ET-1 peptide in whole lung have been demonstrated in an experimental model of hypoxic pulmonary hypertension [6 -11]. Furthermore, blocking ETA receptors with selective antagonists attenuates the rise in pulmonary arte...

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Endothelin receptors mediating contraction of rat and human pulmonary resistance arteries: effect of chronic hypoxia in the rat

Cited by 72 publications

References 37 publications

Endothelin Receptor Blockers in Cardiovascular Disease

Endothelin Receptor Blockers in Cardiovascular Disease

Development of Occlusive Neointimal Lesions in Distal Pulmonary Arteries of Endothelin B Receptor–Deficient Rats

Discrepant distribution of big endothelin (ET)-1 and ET receptors in the pulmonary artery

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