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.