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- Title
Potentiation of intracellular Ca<sup>2+</sup> mobilization by hypoxia-induced NO generation in rat brain striatal slices and human astrocytoma U-373 MG cells and its involvement in tissue damage.
- Authors
Meini, Antonella; Benocci, Alberto; Frosini, Maria; Sgaragli, Gian Pietro; Garcia, Julian Blanco; Pessina, Gian Paolo; Aldinucci, Carlo; Palmi, Mitri
- Abstract
Abstract The relationship between nitric oxide (NO) and intracellular Ca2+ in hypoxic–ischemic brain damage is not known in detail. Here we used rat striatal slices perfused under low-oxygen and Ca2+ -free conditions and cultured human astrocytoma cells incubated under similar conditions as models to study the dynamics of intracellular NO and Ca2+ in hypoxia-induced tissue damage. Exposure of rat striatal slices for 70 min to low oxygen tension elicited a delayed and sustained increase in the release of 45 Ca2+ . This was potentiated by the NO donors sodium nitroprusside (SNP) and spermine–NO and inhibited by N-ω-nitro-L-arginine methyl ester (L-NAME) or by the NO scavenger 2-phenyl-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide (PTIO). A membrane-permeant form of heparin in combination with either ruthenium red (RR) or ryanodine (RY) also inhibited 45 Ca2+ release. In human astrocytoma U-373 MG cells, hypoxia increased intracellular Ca2+ concentration ([Ca2+ ]i ) by 67.2 ± 13.1% compared to normoxic controls and this effect was inhibited by L-NAME, PTIO or heparin plus RR. In striatal tissue, hypoxia increased NO production and LDH release and both effects were antagonized by L-NAME. Although heparin plus RR or RY antagonized hypoxia-induced increase in LDH release they failed to counteract increased NO production. These data therefore indicate that NO contributes to hypoxic damage through increased intracellular Ca2+ mobilization from endoplasmic reticulum and suggest that the NO–Ca2+ signalling might be a potential therapeutic target in hypoxia-induced neuronal degeneration.
- Subjects
NITRIC oxide; CALCIUM ions; ASTROCYTOMAS; HYPOXEMIA
- Publication
European Journal of Neuroscience, 2003, Vol 17, Issue 4, p692
- ISSN
0953-816X
- Publication type
Article
- DOI
10.1046/j.1460-9568.2003.02483.x