The pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and EDRF

William Harvey Research Institute, St Bartholomew's Hospital Medical College, London, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 01/1989; 85(24):9797-800. DOI: 10.1073/pnas.85.24.9797
Source: PubMed

ABSTRACT Endothelin releases prostacyclin and thromboxane A2 from guinea pig or rat isolated lungs and endothelium-derived relaxing factor in the perfused mesentery of the rat. Endothelin is also substantially removed by the pulmonary circulation of the rat in vitro and in vivo and by guinea pig lungs in vitro. In the rat, the effects of endothelin on the blood pressure vary from pressor (in pithed rats) to purely depressor in anesthetized rats where the resting blood pressure is high. It therefore has the characteristics of a local pressor hormone, rather than a circulating one.

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    • "In order to exclude any effects of nitric oxide (NO), which modulate both the production and the action of ET-1 (de Nucci et al., 1988; Boulanger and Lüscher, 1990; Vanhoutte, 2000; Félétou et al., 2012) and the release of which could be initiated by ET-1 or serotonin acting on ET B or 5-HT 1D receptors, respectively (Cohen et al., 1983; de Nucci et al., 1988; Schoeffter and Hoyer, 1990; Schini et al., 1991; Hirata et al., 1993), all experiments were performed in the presence of a NO synthase inhibitor. The rings were equilibrated for at least ten minutes prior to incubation with the non-selective nitric oxide synthase inhibitor N ω -nitro-L-arginine methyl ester (L-NAME, 3 × 10 −4 mol/L) for 30 min to block basal and receptor-stimulated generation of NO (Widmer et al., 2006; Baretella et al., 2013). "
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    ABSTRACT: Levels of the endothelium-derived peptide endothelin-1 (ET-1) are elevated in human obesity, and ET-1 mediated vascular tone is increased. Renal arterial smooth muscle is highly responsive to ET-1. Whether or not endothelium-derived ET-1 affects contractions of the renal artery under normal conditions or in obesity is unknown. The present study was designed to investigate whether or not overexpression of endogenous ET-1 in the endothelium affects the responsiveness of main and segmental renal arteries differently in obesity. Mice with tie-1 promoter-driven endothelium-restricted heterozygous overexpression of preproendothelin-1 were used (TET(het)). Obesity was induced in TET(het) mice and wild-type (WT) littermates by feeding a high fat diet for 30 weeks; lean controls were kept on standard chow. The renal arteries were studied in wire myographs testing contractions (in the presence of L-NAME) to ET-1, serotonin, and U46619. Contractions to ET-1 were comparable between groups in main renal arteries, but augmented in segmental preparations from obese mice. Serotonin-induced responses were enhanced in obese TET(het) mice renal arteries compared to lean controls. Concentration-contraction curves to U46619 were shifted significantly to the left in main renal arteries of obese animals, and the maximal response was significantly increased between lean and obese TET(het) mice. These results indicate an augmented responsiveness of main renal arteries in obesity particularly to TP receptor activation. When combined with endothelial ET-1 overexpression this effect is even more pronounced, which may help to gain further insights into the mechanisms of hypertension in obesity.
    Life Sciences 01/2014; 118(2):206-212. DOI:10.1016/j.lfs.2013.12.214 · 2.30 Impact Factor
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    • "Within blood vessels, both receptors are found on smooth muscle cells and their activation results in vasoconstriction. ETB receptors are, however, predominantly found on the vascular endothelium where their activation results in vasodilatation via prostacyclin and NO (DeNucci et al., 1988). Because most ET-1 is released abluminally, plasma concentrations of ET-1 do not accurately reflect ET-1 production. "
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    ABSTRACT: Since its discovery over 20 years ago endothelin-1 (ET-1) has been implicated in a number of physiological and pathophysiological processes. Its role in the development and progression of chronic kidney disease (CKD) is well established and is an area of ongoing intense research. There are now available a number of ET receptor antagonists many of which have been used in trials with CKD patients and shown to reduce BP and proteinuria. However, ET-1 has a number of BP-independent effects. Importantly, and in relation to the kidney, ET-1 has clear roles to play in cell proliferation, podocyte dysfunction, inflammation and fibrosis, and arguably, these actions of ET-1 may be more significant in the progression of CKD than its prohypertensive actions. This review will focus on the potential role of ET-1 in renal disease with an emphasis on its BP-independent actions.
    British Journal of Pharmacology 06/2012; 167(4):720-31. DOI:10.1111/j.1476-5381.2012.02070.x · 4.99 Impact Factor
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    • "In principal cells of the collecting duct, activation of ET B receptors inhibits sodium and water transport [16]. ET B receptors also mediate clearance of endothelin from the circulation [17], and this effect appears to involve cross-talk with the ET A receptor, at least under physiological conditions [18]. In the vasculature and the kidney, via activation of its ET A receptors, endothelin has a basal ( " tonic " ) vasoconstricting role; endothelins also contribute to myocardial Biochimica et Biophysica Acta 1802 (2010) 1203–1213 "
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    ABSTRACT: Diabetes and arterial hypertension continue to be the main causes of chronic renal failure in 2010, with a rising prevalence in part due to the worldwide obesity epidemic. Proteinuria is a main feature of chronic renal disease and mediated by defects in the glomerular filtration barrier and is as a good predictor of cardiovascular events. Indeed, chronic renal disease due to glomerulosclerosis is one of the important risk factors for the development of coronary artery disease and stroke. Glomerulosclerosis develops in response to inflammatory activation and increased growth factor production. Preclinical and first preliminary clinical studies provide strong evidence that endogenous endothelin-1 (ET-1), a 21-amino-acid peptide with strong growth-promoting and vasoconstricting properties, plays a central role in the pathogenesis of proteinuria and glomerulosclerosis via activation of its ET(A) subtype receptor involving podocyte injury. These studies have not only shown that endothelin participates in the disease processes of hypertension and glomerulosclerosis but also that features of chronic renal disease such as proteinuria and glomerulosclerosis are reversible processes. Remarkably, the protective effects of endothelin receptors antagonists (ERAs) are present even on top of concomitant treatments with inhibitors of the renin-angiotensin system. This review discusses current evidence for a role of endothelin for proteinuric renal disease and podocyte injury in diabetes and arterial hypertension and reviews the current status of endothelin receptor antagonists as a potential new treatment option in renal medicine.
    Biochimica et Biophysica Acta 03/2010; 1802(12):1203-13. DOI:10.1016/j.bbadis.2010.03.012 · 4.66 Impact Factor
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