Journal articles: 'Endothelin receptor'

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Saenz de Tejada, I., M. P. Carson, A. de las Morenas, I. Goldstein, and A. M. Traish. "Endothelin: localization, synthesis, activity, and receptor types in human penile corpus cavernosum." American Journal of Physiology-Heart and Circulatory Physiology 261, no. 4 (October 1, 1991): H1078—H1085. http://dx.doi.org/10.1152/ajpheart.1991.261.4.h1078.

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The localization, synthesis, and activity of endothelin and the receptor types mediating its effects in penile corpus cavernosum were investigated in whole tissue and in cultured cells derived from this tissue. With immunocytochemistry, utilizing an antiendothelin 1 (ET-1) monoclonal antibody, endothelin-like immunoreactivity was localized intensely in the endothelium and to a lesser degree in the trabecular smooth muscle. Human corpus cavernosum endothelial cells in culture expressed preproendothelin 1 mRNA, as determined by Northern blot analysis. Significant amounts of endothelin-like immunoreactivity were measured by radioimmunoassay in the supernatants of corpus cavernosum endothelial cells in culture. Endothelins are potent constrictors and caused long-lasting contractions of corporeal strips in organ chambers. Equilibrium binding analysis of endothelins to their receptor sites revealed high-affinity, specific, and saturable binding of labeled endothelins to corporeal membranes. Competition binding experiments demonstrated receptors with high affinity for ET-1 and -2 and low affinity for ET-3 and another, less abundant, set of receptors with high affinity for ET-1, -2, and -3. Affinity labeling of endothelins to corporeal membranes, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, revealed that ET-1 and -2 cross-linked specifically to three different molecular mass components (75, 52, and 34 kDa). ET-3 bound only to the 34-kDa component. It is concluded that human corpus cavernosum endothelium has the ability to synthesize and release endothelin, that endothelins contract corporeal smooth muscle, and that at least two distinct endothelin receptors may exist and are differentiated by their affinity for ET-3.

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Barton, Matthias, and Masashi Yanagisawa. "Endothelin: 30 Years From Discovery to Therapy." Hypertension 74, no. 6 (December 2019): 1232–65. http://dx.doi.org/10.1161/hypertensionaha.119.12105.

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Discovered in 1987 as a potent endothelial cell–derived vasoconstrictor peptide, endothelin-1 (ET-1), the predominant member of the endothelin peptide family, is now recognized as a multifunctional peptide with cytokine-like activity contributing to almost all aspects of physiology and cell function. More than 30 000 scientific articles on endothelin were published over the past 3 decades, leading to the development and subsequent regulatory approval of a new class of therapeutics—the endothelin receptor antagonists (ERAs). This article reviews the history of the discovery of endothelin and its role in genetics, physiology, and disease. Here, we summarize the main clinical trials using ERAs and discuss the role of endothelin in cardiovascular diseases such as arterial hypertension, preecclampsia, coronary atherosclerosis, myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) caused by spontaneous coronary artery dissection (SCAD), Takotsubo syndrome, and heart failure. We also discuss how endothelins contributes to diabetic kidney disease and focal segmental glomerulosclerosis, pulmonary arterial hypertension, as well as cancer, immune disorders, and allograft rejection (which all involve ET A autoantibodies), and neurological diseases. The application of ERAs, dual endothelin receptor/angiotensin receptor antagonists (DARAs), selective ET B agonists, novel biologics such as receptor-targeting antibodies, or immunization against ET A receptors holds the potential to slow the progression or even reverse chronic noncommunicable diseases. Future clinical studies will show whether targeting endothelin receptors can prevent or reduce disability from disease and improve clinical outcome, quality of life, and survival in patients.

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Auguet, Michel, Sylvie Delaflotte, Pierre-Etienne Chabrier, and Pierre Braquet. "Characterization of endothelin receptors mediating contraction and relaxation in rabbit saphenous artery and vein." Canadian Journal of Physiology and Pharmacology 71, no. 10-11 (October 1, 1993): 818–23. http://dx.doi.org/10.1139/y93-122.

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The endothelin receptors in rabbit isolated rings of saphenous artery and saphenous vein have been characterized using endothelin-1, endothelin-2, endothelin-3, sarafotoxin S6c, and BQ123. Although artery rings were more sensitive than those from vein to the contractile action of phenylephrine, endothelin-1 was about three times more potent as a contractile agonist on vein than on artery. In rings precontracted with phenylephrine, carbachol was 10 times more potent in vein than in artery rings to induce endothelium-dependent relaxation. However, in rings precontracted to a similar tone by endothelin-1, the relaxation elicited by carbachol was reduced in the vein but remained unchanged in the artery. In endothelium-denuded saphenous artery, endothelin-1 and endothelin-2 elicited contraction with equal potency, whereas endothelin-3 and sarafotoxin S6c were weak agonists. In saphenous vein, the rank order of sensitivity was sarafotoxin S6c > endothelin-2 > endothelin-1 = endothelin-3, whereas sarafotoxin S6c and, to a lesser extent, endothelin-3 act as partial agonists. The ETA receptor antagonist BQ123 shifted, to the right, the concentration–response curves of endothelin-1 on endothelium-denuded saphenous artery (pA2 = 7.25). In the endothelium-denuded saphenous vein, 10 μM BQ123 shifted to the right only the response to high concentrations of endothelin-1. In vein but not in artery, endothelin-1 and sarafotoxin S6c induced an endothelium-dependent relaxation, which was increased, in the case of endothelin-1, in the presence of BQ123. These results indicate that the rabbit saphenous vein contains a mixed population of ETA and ETB vasoconstrictor receptors located in the smooth muscle cells and vasorelaxant ETB receptors situated on endothelial cells. In contrast, the saphenous artery only possesses smooth muscle cell ETA receptors responsible for constriction.Key words: endothelium, endothelin, vein, artery, BQ123.

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Lüscher, Thomas F., and Matthias Barton. "Endothelins and Endothelin Receptor Antagonists." Circulation 102, no. 19 (November 7, 2000): 2434–40. http://dx.doi.org/10.1161/01.cir.102.19.2434.

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Nandagopal, Anitha, and Mubeen Unnisa Shamsia. "A REVIEW ON ENDOTHELINS: AN UPDATE." Asian Journal of Pharmaceutical and Clinical Research 11, no. 4 (April 1, 2018): 38. http://dx.doi.org/10.22159/ajpcr.2018.v11i4.23255.

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Endothelin (ET) is the most potent vasoconstrictor. It is secreted by the endothelial cells. At low concentration, it acts as an agonist for endothelium-derived relaxing factors and thereby causes vasodilatation, and at higher concentration it acts as a potent vasoconstrictor. It is synthesized by proteolytic cleavage of preproendothelin to proendothelin by the action of metallopeptidases and chymase, which is further cleaved into mature form of ET by endothelin converting enzyme. There are four isoforms of ET, namely, ET-1, ET-2, ET-3, and ET-4. ET acts on 2 types of receptors. Binding of ET-1 to ETA receptor at the vascular smooth muscle cells induces vasoconstriction. It also produces vasoconstriction by acting on the ETB2 receptor of vascular smooth muscle cells but promotes vasodilatation at ETB1 receptor present on the endothelial cell.

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Barber, D. A., S. R. Michener, S. C. Ziesmer, and V. M. Miller. "Chronic increases in blood flow upregulate endothelin-B receptors in arterial smooth muscle." American Journal of Physiology-Heart and Circulatory Physiology 270, no. 1 (January 1, 1996): H65—H71. http://dx.doi.org/10.1152/ajpheart.1996.270.1.h65.

