Chronic Treatment In Vivo with Dimethylthiourea, a Hydroxyl Radical Scavenger, Prevents Diabetes-Induced Endothelial Dysfunction

Pieper, Galen M.; Siebeneich, Wolfgang; Roza, Allan M.; Jordan, Milan; Adams, Mark B.

doi:10.1097/00005344-199612000-00002

Cited by 46 publications

(28 citation statements)

References 18 publications

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“…Peroxynitrite, the product of the reaction of ·O 2 ± with NO, is a very toxic radical species which decomposes to hydroxyl radicals (·OH). The observation that ·OH are detected in plasma after 72 h of diabetes in the rat [62], that the chronic treatment with dimethylthiourea, a ·OH scavenger, and that a unique form of iron chelator (which prevents metal ion-catalysed ·OH formation) both prevent endothelial dysfunction [63,64] are all consistent with this pathway for the aetiology of diabetes-induced endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 77%

Long-term treatment in vivo with NOX-101, a scavenger of nitric oxide, prevents diabetes-induced endothelial dysfunction

1998

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Considerable evidence using experimental models [1±5] have shown that diabetes mellitus is an independent risk factor for the development of impaired endothelium-dependent relaxation ± that is, endothelial dysfunction. This defect has been confirmed in Type I (insulin-dependent) [6,7] and Type II (non-insulindependent) [8] diabetic patients. The factor(s) which contribute to endothelial dysfunction in diabetic patients is not known but data derived in experimental models have suggested several possibilities including: (a) concurrent release of an endothelium-derived constricting factor arising from the cyclooxygenase pathway [9,10] Summary Substantial evidence exists that diabetes results in impaired endothelial dysfunction suggesting diminished nitric oxide production from diabetic endothelium. It is not known what factors contribute to the development of this defect. In this study, we tested whether chronic treatment in vivo with NOX-101, a water-soluble nitric oxide scavenger, prevents endothelial dysfunction in diabetes. Sprague-Dawley rats were made diabetic by an intravenous injection of streptozotocin. A subgroup of control or diabetic animals received twice daily subcutaneous injections of 80 mg/kg NOX-101 beginning at 48 h after streptozotocin was injected and throughout 8 weeks of diabetes. Body weights and glucose concentrations were monitored weekly. At the end of 8 weeks, blood glucose and glycosylated haemoglobin was raised in diabetic rats but serum insulin concentrations were reduced. Treatment with NOX-101 did not alter glucose or insulin concentrations in control or diabetic rats; however, total glycosylated haemoglobin was partially reduced compared with untreated rats. In a subgroup of 2-week diabetic and age-matched rats fasted for 24 h, NOX-101 abolished total urinary nitrate plus nitrite (an index of nitric oxide production in vivo). In isolated tissue baths, relaxation to the endothelium-dependent vasodilator, acetylcholine, was impaired in diabetic aortic rings and relaxation to nitroglycerin was unaltered. Treatment of control rats with NOX-101 did not alter maximum relaxation to acetylcholine but shifted the response curve slightly to the right. In contrast in diabetic rats, NOX-101 prevented the impairment in endothelium-dependent relaxation but had no effect on relaxation induced by nitroglycerin. These data suggest the possibility that diabetes-induced endothelial dysfunction in diabetes results, in part, from a paradoxical increase in nitric oxide production during the course of the disease. This suggests a novel pathway of vascular complications. [Diabetologia (1998

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Section: Discussionmentioning

confidence: 77%

Long-term treatment in vivo with NOX-101, a scavenger of nitric oxide, prevents diabetes-induced endothelial dysfunction

1998

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“…[3][4][5][6][7][8]13,[31][32][33][34] Moreover, a considerable body of evidence now suggests that the impairment of endothelium-dependent relaxation seen in diabetes and atherosclerosis may involve inactivation of NO by oxygen-derived free radicals. 4,33,[35][36][37] Production of superoxide anion leads to inactivation of NO, 35,38) and dismutation of free radicals has generally 33,36,37) been found to improve impaired endothelium-dependent relaxation in experimental models of diabetes. Indeed, we recently reported that NO is metabolized by O 2 Ϫ to NO 3…”

Section: Discussionmentioning

confidence: 99%

Effects of Chronic Administration of Fruit Extract (Citrus unshiu MARC) on Endothelial Dysfunction in Streptozotocin-Induced Diabetic Rats

Kamata

Kobayashi

Matsumoto

et al. 2005

Biological & Pharmaceutical Bulletin

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“…Production of superoxide anion inactivates NO (Marshall et al, 1988;Rubanyi & Vanhoutte, 1986;Kobayashi & Kamata, 2001) and dismutation of free radicals has generally (Pieper et al, 1996;Hattori et al, 1991;Kamata & Kobayashi, 1996) but not always (Heygate et al, 1995) been found to improve impaired endothelium-dependent relaxation in experimental models of diabetes. Indeed, we recently reported that NO is metabolized by O 2 7 to NO 3…”

Section: Discussionmentioning

confidence: 99%

Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat

Kanie

Kamata

2002

British J Pharmacology

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1 The biosynthesis of endothelin-1 is increased in the diabetic state. So this peptide may cause diabetic vascular complications. We tested this possibility by chronically administering J-104132, a potent orally active mixed antagonist of endothelin A and B (ET A /ET B ) receptors to streptozotocin (STZ)-induced diabetic rats and focusing on changes in endothelial function. 2 The acetylcholine (ACh)-induced endothelium-dependent relaxation was impaired in diabetic rats and this impairment was signi®cantly attenuated following chronic administration of J-104132 (10 mg kg 71 , p.o., daily for 4 weeks).3 In an in vitro experiment using aortae from diabetic rats, the ACh-induced relaxation was not changed by the presence of J-104132 (3610 79 M). 4 The expression levels of the mRNA for endothelial nitric oxide synthase was comparable among aortae from the three groups (control, diabetic and chronically J-104132-treated diabetic). 5 The amount of superoxide anion was signi®cantly greater in aortae from diabetic rats than in controls. Chronic J-104132 treatment signi®cantly decreased the level of superoxide anion in diabetic rats. 6 The expression of the p22phox mRNA for the NADH/NADPH oxidase subunit was signi®cantly increased in STZ-induced diabetic rats and this increase was completely prevented by chronic administration of J-104132. 7 These results suggest that in STZ-induced diabetic rats, ET-1 may be directly involved in impairing endothelium-dependent relaxation via increased superoxide-anion production.

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Chronic Treatment In Vivo with Dimethylthiourea, a Hydroxyl Radical Scavenger, Prevents Diabetes-Induced Endothelial Dysfunction

Cited by 46 publications

References 18 publications

Long-term treatment in vivo with NOX-101, a scavenger of nitric oxide, prevents diabetes-induced endothelial dysfunction

Long-term treatment in vivo with NOX-101, a scavenger of nitric oxide, prevents diabetes-induced endothelial dysfunction

Effects of Chronic Administration of Fruit Extract (Citrus unshiu MARC) on Endothelial Dysfunction in Streptozotocin-Induced Diabetic Rats

Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat

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