Diabetes-Induced Endothelial Dysfunction is Prevented by Long-Term Treatment with the Modified Iron Chelator, Hydroxyethyl Starch Conjugated-Deferoxamine

Pieper, Galen M.; Siebeneich, Wolfgang

doi:10.1097/00005344-199712000-00006

Cited by 78 publications

(39 citation statements)

References 25 publications

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“…This agrees with previous reports in rat, rabbit and man [1±3]. Nitric oxide is the major vasodilator released by corpus cavernosum endothelium and a diabetic deficit in synthesis, release or action, is in line with many observations including those from in vitro studies on large arteries [7±9, 11,12], small muscle arteries [15], heart and mesenteric vascular beds [10,29] and in vivo studies on sciatic vasa nervorum [16,17], brain [14,30] and skin [21]. In the majority of these tissues, relaxation to NO donors, such as sodium nitroprusside or glyceryl trinitrate, was not affected by diabetes, as observed in this study for corpus cavernosum.…”

Section: Discussionsupporting

confidence: 92%

Effects of diabetes and treatment with the antioxidant α-lipoic acid on endothelial and neurogenic responses of corpus cavernosum in rats

1999

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Males with diabetes mellitus have an increased prevalence of erectile dysfunction. Some of the organic causes have been studied in corpus cavernosum strips isolated from men undergoing penile prosthesis implantation. Defects in endothelium-dependent and nerve-mediated vascular smooth muscle relaxation have been found [1]. Similar deficits were noted for alloxan-diabetic rabbits [2] and recently diminished neurogenic erections were reported in streptozotocin-diabetic rats [3]. The nitric oxide (NO) systems of corpus cavernosum endothelium and nerve supply are crucial for smooth muscle relaxation and erectile Diabetologia (1999) Summary Diabetes mellitus is associated with impotence in animal models and patients. Raised reactive oxygen species contribute to diabetic neurovascular deficits, which are amenable to antioxidant treatment. Our aim was to examine the effects of streptozotocin-induced diabetes in rats and long-term treatment with the antioxidant, a-lipoic acid, on responses of an in vitro corpus cavernosum preparation. Diabetes duration was 8 weeks and preventive and reversal (4 weeks untreated diabetes, 4 weeks of treatment) studies were done. Four and 8 weeks of diabetes caused an about 41 % reduction in endothelium-dependent nitric oxide mediated relaxation to acetylcholine in phenylephrine-precontracted cavernosum. This deficit was prevented (93.9 ± 7.1 %) by treatment with a-lipoic acid; reversal studies showed 64.9 ± 19.5 % correction. Neither diabetes nor treatment with a-lipoic acid altered endothelium-independent relaxation to the nitric oxide donor, sodium nitroprusside. Stimulation of corpus cavernosum autonomic innervation caused noradrenergic-mediated contractions that were unaffected by diabetes or a-lipoic acid. Non-adrenergic, non-cholinergic nerve responses, largely dependent on nitric oxide, were seen after phenylephrine precontraction in the presence of atropine and guanethidine. Non-adrenergic, non-cholinergic stimulation caused frequency dependent relaxation to a maximum of about 40 %. Diabetes reduced this to about 25 %, however with preventive a-lipoic acid treatment, non-adrenergic, noncholinergic relaxation was in the nondiabetic range. In the reversal a-lipoic acid treated diabetic group, its deficit was corrected by 52.1 ± 14.6 %. Thus, diabetes reduces endothelium and non-adrenergic, noncholinergic nerve nitric oxide-mediated relaxation of corpus cavernosum smooth muscle, which is likely to be the organic base for impotence. Prevention and partial correction by a-lipoic acid emphasises the importance of reactive oxygen species and suggests a potential therapeutic approach. [Diabetologia (1999) 42: 343±350]

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Section: Discussionsupporting

confidence: 92%

Effects of diabetes and treatment with the antioxidant α-lipoic acid on endothelial and neurogenic responses of corpus cavernosum in rats

1999

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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: 82%

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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“…ONOO also rapidly breaks down to produce other toxic free radicals [12]. Several studies have now shown a reduction of nitric oxide and an increase in O 2 -formation by the vasculature of diabetic laboratory animals [8,9,20,21,22,23]. In support of these observations, the adenoviral gene transfer of both eNOS and SOD have been shown to reverse the reduction of endothelium-dependent relaxation in the diabetic rabbit [24,25].…”

Section: Discussionmentioning

confidence: 87%

“…In humans, Type I (insulin-dependent) diabetes mellitus is also associated with reduced SOD activity due to increased glycation of the enzyme [27]. The excess production of O 2 -by the vasculature of diabetic animals has also been attributed to the over-expression of endogenous O 2 -generating enzymes, including NADPH oxidase, xanthine oxidase, cyclooxgenase and lipoxygenase as well as the auto-oxidation of glucose and mitochondrial respiration [8,7,20].…”

Section: Discussionmentioning

confidence: 99%

Homocysteine enhances impairment of endothelium-dependent relaxation and guanosine cyclic monophosphate formation in aortae from diabetic rabbits

et al. 2002

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Aims/hypothesis. Both diabetes mellitus and hyperhomocysteinaemia are risk factors for cardiovascular disease and are associated with impaired endothelial nitric oxide and with excess superoxide formation. To explore potential vasculopathic interactions between these risk factors, the effect of homocysteine on endothelium-dependent relaxation and cyclic GMP formation was investigated in aortae from diabetic rabbits. Methods. Rabbits were rendered diabetic by intravenous injection of alloxan. Six months later, the aortae were excised, cut into rings and mounted in an organ bath for isometric measurement of acetylcholineevoked relaxation in rings pre-contracted with phenylephrine. Cyclic GMP formation by aortic rings after stimulation with acetylcholine, calcium ionophore A23187 and sodium nitroprusside was assessed using radioimmunoassay. The effect of homocysteine on these parameters was then studied.Results. Ach-evoked relaxation and cyclic GMP formation induced with acetylcholine and calcium ionophore A23187 were impaired in aortae from diabetic rabbits compared with the control rabbits, effects that were reversed with superoxide dimutase (SOD) and augmented by 10-100 µmol/l homocysteine, an effect again reversed by SOD. Conclusion/interpretation. These data show that the bioavailability of nitric oxide is reduced in aortae from diabetic rabbits due to excess production of superoxide, an effect augmented by homocysteine. These results indicate that patients with diabetes mellitus could be susceptible to homocysteine-mediated angiopathy at lower concentrations than those that promote vasculopathy in non-diabetic patients. [Diabetologia (2002[Diabetologia ( ) 45:1325[Diabetologia ( -1331

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Diabetes-Induced Endothelial Dysfunction is Prevented by Long-Term Treatment with the Modified Iron Chelator, Hydroxyethyl Starch Conjugated-Deferoxamine

Cited by 78 publications

References 25 publications

Effects of diabetes and treatment with the antioxidant α-lipoic acid on endothelial and neurogenic responses of corpus cavernosum in rats

Effects of diabetes and treatment with the antioxidant α-lipoic acid on endothelial and neurogenic responses of corpus cavernosum in rats

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

Homocysteine enhances impairment of endothelium-dependent relaxation and guanosine cyclic monophosphate formation in aortae from diabetic rabbits

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