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Experiments were designed to characterize endothelin receptors in arteries after chronic increases in blood flow. A fistula was created between the femoral artery and vein in one hindlimb of dogs; contralateral blood vessels were sham operated. Sham- and fistula-operated arteries were removed 6 wk postoperatively. Some arteries were prepared for measurement of isometric force or for isolation of membrane proteins. Other arteries were used for histological staining with an endothelin-B (ETB) receptor antibody. In arteries suspended for the measurement of isometric force, endothelin-1 produced concentration-dependent increases in tension that were significantly greater in fistula- than in sham-operated arteries without endothelium. The ETB-receptor-selective peptide sarafotoxin S6c produced concentration-dependent increases in tension only in fistula-operated arteries. In receptor-binding studies of membrane proteins, Scatchard analysis of saturation binding with 125I-labeled endothelin-1 (125I-endothelin-1) indicated that the total number of receptors was greater in fistula-operated arteries; affinity was threefold less in fistula- than in sham-operated arteries. Competitive displacement of 125I-endothelin-1 by endothelin-3 was significant for a two-site model in membranes prepared from sham-and fistula-operated arteries. Competitive inhibition of 125I-endothelin-1 binding by sarafotoxin S6c was significant for a one-site binding model in all arteries. Sarafotoxin S6c binding sites were elevated significantly in fistula-operated arteries. Immunohistochemical staining for the ETB receptor was significantly greater in both the endothelium and smooth muscle of fistula- than in sham-operated arteries. These results suggest that chronic increases in blood flow upregulate endothelin receptors, including ETB receptors in arterial smooth muscle.

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Hagiwara, H., T. Nagasawa, T. Yamamoto, K. M. Lodhi, T. Ito, N. Takemura, and S. Hirose. "Immunochemical characterization and localization of endothelin ETB receptor." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 264, no. 4 (April 1, 1993): R777—R783. http://dx.doi.org/10.1152/ajpregu.1993.264.4.r777.

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A highly specific antiserum was raised against purified bovine endothelin ETB receptor and used to determine the tissue distribution of the receptor subtype ETB and to localize the receptor immunohistochemically in the kidney, adrenal gland, lung, cerebellum, and pituitary gland whose functions are known to be under strong influence of endothelin. The antiserum raised in a rabbit specifically recognized the receptor band on Western blot analysis of membrane proteins. Furthermore, it immunoprecipitated only ETB, establishing its ETB specificity. By determination of the percentage of the total number of the endothelin receptors that is immunoprecipitable with the antiserum, the amounts of the ETB relative to those of the ET receptors were found to vary from tissue to tissue: lung (70%), cerebellum (55%), pituitary gland (50%), kidney (25%), adrenal gland (10%), and testis (< 2%). This means that, in the lung, ET is the major form, whereas in the testis, ETA is predominant, comprising >95% of the receptors. Immunohistochemical examination of tissue sections revealed endothelium localization of the ETB endothelin receptor.

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8

Moreland, Suzanne. "Endothelin receptor antagonists: a brief review." Canadian Journal of Physiology and Pharmacology 72, no. 11 (November 1, 1994): 1469–71. http://dx.doi.org/10.1139/y94-212.

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The endothelins are a family of potent vasoconstrictors, some of which also have vasodilatory activity. In many diseases associated with tissue hypoxia or ischemia and in diseases in which vasoconstriction plays a role, the circulating levels of endothelin are higher than in healthy, control subjects. These findings stimulated research aimed at discovering endothelin receptor antagonists. This review focuses on the binding potency and vascular activity of these new peptide and nonpeptide endothelin receptor antagonists.Key words: endothelin, endothelin receptor subtypes, vascular smooth muscle, endothelin receptor antagonist.

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Sakaguchi, H., M. Kozuka, S. Hirose, T. Ito, and H. Hagiwara. "Properties and localization of endothelin-1-specific receptors in rat testicles." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 263, no. 1 (July 1, 1992): R15—R18. http://dx.doi.org/10.1152/ajpregu.1992.263.1.r15.

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The characterization and localization of rat testicular endothelin receptors were studied. Receptor binding assay with radiolabeled members of the endothelin family revealed that endothelin-1-specific receptors were present in rat testes; a maximal binding capacity of 250 +/- 62 fmol/mg protein and a dissociation constant value of 0.35 +/- 0.06 nM were calculated from the Scatchard plot. The affinities for endothelin analogues were endothelin-1 = endothelin-2 much greater than endothelin-3 much greater big endothelin-1 for the membrane-bound receptors. Receptors of endothelin-1 were localized in peritubular myoid cells and interstitial cells of rat testis by 125I-labeled endothelin-1 autoradiography; the receptors were undetectable in spermatogenic cells. The presence of endothelin-1 receptors in the rat testis raises the possibility that one or more of the endothelins may play a physiological role in the regulation of testicular function.

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Lankhorst, Stephanie, A. H. Jan Danser, and Anton H. van den Meiracker. "Endothelin-1 and antiangiogenesis." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 310, no. 3 (February 1, 2016): R230—R234. http://dx.doi.org/10.1152/ajpregu.00373.2015.

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Antiangiogenesis, targeting vascular endothelial growth factor (VEGF), has become a well-established treatment for patients with cancer. This treatment is associated with nitric oxide (NO) suppression and a dose-dependent activation of the endothelin system, resulting in preeclampsia-like features, particularly hypertension and renal injury. Studies in endothelium NO synthase (eNOS)-deficient mice and pharmacological treatment with endothelin receptor blockers and sildenafil indicate that an activated endothelin system, rather than NO suppression, mediates the side effects of angiogenesis inhibitors. Activation of the endothelin system is also observed in preeclamptic women, where it is related to the increased placental production of sFlt-1, the soluble form of the VEGF receptor-1. This receptor binds VEGF, thereby having the same consequences as antiangiogenic treatment with VEGF inhibitors. The side effects of antiangiogenic treatment in patients with cancer may be dose limiting, thereby impairing its therapeutic potential. In addition, because endothelin exerts proangiogenic effects, investigation of the effects of endothelin receptor blockade in patients with cancer treated with angiogenesis inhibitors is warranted.

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Lin, J., and C. Wei. "Enhancement of Endothelin Converting Enzyme and Endothelin Receptor Subtypes in Human Myocardium with Congestive Heart Failure." Microscopy and Microanalysis 6, S2 (August 2000): 608–9. http://dx.doi.org/10.1017/s1431927600035534.

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Endothelin-1 (ET-1) is a potent endothelial cell-drived vasoconstrictive peptide which is increased in congestive heart failure (CHF). ET-1 is converted from its precursor big ET-1 by activation of endothelin converting enzyme (ECE). ET-1 binding to ET-A receptor in vascular smooth muscle cells stimulates vasoconstriction and binding to ET-B receptor in vascular endothelial cells mediates vasodilation. In previous studies, we and others demonstrated that plasma ET-1 was significantly increased in congestive heart failure. However, the presentation and localization of endothelin converting enzyme and endothelin receptors (ET-A and ET-B) in human cardiac tissue with and without heart failure remain unclear. Therefore, the current study was designed to investigate the expression and localization of endothelin receptors and endothelin converting enzyme in human myocardium in the absence or presence of congestive heart failure.Human atrial tissues (n=6) were obtained from normal subjects and end-stage CHF patients during cardiac transplantation. The expression of ECE, ET-A and ET-B were determined by immunohistochemical staining (IHCS).

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Lee, Claudia, Gayathri Viswanathan, Issac Choi, Chanpreet Jassal, Taylor Kohlmann, and Sudarshan Rajagopal. "Beta-Arrestins and Receptor Signaling in the Vascular Endothelium." Biomolecules 11, no. 1 (December 23, 2020): 9. http://dx.doi.org/10.3390/biom11010009.

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The vascular endothelium is the innermost layer of blood vessels and is a key regulator of vascular tone. Endothelial function is controlled by receptor signaling through G protein-coupled receptors, receptor tyrosine kinases and receptor serine-threonine kinases. The β-arrestins, multifunctional adapter proteins, have the potential to regulate all of these receptor families, although it is unclear as to whether they serve to integrate signaling across all of these different axes. Notably, the β-arrestins have been shown to regulate signaling by a number of receptors important in endothelial function, such as chemokine receptors and receptors for vasoactive substances such as angiotensin II, endothelin-1 and prostaglandins. β-arrestin-mediated signaling pathways have been shown to play central roles in pathways that control vasodilation, cell proliferation, migration, and immune function. At this time, the physiological impact of this signaling has not been studied in detail, but a deeper understanding of it could lead to the development of novel therapies for the treatment of vascular disease.

