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: 9.67). 01/1989; 85(24):9797-800. DOI: 10.1073/pnas.85.24.9797
Source: PubMed


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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    • "The inability to detect NOS inhibitor-elevated ET-1 plasma levels may be due to clearance of plasma ET-1 by ETB receptors located in the lung and other tissues (de Nucci et al., 1988). However, elevated ET-1 plasma levels were still not detected in the rabbit when ETB receptor antagonist was added 10 min after bolus injection of NOS inhibitor (Gratton et al., 1997). "
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    ABSTRACT: Key evidence that endogenous nitric oxide (NO) inhibits the continuous, endothelin (ET)-1-mediated drive to elevate arterial pressure includes demonstrations that ET-1 mediates a significant component of the pressure elevated by acute exposure to NO synthase (NOS) inhibitors. This review examines the characteristics of this pressure elevation in order to elucidate potential mechanisms associated with the negative regulation of ET-1 by NO and, thereby, provide potential insight into the vascular pathophysiology underlying NO dysregulation. We surmise that the magnitude of the ET-1-dependent component of the NOS inhibitor-elevated pressure is (1) independent of underlying arterial pressure and other pressor pathways activated by the NOS inhibitors and (2) dependent on relatively higher NOS inhibitor dose, release of stored and de novo synthesized ET-1, and ETA receptor-mediated increased vascular resistance. Major implications of these conclusions include: (1) the marked variation of the ET-1-dependent component, i.e., from 0 to 100% of the pressure elevation, reflects the NO-ET-1 regulatory pathway. Thus, NOS inhibitor-mediated, ET-1-dependent pressure elevation in vascular pathophysiologies is an indicator of the level of compromised/enhanced function of this pathway; (2) NO is a more potent inhibitor of ET-1-mediated elevated arterial pressure than other pressor pathways, due in part to inhibition of intravascular pressure-independent release of ET-1. Thus, the ET-1-dependent component of pressure elevation in vascular pathophysiologies associated with NO dysregulation is of greater magnitude at higher levels of compromised NO.
    Frontiers in Pharmacology 04/2014; 5:57. DOI:10.3389/fphar.2014.00057 · 3.80 Impact Factor
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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 · 2.70 Impact Factor
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    • "ETB receptors are expressed predominantly in endothelial cells and at lower levels in vascular smooth muscle cells [6]. Stimulation of the endothelial ETB receptor results in release of NO and prostacyclin [30] causing vasodilatation, whereas stimulation of the ETB receptor in the vascular smooth muscle cell results in vasoconstriction. Thus, the net effect produced by ET-1 is determined by the balance between ETA and ETB receptors and their localization. "
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    ABSTRACT: Obstructive sleep apnoea (OSA) is a risk factor for cardiovascular disorders and in some cases is complication of pulmonary hypertension. We simulated OSA by exposing rats to cyclic intermittent hypoxia (CIH) to investigate its effect on pulmonary vascular endothelial dysfunction. Sprague-Dawley Rats were exposed to CIH (FiO2 9% for 1 min, repeated every 2 min for 8 h/day, 7 days/wk for 3 wk), and the pulmonary arteries of normoxia and CIH treated rats were analyzed for expression of endothelin-1 (ET-1) and ET receptors by histological, immunohistochemical, RT-PCR and Western Blot analyses, as well as for contractility in response to ET-1. In the pulmonary arteries, ET-1 expression was increased, and ET-1 more potently elicited constriction of the pulmonary artery in CIH rats than in normoxic rats. Exposure to CIH induced marked endothelial cell damage associated with a functional decrease of endothelium-dependent vasodilatation in the pulmonary artery. Compared with normoxic rats, ETA receptor expression was increased in smooth muscle cells of the CIH rats, while the expression of ETB receptors was decreased in endothelial cells. These results demonstrated endothelium-dependent vasodilation was impaired and the vasoconstrictor responsiveness increased by CIH. The increased responsiveness to ET-1 induced by intermittent hypoxia in pulmonary arteries of rats was due to increased expression of ETA receptors predominantly, meanwhile, decreased expression of ETB receptors in the endothelium may also participate in it.
    PLoS ONE 03/2013; 8(3):e58078. DOI:10.1371/journal.pone.0058078 · 3.23 Impact Factor
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