ETA and ETB receptor antagonists synergistically increase extracellular endothelin-1 levels in primary rat astrocyte cultures

Hasselblatt, Martin; Kamrowski-Kruck, Heike; Jensen, Niels H.; Schilling, Lothar; Kratzin, Hartmut; Sirén, Anna‐Leena; Ehrenreich, Hannelore

doi:10.1016/s0006-8993(97)01368-1

Cited by 32 publications

(37 citation statements)

References 33 publications

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“…For example, ET B receptors in the anterior pituitary gland appeared to only bind ET-1 during blockade of ET A receptors (52). Clearance of ET-1 by astrocytes and production of superoxide by rat aorta is blocked only by a combination of ET A and ET B receptor antagonists while being unaffected by administration of either agent alone (22,53). Further, either ET A or ET B selective receptor antagonists can completely block the vasoconstrictor actions of ET-1 in renal afferent arterioles (54).…”

Section: Dimerization Of Et a And Et B Receptorsmentioning

confidence: 99%

Contrasting Actions of Endothelin ET_Aand ET_BReceptors in Cardiovascular Disease

Schneider

Boesen

Pollock

2007

Annu. Rev. Pharmacol. Toxicol.

262

247

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First identified as a powerful vasoconstrictor, endothelin has an extremely diverse set of actions that influence homeostatic mechanisms throughout the body. Two receptor subtypes, ET A and ET B , which usually have opposing actions, mediate the actions of endothelin. ET A receptors function to promote vasoconstriction, growth, and inflammation while ET B receptors produce vasodilation, increases in sodium excretion, and inhibit growth and inflammation. Potent and selective receptor antagonists have been developed and have shown promising results in the treatment of cardiovascular diseases such as pulmonary arterial hypertension, acute and chronic heart failure, hypertension, renal failure and atherosclerosis. However, results are often contradictory and complicated because of the tissue-specific vasoconstrictor actions of ET B receptors and the fact that endothelin is an autocrine and paracrine factor whose activity is difficult to measure in vivo. Considerable questions remain regarding whether ET A selective or non-selective ET A /ET B receptor antagonists would be useful in a range of clinical settings. Keywordsreceptor localization; pulmonary hypertension; heart failure; chronic kidney disease Shortly after it was discovered that the vascular endothelium releases a peptide capable of profound vasoconstriction, a considerable amount of attention was paid to the potential actions of endothelin in the pathogenesis of cardiovascular disease. We have since learned a great deal about how this paracrine factor influences function in an extremely wide range of areas including neurotransmission, cell growth and epithelial transport, just to name a few. This myriad of activities has allowed the endothelin system to garner a tremendous amount of attention from the pharmaceutical industry with the development of numerous receptor specific and non-specific antagonists as well as efforts to identify drugs that inhibit endothelin synthesis. This work has led to new therapeutic approaches to pulmonary arterial hypertension and most likely other diseases in the not too distant future. In addition to this enormous drug discovery effort, it has also become clear that endothelin plays an important physiological role in maintaining blood pressure homeostasis, for example, by facilitating the excretion of a high salt diet. Because of the almost bewildering range of actions of the endothelin peptides, we limit this review to focus on the receptor-specific cardiovascular actions of endothelin. ENDOTHELIN PEPTIDESEndothelin-1, a 21-amino-acid long peptide first isolated from the supernatant of cultured endothelial cells, is perhaps the most potent vasoconstrictor substance known (1). The human Address for Correspondence: David M. Pollock, Ph.D., Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA 30912-2500, +1-706-721-8517 office, +1-706-721-9799 fax, dpollock@mcg.edu. NIH Public Access Author ManuscriptAnnu Rev Pharmacol Toxicol. Author manuscript; available in PMC 2010 February 22. P...

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Section: Dimerization Of Et a And Et B Receptorsmentioning

confidence: 99%

Contrasting Actions of Endothelin ET_Aand ET_BReceptors in Cardiovascular Disease

Schneider

Boesen

Pollock

2007

Annu. Rev. Pharmacol. Toxicol.