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Opdecamp, Karin, Lidia Kos, Heinz Arnheiter, and William J. Pavan. "Endothelin signalling in the development of neural crest-derived melanocytes." Biochemistry and Cell Biology 76, no. 6 (December 1, 1998): 1093–99. http://dx.doi.org/10.1139/o99-006.

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In both mice and humans, mutations in the genes encoding the endothelin B receptor and its ligand endothelin 3 lead to deficiencies in neural crest-derived melanocytes and enteric neurons. The discrete steps at which endothelins exert their functions in melanocyte development were examined in mouse neural crest cell cultures. Such cultures, kept in the presence of fetal calf serum, gave rise to cells expressing the early melanoblast marker Dct even in the absence of the phorbol ester tetradecanoyl phorbol acetate (TPA) or endothelins. However, these early (Dct+) cells did not proliferate and pigmented cells never formed unless TPA or endothelins were added. In fact, endothelin 2 was as potent as TPA in promoting the generation of both Dct+ melanoblasts and pigmented cells, and endothelin 1 or endothelin 3 stimulated the generation of melanoblasts and of pigmented cells to an even greater extent. The inhibition of this stimulation by the selective endothelin B receptor antagonist BQ-788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-alpha-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine) suggested that the three endothelins all signal through the endothelin B receptor. This receptor was indeed expressed in Dct+ melanoblasts, in addition to cells lacking Dct expression. The results demonstrate that endothelins are potent stimulators of melanoblast proliferation and differentiation.Key words: neural crest, melanocyte, endothelin, differentiation.

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Taner, C. Burcin, Sandra R. Severson, Patricia J. M. Best, Amir Lerman, and Virginia M. Miller. "Treatment with endothelin-receptor antagonists increases NOS activity in hypercholesterolemia." Journal of Applied Physiology 90, no. 3 (March 1, 2001): 816–20. http://dx.doi.org/10.1152/jappl.2001.90.3.816.

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In experimental hypercholesterolemia, endothelium-dependent relaxations decrease, as does endothelial immunoreactivity for nitric oxide (NO) synthase (NOS; eNOS) in coronary arteries. Systemic levels of NO also decrease with concomitant elevations in systemic circulating levels of endothelin (ET)-1. Chronic treatment of hypercholesterolemic pigs with ET-receptor antagonists increases circulating NO and improves endothelium-dependent relaxations. Mechanisms causing these increases are not known. Therefore, experiments were designed to test the hypothesis that chronic administration of ET-receptor antagonists to hypercholesterolemic pigs increases NO production through increases in NOS activity. Female juvenile pigs were fed a 2% cholesterol atherogenic diet and were randomly allocated to receive no treatment (controls), a selective ETA-receptor antagonist (ABT-624), or a combined ETA + ETB-receptor antagonist (RO-48-5695) daily for 12 wk. After 12 wk, endothelial cells from thoracic aorta were prepared for measurement of eNOS mRNA or eNOS activity. Total cholesterol, low-density-lipoprotein cholesterol, and concentrations of ET-1 were significantly higher in all three groups at 12 wk compared with baseline levels. Circulating plasma-oxidized products of NO (NOx) increased with ET-receptor blockade. NOS mRNA was similar among groups. Total and Ca-dependent NOS activity was significantly higher in aortic endothelial cells from the ETA + ETB-treated pigs compared with those treated with ETA antagonist alone. These results suggest that changes in systemic NOx after chronic inhibition of ETA + ETB receptors in hypercholesterolemia may result from posttranscriptional changes in NOS.

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Dièye, Amadou Moctar, and Alexis Gairard. "Endothelium and aortic contraction to endothelin-1 in the pregnant rat." Canadian Journal of Physiology and Pharmacology 78, no. 5 (April 10, 2000): 372–77. http://dx.doi.org/10.1139/y99-150.

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Endothelium-derived factors modulate tone and may be involved in hyporeactivity to vasoconstrictors, such as norepinephrine or angiotensin II, as has been previously described during gestation. The endothelium produces endothelin-1, a major vasoconstrictor peptide, therefore aortic contractions to endothelin-1 (10-10 to 3 ×10-7 M) were used to assess the role of the endothelium in pregnant Wistar rats (at 20 days of gestation). Late pregnancy is characterized by a significantly diminished systolic blood pressure in conscious rats (-17 mmHg, P < 0.001, n = 14). In pregnant and in age-matched nonpregnant female rats, endothelin-1 induced aortic contraction was greater when endothelium was present (at least P < 0.01). Indomethacin significantly reduced this contraction in aortic rings with intact endothelium in all groups. In aortic rings that had endothelium physically removed, contraction to endothelin-1 was greater in pregnant rats than in nonpregnant ones. Indomethacin decreased contraction of aortic rings in pregnant rats only. These results suggest an enhanced synthesis of vasoconstrictors by cyclooxygenases in vascular smooth muscle during pregnancy. In vessels with intact endothelium, we did not find hyporeactivity to endothelin-1 during late pregnancy. Contraction to endothelin-1 involved ETA receptors because it was decreased by BQ-123, an ETA receptor antagonist, whereas there was no significant change when using BQ-788, an ETB receptor antagonist. Key words: endothelin-1, endothelium, contraction, aorta, gestation.

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Liang, Faquan, Christopher B. Glascock, Denise L. Schafer, Jennifer Sandoval, LouAnn Cable, Lawrence Melvin, J. Craig Hartman, and Kelly R. Pitts. "Darusentan is a potent inhibitor of endothelin signaling and function in both large and small arteriesThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research." Canadian Journal of Physiology and Pharmacology 88, no. 8 (August 2010): 840–49. http://dx.doi.org/10.1139/y10-061.

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Endothelin is a potent vasoconstrictor often up-regulated in hypertension. Endothelin vasoconstriction is mediated via the G-protein coupled endothelin A (ETA) receptor present on vascular smooth muscle. Endothelin receptor antagonists (ERAs) have been shown to antagonize ET-induced vasoconstriction. We describe the primary pharmacology of darusentan, a propanoic acid based ERA currently in phase 3 clinical trials for resistant hypertension. Darusentan was tested in membrane-, cell-, and tissue-based assays to determine its biochemical and functional potency. Rat aortic vascular smooth muscle cells (RAVSMs) were characterized using flow cytometry. RAVSM membrane fractions tested in saturation experiments exhibited moderate endothelin receptor density. Receptor counting revealed that >95% of the endothelin receptors in these fractions were the ETA subtype. (S)-Darusentan competed for radiolabeled endothelin binding in RAVSM membranes with single-site kinetics, exhibiting a Ki = 13 nmol/L. (R)-Darusentan exhibited no binding activity. In cultured RAVSMs, endothelin induced increases in inositol phosphate and Ca2+ signaling, both of which were attenuated by (S)-darusentan in a concentration-dependent manner. In isolated endothelium-denuded rat aortic rings, (S)-darusentan inhibited endothelin-induced vascular contractility with a pA2 = 8.1 ± 0.14 (n = 4 animals; mean ± SD). (R)-Darusentan had no effect. The vasorelaxant potency of (S)-darusentan did not change when determined in isolated denuded rat mesenteric arterioles, suggesting a similar mode of action in both conductance and resistance arteries. In vascular smooth muscle, (S)-darusentan is an ERA with high affinity for the ET receptor, which in this preparation is predominantly ETA receptors. (S)-Darusentan inhibits endothelin-induced signaling related to pro-contractile activity and is a potent inhibitor of vasoconstriction in large and small arteries.

