No abstract

OBJECTIVEDiabetes is associated with vascular oxidative stress, activation of NADPH oxidase, and uncoupling of nitric oxide (NO) synthase (endothelial NO synthase [eNOS]). Pentaerithrityl tetranitrate (PETN) is an organic nitrate with potent antioxidant properties via induction of heme oxygenase-1 (HO-1). We tested whether treatment with PETN improves vascular dysfunction in the setting of experimental diabetes.RESEARCH DESIGN AND METHODSAfter induction of hyperglycemia by streptozotocin (STZ) injection (60 mg/kg i.v.), PETN (15 mg/kg/day p.o.) or isosorbide-5-mononitrate (ISMN; 75 mg/kg/day p.o.) was fed to Wistar rats for 7 weeks. Oxidative stress was assessed by optical methods and oxidative protein modifications, vascular function was determined by isometric tension recordings, protein expression was measured by Western blotting, RNA expression was assessed by quantitative RT-PCR, and HO-1 promoter activity in stable transfected cells was determined by luciferase assays.RESULTSPETN, but not ISMN, improved endothelial dysfunction. NADPH oxidase and serum xanthine oxidase activities were significantly reduced by PETN but not by ISMN. Both organic nitrates had minor effects on the expression of NADPH oxidase subunits, eNOS and dihydrofolate reductase (Western blotting). PETN, but not ISMN, normalized the expression of GTP cyclohydrolase-1, extracellular superoxide dismutase, and S-glutathionylation of eNOS, thereby preventing eNOS uncoupling. The expression of the antioxidant enzyme, HO-1, was increased by STZ treatment and further upregulated by PETN, but not ISMN, via activation of the transcription factor NRF2.CONCLUSIONSIn contrast to ISMN, the organic nitrate, PETN, improves endothelial dysfunction in diabetes by preventing eNOS uncoupling and NADPH oxidase activation, thereby reducing oxidative stress. Thus, PETN therapy may be suited to treat patients with cardiovascular complications of diabetes.

Objective: In previous studies we and others have shown that streptozotocin (STZ)-induced diabetes in rats is associated with vascular oxidative stress and dysfunction. In the present study, we sought to determine whether vascular dysfunction and oxidative stress strictly depend on insulin deficiency. Methods: The effects of insulin (2.5 U/day s.c., 2 weeks) therapy on vascular disorders in STZ-induced (60 mg/kg i.v., 8 weeks) diabetes mellitus (type I) were studied in Wistar rats. The contribution of NADPH oxidase to overall oxidative stress was investigated by in vivo (30 mg/kg/day s.c., 4 days) and in vitro treatment with apocynin. Results: Insulin therapy completely normalized blood glucose, body weight, vascular dysfunction and oxidative stress as well as increased cardiac reactive oxygen and nitrogen species formation in diabetic rats, although diabetes was already established for 6 weeks before insulin therapy was started for the last 2 weeks of the total treatment interval. Apocynin normalized cardiac NADPH oxidase activity, and L-NAME effects suggest a role for uncoupled endothelial nitric oxide synthase in diabetic vascular complications. Conclusions: Our findings indicate that STZ-induced diabetes is a model of insulin-dependent diabetes (type 1) and that cardiovascular complications are probably not associated with systemic toxic side effects of STZ.

No abstract

Diels-Alder reactions of the (lH-indol-3-yl)-enacetamides and -endiacetamides l a 4 with some carbodienophiles and 4-phenyl-3H-l,2,4-triazole-3,5(4H)-dione give rise to the novel amino-functionalized carbazoles 4 6 and 8 (Scheme 3). Ethenetetracarbonitrile reacts with l b to furnish the Michael-type adduct 7 (Scheme 3). Structural aspects of the starting materials 1, which exhibit above all 3-vinyl-1H-indole reactivity, are discussed with regard to the prediction of a Diels-Alder process.Introduction. -Diels-Alder reactions of 2-and 3-vinyl-1 H-indoles as 4n -electron components are now well established as a versatile procedure for the regio-and stereoselectively controlled syntheses of [blannelated indoles and/or carbazoles [ 1-51. This methodology should also be useful for the synthesis of compounds B functionalized with alkoxy, alkylthio, or amino groups (see A -+ B, Scheme 1) which could be of interest as building blocks in alkaloid chemistry [6] and/or in the development of pharmacologically active lead compounds [7]. The Diels-Alder reactivity of the precursor 3-vinyl-lH-indoles A has only been sparsely explored in the case of alkoxy-

No abstract

No abstract

No abstract