262

247

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“…nation of ET A and ET B receptor-selective antagonists, but not their individual application increased ET-1 in the extracellular fluid (19). Similarly, the gap junction permeability of astrocytes is cooperatively inhibited via ET A and ET B receptors: only the combined application of ET A and ET B receptor-selective antagonists block ET-1 action (20).…”

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confidence: 95%

Ligand-dependent Differences in the Internalization of Endothelin A and Endothelin B Receptor Heterodimers

Gregan

Jürgensen

Papsdorf

et al. 2004

Journal of Biological Chemistry

117

106

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Endothelin-1 (ET-1) is a potent vasoactive peptide that acts on endothelin A (ETEndothelins (ET-1, ET-2, and ET-3) 1 are important regulators in the vascular system. They act via two receptors: the endothelin A (ET A ) and endothelin B (ET B ) receptors (1, 2). Although human ET A and ET B receptors share 59% amino acid sequence identity (exceeding 75% at the cytoplasmic face), both receptor subtypes couple to different G proteins and differ in their ligand-induced internalization and intracellular trafficking. Whereas the ET A receptor stimulates G proteins of the G q/11 and G 12/13 families, the ET B receptor activates mainly G proteins of the G i and G q/11 families (3, 4). Whether ET B receptors also stimulate proteins of the G 12/13 family is still controversial and may depend on expression levels or cell types investigated (5, 6). Upon ligand binding, both receptor subtypes are rapidly desensitized by phosphorylation through the G protein-coupled receptor kinase type 2 (7). Following internalization via caveolae and/or clathrin-coated pits, the ET A receptor is recycled back to the cell surface (8, 9). In contrast, the ET B receptor is exclusively internalized via a clathrin-dependent pathway and transported to late endosomes and lysosomes (9, 10).The ET A receptor is mainly expressed in vascular smooth muscle cells. Its activation elicits a long-lasting contraction via an increase in cytosolic Ca 2ϩ concentrations and activation of Rho proteins (11,12). The ET B receptor is predominantly expressed in endothelial cells and stimulates the release of NO and prostacyclin, thereby causing relaxation of vascular smooth muscle cells (13). In addition, ET A and ET B receptors are co-expressed in numerous cells, e.g. astrocytes, cardiomyocytes, epithelial cells of the choroid plexus and the anterior pituitary, and certain vascular smooth muscle cells (14 -16). In disease states, such as atherosclerosis and hypercholesterolemia, vascular smooth muscle cells co-express ET A and ET B receptors (17). Because atypical ligand binding was observed for cells co-expressing ET A and ET B receptors, e.g. astrocytes, epithelial cells of the anterior pituitary, or vascular smooth muscle cells, it was suggested that the two receptor subtypes form heterodimers (15,16,18). For example, in epithelial cells of the anterior pituitary, ET B receptor-selective ligands such as sarafotoxin 6c, ET-3, and IRL1620 were competitors of 125 I-ET-1 binding only in the presence of the ET A receptor-selective antagonist BQ123 (16). In astrocytes, ET A and ET B receptors cooperatively control ET-1 clearance, because only the combi-

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“…Several studies have shown that ET-1 affects numerous cell functions of cultured astrocytes such as control of ion channel activity (5), glutamate efflux (52) and uptake (41), glucose utilization (58), permeability of gap junction communications (3, 16), and calcium signaling (3, 64). In turn, astrocytes are a major source of ET-1 (12, 13) and seem to play an important role in the regulation of ET-1 levels within the CNS (14,24,25).In contrast to the cerebrovascular system, in which ET A receptors are the major receptor subtype, astrocytes predominantly express the ET B receptor subtype (26,38). However, at least in cultured astrocytes, there has also been evidence of ET A receptor mRNA expression (13) and an ET A /ET B hybrid receptor has been postulated (31).…”

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confidence: 99%

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ET-1 induces cortical spreading depression via activation of the ET_Areceptor/phospholipase C pathway in vivo

