Endothelin B receptor-deficient rats as a subtraction model to study the cerebral endothelin system

Ehrenreich, Hannelore; Oldenburg, Jan; Hasselblatt, Martin; Herms, Jochen; Dembowski, Christoph; Löffler, Bernd–Michael; Brück, Wolfgang; Kamrowski-Kruck, Heike; Gall, Stefan; Sirén, Anna‐Leena; Schilling, Lothar

doi:10.1016/s0306-4522(98)00663-0

Cited by 38 publications

(47 citation statements)

References 43 publications

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“…These rats have a deletion in the ET B gene (sl) resulting in the loss of functional ET B receptors (Gariepy et al, 1996;Ehrenreich et al, 1999b). ET B -deficient (sl/sl) animals were bred in our laboratory by mating of heterozygous sl/ϩ rats.…”

Section: Materials and Methods Ratsmentioning

confidence: 99%

“…ET B -deficient (sl/sl) animals were bred in our laboratory by mating of heterozygous sl/ϩ rats. The genotype of each animal used for experiments was confirmed by PCR amplification of genomic DNA (Ehrenreich et al, 1999b).…”

Section: Materials and Methods Ratsmentioning

confidence: 99%

“…Astrocyte cultures were prepared from wildtype (ϩ/ϩ) or mutant (sl/sl) animals as described previously (Ehrenreich et al, 1999b). Cells were grown to confluence in glutamine-free Dulbecco's modified Eagle's medium (DMEM) containing 5.55 mM glucose (Bio-Whittaker, Verviers, Belgium) supplemented with 10% fetal calf serum (FCS) (Invitrogen, Karlsruhe, Germany).…”

Section: Cell Culturementioning

confidence: 99%

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Effect of endothelin‐1 on astrocytic protein content

Hasselblatt

Bunte

Dringen

et al. 2003

Glia

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The astrocytic endothelin (ET) receptors, ET(A) and ET(B), modulate calcium signaling and the astrocytic gap junctional network. The nonselective ET receptor ligand ET-1 inhibits gap junction permeability, an effect that can be blocked by tolbutamide. This mechanism may play a role in pathophysiological conditions such as ischemic stroke, characterized by elevated tissue ET-1 levels and hypertrophic-appearing reactive astrocytes. Therefore, the effect of ET-1 on cellular protein content was investigated in confluent once-passaged rat astrocyte cultures under serum-free conditions, by the Lowry method. Gap junction permeability was determined by the dye transfer technique. ET-1 prevented the decrease in astrocytic protein content observed in controls. The effect of ET-1 on cellular protein content was most pronounced in cultures seeded at high density, but it was attenuated in ET(B)-deficient (sl/sl) astrocytes. This effect could be blocked by the nonselective ET antagonist LU 302872 (10 micro M), as well as by the protein synthesis inhibitor cycloheximide (10 micro M). This increase in astrocytic protein content was inhibited by the ATP-sensitive K(+) channel blocker tolbutamide, which also antagonized the ET-1-induced reduction of gap junction permeability and reversed the morphological changes observed in astrocytes upon ET-1 treatment. Cytosine arabinoside (10 micro M), a DNA synthesis blocker, inhibited the ET-1-induced BrdU uptake without affecting the ET-1-induced increase in astrocytic protein content. To conclude, ET-1 induces an increase in astrocytic protein content as well as changes in astrocyte morphology in vitro. This hypertrophic response involves uncoupling of the astrocytic gap junctional network and is not dependent on DNA synthesis.

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Section: Materials and Methods Ratsmentioning

confidence: 99%

Section: Materials and Methods Ratsmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

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Effect of endothelin‐1 on astrocytic protein content

Hasselblatt

Bunte

Dringen

et al. 2003

Glia

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show abstract

“…These rats have a deletion in the ET B gene (sl), resulting in the loss of functional ET B receptors (Gariepy et al, 1996;Ehrenreich et al, 1999b). The animals were bred in our laboratory by mating heterozygous sl/ϩ rats.…”

Section: Materials and Methods Ratsmentioning

confidence: 99%

“…Astrocytes from ET Bdeficient rats (Ehrenreich et al, 1999b) and pharmacological tools designed to block or downregulate ET receptors in wildtype cells were used to study the role of ET B receptors under these conditions.…”

Section: Introductionmentioning

confidence: 99%

Role of the astrocytic ET_B receptor in the regulation of extracellular endothelin‐1 during hypoxia

Hasselblatt

Lewczuk

Löffler

et al. 2001

Glia

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Astrocytes are known to possess an effective endothelin (ET) eliminatory system which involves astrocytic ET(A) and ET(B) receptors and may become particularly relevant under pathophysiological conditions. The present study has therefore been designed to explore the effect of standardized hypoxia on extracellular concentrations of endothelin-1 (ET-1) and on endothelin-converting enzyme (ECE) activity in primary rat astrocytes genetically (sl/sl) or experimentally (dexamethasone) deficient in ET(B) receptors. The results revealed (1) a hypoxia-mediated decrease of extracellular ET-1 in wildtype astrocytes (+/+) that was not observed in ET(B)-deficient (sl/sl) cultures; (2) an ET receptor antagonist-induced increase in ET-1 in the media of both genotypes with further elevation upon hypoxia in +/+ cultures only; (3) augmentation of the dexamethasone-induced increase in extracellular ET-1 by hypoxia in +/+, but not in sl/sl cultures; (4) synergistic reduction of ET(B) gene transcription by hypoxia and dexamethasone; and (5) significant increases in endothelin-converting enzyme activity in the presence of hypoxia. To conclude, hypoxia stimulates astrocytic release of mature ET-1. This stimulation is (over)compensated for by increased ET-1 binding to functional ET(B) receptors. ET(B) deficiency, whether genetic or experimentally induced, impairs elimination of extracellular ET-1.

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Endothelin Receptors in Cerebrovascular Diseases

Briyal

Ranjan

Gulati

2022

GPCRs as Therapeutic Targets

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Endothelin B receptor-deficient rats as a subtraction model to study the cerebral endothelin system

Cited by 38 publications

References 43 publications

Effect of endothelin‐1 on astrocytic protein content

Effect of endothelin‐1 on astrocytic protein content

Role of the astrocytic ET_B receptor in the regulation of extracellular endothelin‐1 during hypoxia

Endothelin Receptors in Cerebrovascular Diseases

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Endothelin B receptor-deficient rats as a subtraction model to study the cerebral endothelin system

Cited by 38 publications

References 43 publications

Effect of endothelin‐1 on astrocytic protein content

Effect of endothelin‐1 on astrocytic protein content

Role of the astrocytic ETB receptor in the regulation of extracellular endothelin‐1 during hypoxia

Endothelin Receptors in Cerebrovascular Diseases

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Product

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Role of the astrocytic ET_B receptor in the regulation of extracellular endothelin‐1 during hypoxia