Endothelin-mediated induction of heme oxygenase-1 in the spinal cord is attenuated in transgenic mice overexpressing superoxide dismutase.
Spinal cord blood flow and the induction of heme oxygenase-1 (HO-1), an indicator of oxidative stress, were studied in the spinal cords of adult wild-type and transgenic mice overexpressing the antioxidant copper, zinc superoxide dismutase (CuZn SOD) after intrathecal administration of the potent vasoactive peptide endothelin-1 (ET-1). Gelfoam, saturated with ET-1 (40, 80, or 400 micromol/L), was positioned in the intrathecal space at the midthoracic level in anesthetized animals. Blood flow was continuously monitored by laser Doppler for 10 min after the intrathecal application of ET-1. There was a significant reduction in spinal cord blood flow to approximately 40% of control values by 10 min after the intrathecal application of the peptide in both wild-type and transgenic mice. Moreover, SB209670, a nonselective endothelin receptor antagonist, blocked this reduction in flow. Each animal was euthanized 24 h after the intrathecal administration of ET-1, and the spinal cord was prepared for quantitative immunocytochemistry. HO-1 was primarily induced in astrocytes near the dorsal surface of the spinal cord in wild-type mice. This induction was attenuated in both wild-type, treated with SB209670, and untreated transgenic mice. Together, these findings suggest that ET-1 mediates oxidative stress in the spinal cord through the modulation of spinal cord blood flow.
Weinzierl
Martin
M
Department of Neurological Surgery, RWTH Aachen, Germany.
Mautes
A E
AE
Whetstone
William
W
Lin
Yong
Y
Noble-Haeusslein
Linda J
LJ
D000818:Animals; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D007189:Indans / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D013116:Spinal Cord / Q000098:blood supply* / Q000201:enzymology*; D013482:Superoxide Dismutase / Q000235:genetics*
D019332:Endothelin-1; D007189:Indans; D008565:Membrane Proteins; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D013482:Superoxide Dismutase