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Liu, James J., Joan R. Chen, and Brian F. Buxton. "Unique Response of Human Arteries to Endothelin B Receptor Agonist and Antagonist." Clinical Science 90, no. 2 (February 1, 1996): 91–96. http://dx.doi.org/10.1042/cs0900091.

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1. The role of the ETB receptor in human arteries has not been well studied because of the lack of specific ETB receptor antagonists. In the present studies the specific ETB receptor antagonist BQ-788 and the specific ETB agonist IRL-1620 were used to characterize the function of the ETB receptor in human radial arteries and internal mammary arteries. 2. The results showed that the ETB antagonist BQ-788 significantly inhibited endothelin-1-induced contraction in internal mammary arteries, but not in radial arteries. In internal mammary arteries, BQ-788 at a concentration of 10 μmol/l shifted the endothelin-1-induced concentration-dependent curve to the right by one order. By comparison, the ETA receptor antagonist BQ-610 at 1 μmol/l produced a much more potent inhibitory effect (three-order shifting) on endothelin-1-induced contraction in internal mammary arteries, and also potently inhibited the contraction in radial arteries. 3. The ETB agonist IRL-1620 caused a contraction in internal mammary arteries, but not in radial arteries, although the response of radial arteries to endothelin-1 was very strong. The contraction induced by IRL-1620 was weaker than that induced by endothelin-1; however, the maximal contraction to IRL-1620 was obtained at 3 nmol/l, which was lower than that with endothelin-1 (maximal contraction at 10 nmol/l). 4. In internal mammary arteries the contraction to endothelin-1 and IRL-1620 gradually changed to relaxation with high concentrations of endothelin-1 (from 30 nmol/l) and IRL-1620 (from 3 nmol/l), whereas it did not in radial arteries; suggesting that the ETB receptor on human arterial smooth muscle cells may mediate contraction at low agonist concentrations and relaxation at high agonist concentrations. 5. The ETB agonist IRL-1620, endothelin-1 and endothelin-3 did not cause endothelium-dependent relaxation in either precontracted radial arteries or internal mammary arteries, although endothelium-dependent relaxation was fully induced by acetylcholine in these two arterial preparations. 6. In conclusion, the present studies demonstrate that the responses of internal mammary arteries and radial arteries to an ETB antagonist and an ETB agonist are significantly different from those of animal vascular vessels, and also from each other. The ETB receptor may play only a minor role in endothelium-dependent relaxation of these human arteries. Endothelin-1-induced contraction is mediated by both the ETA (major) and the ETB (minor) receptors in internal mammary arteries, but only by the ETA receptor in radial arteries. These studies may help to determine therapeutic strategy.

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Zhang, Junlan, Yiqun Ling, Liping Tang, Bao Luo, David M. Pollock, and Michael B. Fallon. "Attenuation of experimental hepatopulmonary syndrome in endothelin B receptor-deficient rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 296, no. 4 (April 2009): G704—G708. http://dx.doi.org/10.1152/ajpgi.90627.2008.

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Experimental hepatopulmonary syndrome (HPS) after common bile duct ligation (CBDL) in rat is accompanied by increased lung vascular endothelial endothelin B (ETB) receptor expression and increased circulating levels of endothelin-1 (ET-1). The onset of HPS is hypothesized to be triggered by ET-1/ETB receptor activation of endothelial nitric oxide synthase (eNOS)-derived NO production in the pulmonary endothelium. However, whether functional pulmonary vascular ETB receptors are required for the development of experimental HPS is not defined. We evaluated the effects of vascular ETB receptor deficiency on the development of experimental HPS. The molecular and physiological alterations of HPS were compared in 2-wk CBDL wild-type and ETB receptor-deficient (transgenic sl/sl) rats. Relative to wild-type rats, basal hepatic and plasma ET-1 levels were elevated in sl/sl controls although, unlike wild-type animals circulating ET-1 levels, did not increase further after CBDL in sl/sl animals. In contrast to wild-type animals, ETB receptor-deficient rats did not develop increased Akt and eNOS expression and activation and did not develop gas exchange abnormalities of HPS after CBDL. There was a similar degree of pulmonary intravascular monocyte accumulation in both 2-wk CBDL sl/sl and wild-type animals. In conclusion, ETB receptor deficiency inhibits lung Akt/eNOS activation and prevents the onset of experimental HPS after CBDL. This effect is independent of inhibition of pulmonary intravascular monocyte accumulation. These results demonstrate that ET-1/ETB receptor signaling plays a key role in the initiation of experimental HPS.

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Moreau, Pierre, and Ernesto L. Schiffrin. "Role of endothelins in animal models of hypertension: focus on cardiovascular protection." Canadian Journal of Physiology and Pharmacology 81, no. 6 (June 1, 2003): 511–21. http://dx.doi.org/10.1139/y03-015.

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Investigation of the regulation of vascular function by endothelium-derived factors has been a prominent topic of research in the field of hypertension during the last decade. Of the different endothelial factors, endothelins, which play an important role in vasodilatationvasoconstriction balance, have been the subject of great interest and an impressive number of publications. This peptide, a very potent vasoconstrictor, triggers as well events involved in growth, proliferation, matrix production and local inflammation. In parallel, its role in hypertension has evolved from a simple vasoconstrictor to a central local regulator of vascular homeostasis contributing not only to the elevation of blood pressure, but also to the complications of hypertension. This review summarizes research on endothelins and its receptor antagonists in experimental hypertension, with special emphasis on vascular remodeling and target-organ protection.Key words: endothelin, endothelin antagonists, hypertension, vascular remodeling, hypertrophy, target-organ damage.

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Kinjo, M., J. Papadimitriou, C. Drachenberg, M. R. Weir, and C. Wei. "Expression and Localization of Renal Endothelin-1, Endotehlin Receptors and Endothelin Converting Enzyme in Human Renal Biopsy with Rejection after Kidney Transplantation." Microscopy and Microanalysis 6, S2 (August 2000): 610–11. http://dx.doi.org/10.1017/s1431927600035546.

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Endothelin (ET-1) is a potent renal and systemic vasoconstrictor and sodium regulating peptide. Endothelin synthesis in the kidney have been reported in glomerulus endothelial, epithelial and mesangial cells as well as in inner medullary collecting duct. Factors stimulating the production of endothelin include shear stress, hypoxia, vasoactive agents and cytokines. Endothelin binding to ET-A receptor in vascular smooth muscle cells stimulates vasoconstriction.Renal graft rejection is a major problem after kidney transplantation with severe renal damage and renal vasoconstriction. We hypothesized that renal tissue level of endothelin-1, endothelin receptors and endothelin converting enzyme (ECE) may increase in renal tissue with rejection after kidney transplantation. Therefore, the current study was designed to determine the endothelin-1 and endothelin receptors (ET-A and ET-B) as well as endothelin converting enzyme level by immunohistochemical staining (IHCS) in human renal tissue with rejection after kidney transplantation.

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Leuchte, Hanno H., Tobias Meis, Michal El-Nounou, Jens Michalek, and Jürgen Behr. "Inhalation of endothelin receptor blockers in pulmonary hypertension." American Journal of Physiology-Lung Cellular and Molecular Physiology 294, no. 4 (April 2008): L772—L777. http://dx.doi.org/10.1152/ajplung.00405.2007.

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Endothelin 1 (ET-1) is a potent pulmonary vasoconstrictor and mediator of lung diseases. Antagonism of the ET-1-mediated effects has become an important therapeutic approach. ET-1 (A and B) receptors are differentially distributed in the lung vasculature. Whereas the ETA receptors mainly mediate vasoconstriction, the endothelial ETB receptor seems to have vasodilative properties. We sought to determine if antagonism of ET receptors can be achieved by inhalation of specific blockers in a model of ET-1-mediated pulmonary hypertension.

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Karoli, N. A., S. I. Sazhnova, and A. P. Rebrov. "Pulmonary hypertension: reasonable selection of specific therapy." Systemic Hypertension 15, no. 1 (March 15, 2018): 45–50. http://dx.doi.org/10.26442/2075-082x_15.1.45-50.

