Angiotensin receptor type 1 blockade in astroglia decreases hypoxia-induced cell damage and TNF alpha release.
The present study investigated the role of angiotensin receptors (AT-R) in the survival and inflammatory response of astroglia upon hypoxic injury. Exposure of rat astroglial primary cultures (APC) to hypoxic conditions (HC) led to decreased viability of the cells and to a 3.5-fold increase in TNF-alpha release. AT-R type1 (AT1-R) antagonist losartan and its metabolite EXP3174 decrease the LDH release (by 36 +/- 9%; 45 +/- 6%) from APC under HC. Losartan diminished TNF-alpha release (by 40 +/- 15%) and the number of TUNEL-cells by 204 +/- 38% under HC, alone and together with angiotensin II (ATII), while EXP3174 was dependent on ATII for its effect on TNF-alpha. The AT2-R antagonist, PD123.319, did not influence the release of LDH and TNF-alpha under normoxic (NC) and HC. These data suggest that AT1-R may decrease the susceptibility of astrocytes to hypoxic injury and their propensity to release TNF-alpha. AT1-R antagonists may therefore be of therapeutic value during hypoxia-associated neurodegeneration.
Danielyan
Lusine
L
Department of Clinical Pharmacology, University Hospital of Tuebingen, Otfried-Mueller Strasse 45, 72076 Tuebingen, Germany. lusine.danielyan@med.uni-tuebingen.de
Lourhmati
Ali
A
Verleysdonk
Stephan
S
Kabisch
Daniela
D
Proksch
Barbara
B
Thiess
Ulrike
U
Umbreen
Sumaira
S
Schmidt
Boris
B
Gleiter
Christoph H
CH
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000187:drug effects*; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis; D013777:Tetrazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; C066026:losartan carboxylic acid; D019808:Losartan