Kleeberg

Petzold

Major

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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. ET-1 induces cortical spreading depression via activation of the ETA receptor/phospholipase C pathway in vivo. Am J Physiol Heart Circ Physiol 286: H1339-H1346, 2004. First published December 4, 2003 10.1152 10. /ajpheart.00227.2003 has been shown that brain topical superfusion of endothelin (ET)-1 at concentrations around 100 nM induces repetitive cortical spreading depressions (CSDs) in vivo. It has remained unclear whether this effect of ET-1 is related to a primary neuronal/astroglial effect, such as an increase in neuronal excitability or induction of interastroglial calcium waves, or a penumbra-like condition after vasoconstriction. In vitro, ET-1 regulates interastroglial communication via combined activation of ETA and ETB receptors, whereas it induces vasoconstriction via single activation of ETA receptors. We have determined the ET receptor profile and intracellular signaling pathway of ET-1-induced CSDs in vivo. In contrast to the ETB receptor antagonist BQ-788 and concentration dependently, the ETA receptor antagonist BQ-123 completely blocked the occurrence of ET-1-induced CSDs. The ETB receptor antagonist did not increase the efficacy of the ETA receptor antagonist. Direct stimulation of ETB receptors with the selective ETB agonist BQ-3020 did not trigger CSDs. The phospholipase C (PLC) antagonist U-73122 inhibited CSD occurrence in contrast to the protein kinase C inhibitor Gö-6983. Our findings indicate that ET-1 induces CSDs through ETA receptor and PLC activation. We conclude that the induction of interastroglial calcium waves is unlikely the primary cause of ET-1-induced CSDs. On the basis of the receptor profile, likely primary targets of ET-1 mediating CSD are either neurons or vascular smooth muscle cells.endothelin-1; endothelin receptor antagonists; interastroglial calcium waves; gap junction communication; protein kinase C inhibition; arachidonic acid; cortical spreading depression ENDOTHELIN (ET)-1 was initially believed to influence brain functions only indirectly through regulation of cerebral perfusion due to its vasoconstrictor activity. However, over the past few years, evidence has accumulated that ET-1 may fulfill a wider range of physiological actions within the central nervous system (CNS), which has also led to its recognition as a neuropeptide (for reviews, see Refs. 33 and 36). Beside neurons, astrocytes represent a major ET target. Several studies have shown that ET-1 affects numerous cell functions of cultured astrocytes such as control of ion channel activity (5), glutamate efflux (52) and uptake (41), glucose utilization (58), permeability of gap junction communications (3, 16), and calcium signaling (3, 64). In turn, astrocytes are a major source of ET-1 (12, 13) and seem to play an important role in the regulation of ET-1 levels within the CNS (14,24,25).In contrast to the cerebrovascular system, in which ET A receptors are the major receptor subtype, astrocytes predominantly express the ET B receptor subtype (26,38). However, at least in cultured astrocytes, there ...

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ETA and ETB receptor antagonists synergistically increase extracellular endothelin-1 levels in primary rat astrocyte cultures

Cited by 32 publications

References 33 publications

Contrasting Actions of Endothelin ET_Aand ET_BReceptors in Cardiovascular Disease

Contrasting Actions of Endothelin ET_Aand ET_BReceptors in Cardiovascular Disease

Ligand-dependent Differences in the Internalization of Endothelin A and Endothelin B Receptor Heterodimers

ET-1 induces cortical spreading depression via activation of the ET_Areceptor/phospholipase C pathway in vivo

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ETA and ETB receptor antagonists synergistically increase extracellular endothelin-1 levels in primary rat astrocyte cultures

Cited by 32 publications

References 33 publications

Contrasting Actions of Endothelin ETAand ETBReceptors in Cardiovascular Disease

Contrasting Actions of Endothelin ETAand ETBReceptors in Cardiovascular Disease

Ligand-dependent Differences in the Internalization of Endothelin A and Endothelin B Receptor Heterodimers

ET-1 induces cortical spreading depression via activation of the ETAreceptor/phospholipase C pathway in vivo

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Contrasting Actions of Endothelin ET_Aand ET_BReceptors in Cardiovascular Disease

Contrasting Actions of Endothelin ET_Aand ET_BReceptors in Cardiovascular Disease

ET-1 induces cortical spreading depression via activation of the ET_Areceptor/phospholipase C pathway in vivo