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Pulmonary hypertension is characterized with persistent increase in pulmonary vascular resistance leading to progressive worsening of right ventricular failure and death. The basis for pulmonary arterial hypertension is structural changes in pulmonary arteries and arterioles caused by endothelial dysfunction. Endothelin-1 is the main pathogenic trigger of pulmonary hypertension and potential target for therapeutic exposure. The efficacy of endothelin receptor antagonists is proved in various preclinical and clinical studies. In patients with pulmonary arterial hypertension, the efficacy of dual and selective endothelin receptor antagonists is comparable despite the varied activity against various receptors. Bosentan is the most widely used pulmonary vasodilator which improves exercise tolerance and decelerates disease progression.

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Katakam, Prasad Venkateswera Gurunath, Ferenc Domoki, Laura Lenti, Tamás Gáspár, Adam Institoris, James Andy Snipes, and David William Busija. "Cerebrovascular Responses to Insulin in Rats." Journal of Cerebral Blood Flow & Metabolism 29, no. 12 (September 2, 2009): 1955–67. http://dx.doi.org/10.1038/jcbfm.2009.177.

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Effects of insulin on cerebral arteries have never been examined. Therefore, we determined cerebrovascular actions of insulin in rats. Both PCR and immunoblot studies identified insulin receptor expression in cerebral arteries and in cultured cerebral microvascular endothelial cells (CMVECs). Diameter measurements (% change) of isolated rat cerebral arteries showed a biphasic dose response to insulin with an initial vasoconstriction at 0.1 ng/mL (−9.7%±1.6%), followed by vasodilation at 1 to 100 ng/mL (31.9%±1.4%). Insulin also increased cortical blood flow in vivo (30%±8% at 120 ng/mL) when applied topically. Removal of reactive oxygen species (ROS) abolished the vasoconstriction to insulin. Endothelial denudation, inhibition of K+ channels, and nitric oxide (NO) synthase, all diminished insulin-induced vasodilation. Inhibition of cytochrome P450 enhanced vasodilation in endothelium-intact arteries, but promoted vasoconstriction after endothelial denudation. Inhibition of cyclooxygenase abolished vasoconstriction and enhanced vasodilation to insulin in all arteries. Inhibition of endothelin type A receptors enhanced vasodilation, whereas endothelin type B receptor blockade diminished vasodilation. Insulin treatment in vitro increased Akt phosphorylation in cerebral arteries and CMVECs. Fluorescence studies of CMVECs showed that insulin increased intracellular calcium and enhanced the generation of NO and ROS. Thus, cerebrovascular responses to insulin were mediated by complex mechanisms originating in both the endothelium and smooth muscle.

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Tosun, M., Y. Erac, C. Selli, and N. Karakaya. "Sarcoplasmic-endoplasmic reticulum Ca2+-ATPase inhibition prevents endothelin A receptor antagonism in rat aorta." American Journal of Physiology-Heart and Circulatory Physiology 292, no. 4 (April 2007): H1961—H1966. http://dx.doi.org/10.1152/ajpheart.00298.2006.

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This study tested whether sarcoplasmic-endoplasmic reticulum Ca2+-ATPase regulates the ability of endothelin receptor antagonist to inhibit the endothelin-1 constriction. The endothelin A receptor antagonist BQ-123 (1 μM) completely relaxed constriction to 10 nM endothelin-1 in endothelium-denuded rat aorta. Challenge with cyclopiazonic acid (10 μM), a sarcoplasmic-endoplasmic reticulum Ca2+-ATPase inhibitor, during the plateau of endothelin-1 constriction enhanced the constriction by ∼30%. BQ-123 relaxed the endothelin-1 plus cyclopiazonic acid constriction by only ∼10%. In contrast, prazosin (1 μM), an α-adrenergic receptor antagonist, still completely relaxed the 0.3 μM phenylephrine constriction in the presence of cyclopiazonic acid. Verapamil relaxed the endothelin-1 plus cyclopiazonic acid constriction by ∼30%, whereas Ni2+ and 2-aminoethoxydiphenyl borate, nonselective cation channel and store-operated channel blockers, respectively, completely relaxed the constriction. These results suggest that lowered sarcoplasmic-endoplasmic reticulum Ca2+-ATPase activity selectively decreases the ability of endothelin receptor antagonist to inhibit the endothelin A receptor. The decreased antagonism may be related to the opening of store-operated channels and subsequent greater internalization of endothelin A receptor.

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MIYAZAKI, Hitoshi, Motohiro KONDOH, Hirotoshi WATANABE, Yasushi MASUDA, Kazuo MURAKAMI, Masami TAKAHASHI, Masashi YANAGISAWA, Sadao KIMURA, Katsutoshi GOTO, and Tomoh MASAKI. "Affinity labelling of endothelin receptor and characterization of solubilized endothelin-endothelin-receptor complex." European Journal of Biochemistry 187, no. 1 (January 1990): 125–29. http://dx.doi.org/10.1111/j.1432-1033.1990.tb15285.x.

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Woodcock, E. A., S. L. Land, R. K. Andrews, M. Linsenmeyer, and D. M. Woodcock. "A low-affinity, low-molecular-mass endothelin-A receptor in neonatal rat heart." Biochemical Journal 304, no. 1 (November 15, 1994): 113–19. http://dx.doi.org/10.1042/bj3040113.

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Endothelin receptors with endothelin-A (ETa) specificity were present in neonatal rat ventricle. However, in both receptor-binding studies and studies of inositol phosphate accumulation, these receptors had lower affinity for endothelin-1 than ETa receptors on isolated neonatal cardiomyocytes or adult left atria. Receptors in the three myocardial preparations were cross-linked to 125I-endothelin-1 and their molecular masses measured using SDS/PAGE. Receptors on left atria and neonatal cardiomyocytes had the expected molecular mass of 48 kDa, whereas the receptors in neonatal ventricle were smaller (38 kDa). Despite this, neonatal ventricles contained ETa receptor mRNA which was not different in size from that in the isolated cells (4.5 kb). Thus the 38 kDa ETa receptor present in neonatal ventricle appears to be transcribed from full-length ETa receptor mRNA and is possibly formed by processing of the 48 kDa receptor.

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Clozel, M., B. M. Loffler, V. Breu, L. Hilfiger, J. P. Maire, and B. Butscha. "Downregulation of endothelin receptors by autocrine production of endothelin-1." American Journal of Physiology-Cell Physiology 265, no. 1 (July 1, 1993): C188—C192. http://dx.doi.org/10.1152/ajpcell.1993.265.1.c188.

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The potent vasoconstrictor endothelin-1 (ET-1) is a paracrine, but also autocrine, factor for some types of cells. The goal of our study was to evaluate whether the receptor population in cells expressing endothelin receptor subtype A (rat mesangial cells) or endothelin receptor subtype B (human and rat endothelial cells) was affected by the autocrine production of ET-1. We therefore studied maximal binding capacity of 125I-labeled ET-1 in the presence or absence of the metalloprotease inhibitors phosphoramidon, which blocks the intracellular processing of Big ET-1 to ET-1, and thiorphan, which does not block this conversion. Phosphoramidon inhibited the release of ET-1 by human umbilical vein endothelial cells, rat aortic endothelial cells, and rat mesangial cells, and increased 1.4- to 17-fold the maximal binding capacity in the three types of cells. Thiorphan affected neither ET-1 release nor binding. The increase in receptor binding by phosphoramidon was associated with an increase in the functional effect of ET-1, as measured by arachidonic acid release in rat mesangial cells. We conclude that autocrine production of ET-1 decreases, either by binding or by downregulation, the number of binding sites available for ET-1 of paracrine or systemic sources. This aspect of modulation of the vasoconstrictor effect of endothelin should be considered in pathological situations or after endothelin-converting-enzyme inhibition.

