Preventing Superoxide Formation in Epineurial Arterioles of the Sciatic Nerve from Diabetic Rats Restores Endothelium-dependent Vasodilation
We have previously reported that in streptozotocin-induced diabetic rats that increased formation of superoxide and peroxynitrite is associated with impairment in vascular relaxation in epineurial arterioles of the sciatic nerve. In this study we demonstrate that pretreating epineurial arterioles fr...
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Published in | Free radical research Vol. 37; no. 1; pp. 33 - 40 |
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Language | English |
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2003
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Abstract | We have previously reported that in streptozotocin-induced diabetic rats that increased formation of superoxide and peroxynitrite is associated with impairment in vascular relaxation in epineurial arterioles of the sciatic nerve. In this study we demonstrate that pretreating epineurial arterioles from diabetic rats in vitro with f -lipoic acid, dihydrolipoic acid, tempol or arginine restores acetylcholine-mediated vascular relaxation to near the reactivity observed in vessels from control rats. Suggesting that increased oxidative stress and reduction in nitric oxide availability is partially responsible for the impairment in endothelium-dependent vasodilation observed in epineurial arterioles from diabetic rats. In contrast, pretreating epineurial arterioles from diabetic rats with aminoguanidine or allopurinol had no effect. Studies designed to investigate the source of superoxide formation provided results suggesting that complex I of the mitochondrial electron transport chain and NAD(P)H oxidase are responsible for the increase in superoxide formation observed with epineurial arterioles from the sciatic nerve. Pretreating epineurial arterioles from diabetic rats with the protein kinase C inhibitor bisindolymaleimide I (GF 109203X) improved acetylcholine-mediated vascular relaxation but did not prevent the increase in superoxide formation suggesting that activation of protein kinase C by oxidative stress is downstream of superoxide formation. These studies imply that increased superoxide formation via the mitochondrial electron transport chain and perhaps NAD(P)H oxidase is partially responsible for reduced vascular reactivity observed in epineurial arterioles of the sciatic nerve from diabetic rats. |
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AbstractList | We have previously reported that in streptozotocin-induced diabetic rats that increased formation of superoxide and peroxynitrite is associated with impairment in vascular relaxation in epineurial arterioles of the sciatic nerve. In this study we demonstrate that pretreating epineurial arterioles from diabetic rats in vitro with f -lipoic acid, dihydrolipoic acid, tempol or arginine restores acetylcholine-mediated vascular relaxation to near the reactivity observed in vessels from control rats. Suggesting that increased oxidative stress and reduction in nitric oxide availability is partially responsible for the impairment in endothelium-dependent vasodilation observed in epineurial arterioles from diabetic rats. In contrast, pretreating epineurial arterioles from diabetic rats with aminoguanidine or allopurinol had no effect. Studies designed to investigate the source of superoxide formation provided results suggesting that complex I of the mitochondrial electron transport chain and NAD(P)H oxidase are responsible for the increase in superoxide formation observed with epineurial arterioles from the sciatic nerve. Pretreating epineurial arterioles from diabetic rats with the protein kinase C inhibitor bisindolymaleimide I (GF 109203X) improved acetylcholine-mediated vascular relaxation but did not prevent the increase in superoxide formation suggesting that activation of protein kinase C by oxidative stress is downstream of superoxide formation. These studies imply that increased superoxide formation via the mitochondrial electron transport chain and perhaps NAD(P)H oxidase is partially responsible for reduced vascular reactivity observed in epineurial arterioles of the sciatic nerve from diabetic rats. We have previously reported that in streptozotocin-induced diabetic rats that increased formation of superoxide and peroxynitrite is associated with impairment in vascular relaxation in epineurial arterioles of the sciatic nerve. In this study we demonstrate that pretreating epineurial arterioles from diabetic rats in vitro with alpha-lipoic acid, dihydrolipoic acid, tempol or arginine restores acetylcholine-mediated vascular relaxation to near the reactivity observed in vessels from control rats. Suggesting that increased oxidative stress and reduction in nitric oxide availability is partially responsible for the impairment in endothelium-dependent vasodilation observed in epineurial arterioles from diabetic rats. In contrast, pretreating epineurial arterioles from diabetic rats with aminoguanidine or allopurinol had no effect. Studies designed to investigate the source of superoxide formation provided results suggesting that complex I of the mitochondrial electron transport chain and NAD(P)H oxidase are responsible for the increase in superoxide formation observed with epineurial arterioles from the sciatic nerve. Pretreating epineurial arterioles from diabetic rats with the protein kinase C inhibitor bisindolymaleimide I (GF 109203X) improved acetylcholine-mediated vascular relaxation but did not prevent the increase in superoxide formation suggesting that activation of protein kinase C by oxidative stress is downstream of superoxide formation. These studies imply that increased superoxide formation via the mitochondrial electron transport chain and perhaps NAD(P)H oxidase is partially responsible for reduced vascular reactivity observed in epineurial arterioles of the sciatic nerve from diabetic rats. |
Author | Gellett, Jill S. Coppey, Lawrence J. Davidson, Eric P. Yorek, Mark A. |
Author_xml | – sequence: 1 givenname: Lawrence J. surname: Coppey fullname: Coppey, Lawrence J. organization: Veteran Affairs Medical Center, Diabetes Endocrinology Research Center and Department of Internal Medicine, University of Iowa, Iowa City, IA, 52246, USA – sequence: 2 givenname: Jill S. surname: Gellett fullname: Gellett, Jill S. organization: Veteran Affairs Medical Center, Diabetes Endocrinology Research Center and Department of Internal Medicine, University of Iowa, Iowa City, IA, 52246, USA – sequence: 3 givenname: Eric P. surname: Davidson fullname: Davidson, Eric P. organization: Veteran Affairs Medical Center, Diabetes Endocrinology Research Center and Department of Internal Medicine, University of Iowa, Iowa City, IA, 52246, USA – sequence: 4 givenname: Mark A. surname: Yorek fullname: Yorek, Mark A. organization: Veteran Affairs Medical Center, Diabetes Endocrinology Research Center and Department of Internal Medicine, University of Iowa, Iowa City, IA, 52246, USA |
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SubjectTerms | Animals Arginine - pharmacology Arterioles - drug effects Arterioles - physiopathology Cyclic N-Oxides - pharmacology Diabetes Diabetes Mellitus, Experimental - metabolism Diabetes Mellitus, Experimental - physiopathology Diabetic Neuropathies - etiology Diabetic Neuropathies - physiopathology Endothelium, Vascular - drug effects Endothelium, Vascular - physiopathology Enzyme Inhibitors - pharmacology In Vitro Techniques Indoles - pharmacology Male Maleimides - pharmacology NADH, NADPH Oxidoreductases - metabolism NADPH Oxidases Oxidative Stress Oxidative Stress - drug effects Protein Kinase C Protein Kinase C - antagonists & inhibitors Protein Kinase C - metabolism Rats Rats, Sprague-Dawley Sciatic Nerve - blood supply Spin Labels Superoxides - metabolism Thioctic Acid - analogs & derivatives Thioctic Acid - pharmacology Vascular Reactivity Superoxide Vasodilation - drug effects Vasodilation - physiology |
Title | Preventing Superoxide Formation in Epineurial Arterioles of the Sciatic Nerve from Diabetic Rats Restores Endothelium-dependent Vasodilation |
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