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Koedel, Uwe, Stefan Lorenzl, Corinna Gorriz, Rainer M. Arendt, and Hans-Walter Pfister. "Endothelin B Receptor–Mediated Increase of Cerebral Blood Flow in Experimental Pneumococcal Meningitis." Journal of Cerebral Blood Flow & Metabolism 18, no. 1 (January 1998): 67–74. http://dx.doi.org/10.1097/00004647-199801000-00007.

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Study investigates the role of endothelin (ET) receptors in mediating early changes in cerebral blood flow—as measured by laser Doppler flowmetry (CBFLDF)—during experimental pneumococcal meningitis. Meningitis was induced with heat-killed pneumococci and confirmed by a significant increase in CBFLDF (baseline 100%; 225.3 ± 21.8% after 6 hours; mean ± SD), intracranial pressure (ICP), brain water content, and white blood cell count in the CSF. Intravenous administration of the selective endothelin B (ETB) receptor antagonist BQ-788 immediately before pneumococcal challenge (but not 4 hours afterward) significantly attenuated these pathophysiologic alterations (e.g., CBFLDF 6 hours after pneumococcal challenge: 116.7 ± 17.4%). Pretreatment with BQ-123, a selective endothelin A receptor antagonist, had no significant effect on ICP and brain water content, but augmented the increase in CBFLDF and CSF white blood cell count. Since ET is known to trigger the release of nitric oxide (NO) by ETB receptor activation, we examined specific ET–NO interactions in primary rat cerebromicrovascular endothelial cells after stimulation with heat-killed pneumococci. Pneumococci induced a significant increase in both ET and NO concentrations in endothelial cell culture medium. Treatment with phosphoramidon, an inhibitor of the endothelin-converting enzyme, prevented the production of endothelin and markedly reduced NO generation. Our data provide evidence that ET is involved as a mediator in early pneumococcal meningitis in the rat and contributes to the increase in CBFLDF, ICP, brain water content, and CSF pleocytosis, presumably through ETB receptor–mediated NO production.

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Khan, Zia Ali, and Subrata Chakrabarti. "Endothelins in chronic diabetic complications." Canadian Journal of Physiology and Pharmacology 81, no. 6 (June 1, 2003): 622–34. http://dx.doi.org/10.1139/y03-053.

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Endothelins are widely distributed in the body and perform several vascular and nonvascular functions. Experimental data indicate abnormalities of the endothelin system in several organs affected in chronic diabetic complications. In support of this notion, it has been shown that endothelin-receptor antagonists prevent structural and functional abnormalities in target organs of diabetic complications in animal models. Alterations of plasma endothelin levels have also been demonstrated in human diabetes. This review discusses the role of endothelins in the pathogenesis of chronic diabetic complications. The current experimental evidence suggests that endothelin-receptor antagonism may potentially be an adjuvant therapeutic tool in the treatment of chronic diabetic complications.Key words: endothelins, diabetic complications, retinopathy, nephropathy, neuropathy, cardiomyopathy.

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30

Xu, D.-Y., Q.-X. Zhang, Y.-Q. Ma, X.-L. Zheng, and S.-X. Liu. "Immunohistochemical localisation of endothelin receptor subtypes in the cochlear lateral wall." Journal of Laryngology & Otology 124, no. 10 (June 8, 2010): 1073–77. http://dx.doi.org/10.1017/s0022215110001428.

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AbstractObjective:Endothelin has many biological activities, including regulation of the functions of the cochlear lateral wall. The present study aimed to analyse the expression of endothelin receptors in the cochlear lateral wall, and to investigate the significance of such receptors in maintaining the homeostatic environment of the cochlea.Methods:The cochleae of healthy guinea pigs were fixed, decalcified, embedded in paraffin and serially sectioned. Expression of the endothelin receptor subunits A and B in the cochlear lateral wall was examined using an immunohistochemical technique.Results:Different degrees of endothelin receptor subunit A and endothelin receptor subunit B like activity were found distributed in the cells of the cochlear lateral wall.Conclusion:These findings support the theory that endothelin, via its receptors, plays an important role in maintaining the homeostatic environment of the cochlea.

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Sakai, Hiroshi, Fumitaka Ikomi, and Toshio Ohhashi. "Effects of endothelin on spontaneous contractions in lymph vessels." American Journal of Physiology-Heart and Circulatory Physiology 277, no. 2 (August 1, 1999): H459—H466. http://dx.doi.org/10.1152/ajpheart.1999.277.2.h459.

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A mode of action of endothelin (ET) on spontaneous contractions was investigated in ring preparations of isolated bovine mesenteric lymphatics. ET-1 at concentrations between 10−10 and 10−9 M caused a dose-dependent increase in the frequency of spontaneous contractions. The specific ETA-receptor antagonist BQ-123 (5 × 10−7 M) caused a significant inhibition of the ET-1-induced positive chronotropic effect in the ring preparations with and without the endothelium. Mechanical denudation of the lymphatic endothelial cells produced a significant potentiation of the ET-induced positive chronotropic effect. BQ-3020 (10−8–10−7M), a selective ETB-receptor agonist, induced dose dependently negative chronotropic and inotropic effects on the spontaneous contractions in the ring preparations with intact endothelium. Mechanical removal of the endothelium caused a significant reduction of the BQ-3020-induced negative chronotropic and inotropic effects. The ET-1-induced positive chronotropic effect was potentiated by pretreatment with N ω-nitro-l-arginine methyl ester (l-NAME) (10−5 M) but unaffected by aspirin (10−5 M). Additional treatment with l-arginine (10−4 M) completely reversed the l-NAME-mediated potentiation of the ET-induced chronotropic effect. These results suggest that stimulation of ETA receptors on the lymphatic smooth muscles causes a positive chronotropic effect on the spontaneous contractions, and stimulation of ETB receptors on the lymphatic endothelial cells induces a release of nitric oxide, which results in the chronotropic and inotropic effects on spontaneous contractions in isolated bovine mesenteric lymphatics.

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Goddard, Jane, and David J. Webb. "Endothelin Receptor Antagonists." Drugs in R & D 2, no. 1 (February 1999): 1–12. http://dx.doi.org/10.2165/00126839-199902010-00001.

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Kabunga, Peter, and Gerry Coghlan. "Endothelin Receptor Antagonism." Drugs 68, no. 12 (2008): 1635–45. http://dx.doi.org/10.2165/00003495-200868120-00003.

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34

Pirtskhalaishvili, Georgi, and Joel B. Nelson. "The Endothelin Receptor." American Journal of Cancer 1, no. 2 (2002): 81–91. http://dx.doi.org/10.2165/00024669-200201020-00001.

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35

Warner, Timothy D. "Endothelin Receptor Antagonists." Cardiovascular Drug Reviews 12, no. 2 (June 1994): 105–22. http://dx.doi.org/10.1111/j.1527-3466.1994.tb00286.x.

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36

Motte, Sophie, Kathleen McEntee, and Robert Naeije. "Endothelin receptor antagonists." Pharmacology & Therapeutics 110, no. 3 (June 2006): 386–414. http://dx.doi.org/10.1016/j.pharmthera.2005.08.012.

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Nelson, Joel B. "Endothelin receptor antagonists." World Journal of Urology 23, no. 1 (January 15, 2005): 19–27. http://dx.doi.org/10.1007/s00345-004-0478-9.

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38

Sica, Domenic A. "Endothelin Receptor Antagonism." Hypertension 52, no. 3 (September 2008): 460–61. http://dx.doi.org/10.1161/hypertensionaha.108.117226.

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39

Kirchengast, Michael, and Matthias Luz. "Endothelin Receptor Antagonists." Journal of Cardiovascular Pharmacology 45, no. 2 (February 2005): 182–91. http://dx.doi.org/10.1097/01.fjc.0000152030.61620.57.

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40

Spinella, Michael J., Rebecca Kottke, Harold I. Magazine, Matthew S. Healy, John A. Catena, Philip Wilken, and Thomas T. Andersen. "Endothelin-receptor interactions." FEBS Letters 328, no. 1-2 (August 9, 1993): 82–88. http://dx.doi.org/10.1016/0014-5793(93)80970-6.

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Vigne, P., R. Marsault, J. P. Breittmayer, and C. Frelin. "Endothelin stimulates phosphatidylinositol hydrolysis and DNA synthesis in brain capillary endothelial cells." Biochemical Journal 266, no. 2 (March 1, 1990): 415–20. http://dx.doi.org/10.1042/bj2660415.

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Endothelin-1 (ET-1) is a novel vasoconstricting and cardiotonic peptide that is synthesized by the vascular endothelium. Bovine aortic endothelial cells which secrete ET in vitro lack membrane receptor sites for the peptide. Endothelial cells from rat brain microvessels that do not secrete ET in vitro express large amounts of high-affinity receptors for 125I-labelled ET-1 (Kd 0.8 nM). The ET receptor is recognized by sarafotoxin S6b and the different ET peptides with the following order of potency: ET-1 (Kd 0.5 nM) approximately equal to ET-2 (Kd 0.7 nM) greater than sarafotoxin S6b (Kd 27 nM) greater than ET-3 (Kd 450 nM). This structure-activity relationship is different from those found in vascular smooth muscle cells, renal cells and cardiac cells. ET-1 stimulates DNA synthesis in brain capillary endothelial cells. It is more potent than basic fibroblast growth factor. The action of ET on endothelial cells from microvessels involves phosphatidylinositol hydrolysis and intracellular Ca2+ mobilization. These observations suggest that brain endothelial cells might be an important target for ET.

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Patočka, Jiří, Vladimír Měrka, Vratislav Hrdina, and Radomír Hrdina. "Pharmacological Potential of Endothelin Receptors Agonists and Antagonists." Acta Medica (Hradec Kralove, Czech Republic) 48, no. 2 (2005): 67–73. http://dx.doi.org/10.14712/18059694.2018.34.

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Endothelins are potent predominantly vasoconstricting agents that act as local autocrine and paracrine mediators. Endothelin-1 is the most potent and sustained vasoconstrictor and pressor substance yet identified. Abnormalities of the endothelin system occur in a range of diseases associated with vasoconstriction, vasospasm, and vascular hypertrophy. ET receptor antagonists were until recently regarded as drugs of great promise in patients with congestive heart failure, pulmonary hypertension and others. The aim of this article is a survey of compounds that affect the endothelin receptors and clinical trials with these agents.

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Westerweel, Peter E., and Marianne C. Verhaar. "Protective Actions of PPAR-γActivation in Renal Endothelium." PPAR Research 2008 (2008): 1–9. http://dx.doi.org/10.1155/2008/635680.

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Renal endothelial damage is pivotal in the initiation and progression of renal disease. Damaged renal endothelium may be regenerated through proliferation of local endothelium and circulation-derived endothelial progenitor cells. Activation of the PPAR-γ-receptors present on endothelial cells affects their cellular behavior. Proliferation, apoptosis, migration, and angiogenesis by endothelial cells are modulated, but may involve both stimulation and inhibition depending on the specific circumstances. PPAR-γ-receptor activation stimulates the production of nitric oxide, C-type natriuretic peptide, and superoxide dismutase, while endothelin-1 production is inhibited. Together, they augment endothelial function, resulting in blood pressure lowering and direct renoprotective effects. The presentation of adhesion molecules and release of cytokines recruiting inflammatory cells are inhibited by PPAR-γ-agonism. Finally, PPAR-γ-receptors are also found on endothelial progenitor cells and PPAR-γ-agonists stimulate progenitor-mediated endothelial repair. Together, the stimulatory effects of PPAR-γ-agonism on endothelium make an important contribution to the beneficial actions of PPAR-γ-agonists on renal disease.

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Jeoung, Myoungkun, Sungeun Lee, Hee-kyung Hawng, Yong-Pil Cheon, Youn Kyung Jeong, Myung Chan Gye, Marc Iglarz, CheMyong Ko, and Phillip J. Bridges. "Identification of a Novel Role for Endothelins within the Oviduct." Endocrinology 151, no. 6 (March 31, 2010): 2858–67. http://dx.doi.org/10.1210/en.2009-1155.

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Endothelins were first identified as potent vasoactive peptides; however, diversity in the biological function of these hormones is now evident. We have identified a novel role for endothelins: a requirement for these peptides within the oviduct during fertilization and/or early embryo development. In vivo, treatment after ovulation with a dual endothelin receptor antagonist (tezosentan) decreased the number of two-cell embryos that could be collected from within the oviducts. In vitro fertilization experiments showed that gamete viability and their ability to fertilize were not affected by treatment with this antagonist, suggesting that the effect observed in vivo was mediated by the oviduct itself. Expression of mRNA for all three isoforms of the endothelins and both receptor subtypes was detectable within the oviduct. Expression of mRNA for endothelin-3 was regulated by gonadotropins in epithelial cells of the oviduct and increased specifically within the isthmus of this structure. Immunostaining revealed localization of both endothelin receptors A and B to the columnar epithelial cells within the oviduct, suggestive of a local role for endothelins in the regulation of epithelial function and ultimately oviductal secretions. A microarray analysis revealed three likely endothelin-regulated protein networks for future analysis: the TGFβ, IL-10, and CCAAT/enhancer-binding protein superfamilies. Overall, these results suggest a novel and requisite role for endothelins within the oviduct during fertilization and/or early embryo development.

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Bochenek, Magdalena L., Christiane Leidinger, Nico S. Rosinus, Rajinikanth Gogiraju, Stefan Guth, Lukas Hobohm, Kerstin Jurk, et al. "Activated Endothelial TGFβ1 Signaling Promotes Venous Thrombus Nonresolution in Mice Via Endothelin-1." Circulation Research 126, no. 2 (January 17, 2020): 162–81. http://dx.doi.org/10.1161/circresaha.119.315259.

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Rationale: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by defective thrombus resolution, pulmonary artery obstruction, and vasculopathy. TGFβ (transforming growth factor-β) signaling mutations have been implicated in pulmonary arterial hypertension, whereas the role of TGFβ in the pathophysiology of CTEPH is unknown. Objective: To determine whether defective TGFβ signaling in endothelial cells contributes to thrombus nonresolution and fibrosis. Methods and Results: Venous thrombosis was induced by inferior vena cava ligation in mice with genetic deletion of TGFβ1 in platelets (Plt.TGFβ-KO) or TGFβ type II receptors in endothelial cells (End.TGFβRII-KO). Pulmonary endarterectomy specimens from CTEPH patients were analyzed using immunohistochemistry. Primary human and mouse endothelial cells were studied using confocal microscopy, quantitative polymerase chain reaction, and Western blot. Absence of TGFβ1 in platelets did not alter platelet number or function but was associated with faster venous thrombus resolution, whereas endothelial TGFβRII deletion resulted in larger, more fibrotic and higher vascularized venous thrombi. Increased circulating active TGFβ1 levels, endothelial TGFβRI/ALK1 (activin receptor-like kinase), and TGFβRI/ALK5 expression were detected in End.TGFβRII-KO mice, and activated TGFβ signaling was present in vessel-rich areas of CTEPH specimens. CTEPH-endothelial cells and murine endothelial cells lacking TGFβRII simultaneously expressed endothelial and mesenchymal markers and transcription factors regulating endothelial-to-mesenchymal transition, similar to TGFβ1-stimulated endothelial cells. Mechanistically, increased endothelin-1 levels were detected in TGFβRII-KO endothelial cells, murine venous thrombi, or endarterectomy specimens and plasma of CTEPH patients, and endothelin-1 overexpression was prevented by inhibition of ALK5, and to a lesser extent of ALK1. ALK5 inhibition and endothelin receptor antagonization inhibited mesenchymal lineage conversion in TGFβ1-exposed human and murine endothelial cells and improved venous thrombus resolution and pulmonary vaso-occlusions in End.TGFβRII-KO mice. Conclusions: Endothelial TGFβ1 signaling via type I receptors and endothelin-1 contribute to mesenchymal lineage transition and thrombofibrosis, which were prevented by blocking endothelin receptors. Our findings may have relevant implications for the prevention and management of CTEPH.

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Rioux, Francis, Nathalie Harvey, Steve Moisan, Richard Larivière, Marcel Lebel, John H. Grose, and Kenneth Burhop. "Nonpeptide endothelin receptor antagonists attenuate the pressor effect of diaspirin-crosslinked hemoglobin in rat." Canadian Journal of Physiology and Pharmacology 77, no. 3 (March 1, 1999): 188–94. http://dx.doi.org/10.1139/y99-019.

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Endothelin 1 (ET-1) is a potent vasoactive and mitogenic peptide that is thought to participate in the hemodynamic effects elicited by drugs that block the biosynthesis and release of endothelium-derived nitric oxide (NO), such as NO synthase inhibitors. Using the nonpeptide endothelin receptor antagonists bosentan and LU-135252, we tested the hypothesis that endothelins contribute to the pressor activity of diaspirin-crosslinked hemoglobin (DCLHb), a hemoglobin-based oxygen carrier, whose pressor activity in mammals is attributed primarily to a scavenging action towards NO. The NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME), ET-1, and noradrenaline (NA) were used as reference drugs. Bosentan markedly reduced the pressor effects elicited by DCLHb, L-NAME, and ET-1, but not those evoked by NA. LU-135252 attenuated the pressor effect elicited by DCLHb and ET-1, but not that produced by L-NAME or NA. The decreases in heart rate associated with the pressor effect of DCLHb and L-NAME were reduced by LU-135252, whereas only those elicited by DCLHb were attenuated by bosentan. In contrast with bosentan, LU-135252 caused a decrease in the baseline blood pressure and heart rate. These results suggest that endothelins may participate in the pressor activity of DCLHb. They suggest also that nonpeptide endothelin receptor antagonists such as bosentan or LU-135252 may be useful to counteract endothelin-mediated undesirable hemodynamic effects of drugs that inhibit the activity of the NO system.Key words: hemoglobin, endothelin, nitric oxide, blood pressure, diaspirin-crosslinked hemoglobin (DCLHb).

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Raja, Shahzad G., and Shahbaz M. Raja. "Treating pulmonary arterial hypertension: current treatments and future prospects." Therapeutic Advances in Chronic Disease 2, no. 6 (November 2011): 359–70. http://dx.doi.org/10.1177/2040622311420773.

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Pulmonary arterial hypertension (PAH) consists of a group of heterogeneous but distinct disorders characterized by complex proliferation of the pulmonary vascular endothelium and progressive pulmonary vascular remodeling that leads to right ventricular failure and death. Over the past two decades, significant advances in our understanding of the pathobiology of PAH have led to the development of several therapeutic targets in this disease. Besides conservative therapeutic strategies such as anticoagulation and diuretics, the current treatment paradigm for PAH targets the mediators of the three main biologic pathways that are critical for its pathogenesis and progression: endothelin receptor antagonists inhibit the upregulated endothelin pathway by blocking the biologic activity of endothelin-1; phosphodiesterase-5 inhibitors prevent breakdown and increase the endogenous availability of cyclic guanosine monophosphate, which signals the vasorelaxing effects of the downregulated mediator nitric oxide; and prostacyclin derivatives provide an exogenous supply of the deficient mediator prostacyclin. In addition to these established current therapeutic options, a large number of potential therapeutic targets are being investigated. These novel therapeutic targets include soluble guanylyl cyclase, phosphodiesterases, tetrahydrobiopterin, 5-hydroxytryptamine (serotonin) receptor 2B, vasoactive intestinal peptide, receptor tyrosine kinases, adrenomedullin, rho kinase, elastases, endogenous steroids, endothelial progenitor cells, immune cells, bone morphogenetic protein and its receptors, potassium channels, metabolic pathways, and nuclear factor of activated T cells. This review provides an overview of the current therapeutic options and potential therapeutic targets for PAH.

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Parris, Richard J., and David J. Webb. "The Endothelin System in Cardiovascular Physiology and Pathophysiology." Vascular Medicine 2, no. 1 (February 1997): 31–43. http://dx.doi.org/10.1177/1358863x9700200106.

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Endothelin-1, a member of a novel family of regulatory peptides, is the most potent vasoconstrictor and pressor substance known. Endothelin-1 is a 21-amino-acid endothelium-derived peptide causing uniquely sustained vasoconstriction. In addition, endothelin-1 has pronounced effects on the coronary, renal and cerebral circulations, enhances responses to other vasoconstrictors, and is comitogenic. Recent studies have shown that the endothelins are essential for normal fetal development, and that endothelin-1 plays an important physiological role in the regulation of basal vascular tone and blood pressure in healthy humans. There is now also a wealth of evidence suggesting that endothelin-1 is a key mediator in a range of cardiovascular diseases associated with sustained vasoconstriction, such as chronic heart failure, and with vasospasm, such as subarachnoid haemorrhage. In addition, endothelin-1 appears to act in opposition to nitric oxide to promote the atherosclerotic process. There are a large number of oral and intravenously active endothelin antagonists entering clinical development and a number of clinical studies, particularly with endothelin receptor antagonists, are now under way. Such studies are beginning to define the role of the endothelins in cardiovascular disease and to confirm the potential of the endothelin system as an important new therapeutic target.

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Feng, Hong-Qiang, Nate D. Weymouth, and Don C. Rockey. "Endothelin antagonism in portal hypertensive mice: implications for endothelin receptor-specific signaling in liver disease." American Journal of Physiology-Gastrointestinal and Liver Physiology 297, no. 1 (July 2009): G27—G33. http://dx.doi.org/10.1152/ajpgi.90405.2008.

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Endothelin-1 (ET-1), a potent vasoactive peptide, plays an important role in the pathogenesis of liver disease and portal hypertension. Two major endothelin receptors (ET-A and ET-B) mediate biological effects, largely on the basis of their known downstream signaling pathways. We hypothesized that the different receptors are likely to mediate divergent effects in portal hypertensive mice. Liver fibrosis and cirrhosis and portal hypertension were induced in 8-wk-old male BALB/c mice by gavage with carbon tetrachloride (CCl4). Portal pressure was recorded acutely during intravenous infusion of endothelin receptor antagonists in normal or portal hypertensive mice. In vivo microscopy was used to monitor sinusoidal dynamics. Additionally, the effect of chronic exposure to endothelin antagonists was assessed in mice during induction of fibrosis and cirrhosis with CCl4 for 8 wk. Intravenous infusion of ET-A receptor antagonists into normal and cirrhotic mice reduced portal pressure whereas ET-B receptor antagonism increased portal pressure. A mixed endothelin receptor antagonist also significantly reduced portal pressure. Additionally, the ET-A receptor antagonist caused sinusoidal dilation, whereas the ET-B receptor antagonist caused sinusoidal constriction. Chronic administration of each the endothelin receptor antagonists during the induction of fibrosis and portal hypertension led to reduced fibrosis, a significant reduction in portal pressure, and altered sinusoidal dynamics relative to controls. Acute effects of endothelin receptor antagonists are likely directly on the hepatic and sinusoidal vasculature, whereas chronic endothelin receptor antagonism appears to be more complicated, likely affecting fibrogenesis and the hepatic microcirculation. The data imply a relationship between hepatic fibrogenesis or fibrosis and vasomotor responses.

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Rapoport, Robert M., and Mario Zuccarello. "EndothelinA-endothelinBreceptor cross-talk and endothelin receptor binding." Journal of Pharmacy and Pharmacology 63, no. 11 (July 19, 2011): 1373–77. http://dx.doi.org/10.1111/j.2042-7158.2011.01334.x.

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Journal articles on the topic 'Endothelin receptor'

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