- Original investigation
- Open Access
Aminoguanidine inhibits aortic hydrogen peroxide production, VSMC NOX activity and hypercontractility in diabetic mice
© Oak et al; licensee BioMed Central Ltd. 2009
- Received: 31 July 2009
- Accepted: 30 December 2009
- Published: 30 December 2009
Dysfunctionally uncoupled endothelial nitric oxide synthase (eNOS) is involved in producing reactive oxygen species (ROS) in the diabetic endothelium. The present study investigated whether anti-diabetes drug Aminoguanidine (AG) has any effect on eNOS function and vascular oxidant stress.
Methods and Results
Blood glucose levels were increased to 452.0 ± 15.1 mg/dl in STZ-treated male C57BL/6J mice (148.4 ± 3.2 mg/dl in untreated controls). Aortic productions of NO• and O2•- were measured specifically and sensitively using electron spin resonance. Diabetic mice had a marked increase in aortic O2•- production. Aortic hydrogen peroxide (H2O2) production was also increased in diabetic aortas and significantly attenuated by AG. AG however had only a marginal effect in reducing aortic O2•- production, which corresponded to a minimal effect in improving aortic nitric oxide (NO•) bioavailability. The endothelium-dependent vasodilatation however was modestly but significantly improved by AG, likely consequent to AG-induced reduction in hyper-contractility. N AD(P)H ox idase (NOX)-dependent O2•- production was completely attenuated by AG in endothelium-denuded diabetic aortas.
In summary, despite that AG is not an effective eNOS recoupling agent presumably consequent to its ineffectiveness in preventing endothelial NOX activation, it is inhibitory of aortic H2O2 production, VSMC NOX activity, and hypercontractility in diabetes.
- Electron Spin Resonance
- Vascular Smooth Muscle Cell
- Diabetic Mouse
- Spin Trap
- Vascular Oxidant Stress
Cardiovascular complications are the primary causes of mortality in diabetic patients [1, 2]. Accumulating evidence has demonstrated that increased production of reactive oxygen species (ROS) contributes to etiology of diabetes [3–6] and its cardiovascular complications [4, 6–11]. Various enzymatic systems have been shown responsible for diabetic oxidant stress, including xanthine oxidase , NAD(P)H oxidase [13, 14], and the more recently established, uncoupled endothelial nitric oxide synthase (eNOS) [15, 16]. Oxidant stress contributes to diabetic vascular damages by acceleration of advanced glycation end products (AGEs) formation, modulation of extracellular matrix proteins, promotion of cell proliferation and migration, stimulation of kinases and proinflammatory proteins, and importantly, inactivation of nitric oxide (NO•), all of which are closely associated with the pathogenesis of diabetic vascular complications [17, 18].
Aminoguanidine (AG) is one of the most extensively used inhibitors of AGEs accumulation. Beneficial effects in preventing cardiovascular events in diabetic rats have been observed with AG treatment, likely attributed to its effects on stopping AGE formation . Besides its inhibitory action on AGE formation, AG acts as a competitive and selective inhibitor for inducible nitric oxide synthase (iNOS) . This action of AG has been known to be associated with reduction of peroxinitrite (ONOO-), which has deleterious roles in inducing NO• deficiency and cellular damages through degradation of eNOS cofactor, and inductions of inflammation, lipid peroxidation, protein nitrosylation and DNA fragmentation [18, 21, 22]. Previous investigations have also demonstrated that AG reduced hydrogen peroxide (H2O2) induced intracellular hydroxyl radical formation and apoptosis, further demonstrating a potential antioxidant activity [23, 24]. These multiple actions of AG may improve endothelial function in diabetes independent of its AGE-inhibiting activity [22, 23]. Apart from its beneficial effects, high dose of AG is associated with some adverse effects such as autoimmune symptoms, abnormal liver function, gastrointestinal disturbance, and flu-like symptoms [25, 26]. These side effects are likely related to its structural similarities to hydrazine, an inducing factor of lupus like syndrome, and L-arginine, a substrate of NO• synthase . Thus the potential effect of AG is complex in diabetes associated cardiovascular complication. The direct impact of AG on aortic oxidant stress and eNOS function is completely unknown despite that AG was found to suppress superoxide (O2•-) production, mitochondrial complex III activity and eNOS uncoupling in the kidney [26, 28].
Therefore, in the present study we treated STZ-induced diabetic mice in vivo with AG, and measured aortic O2•- and NO• productions by electron spin resonance (ESR) sensitively and specifically. AG only marginally reduced total aortic O2•- production although it significantly attenuated aortic hydrogen peroxide (H2O2) generation. Endothelium-dependent vasodilatation was modestly yet significantly improved which was accompanied by AG-dependent significant reduction in aortic hypercontractility. N AD(P)H ox idase (NOX)-dependent O2•- production in endothelium-denuded aortas was significantly attenuated by AG, likely contributing to the reduction in phenylephrine (PE)-induced hypercontractility. These data seem to implicate that although AG is ineffective in recoupling eNOS in diabetic aortas, it reduces vascular H2O2 production and hypercontractility in diabetes, which may in part account for its beneficial effects in preventing vascular disease development.
Diabetic mice and drug interventions
Male C57BL/6J mice (6-8 weeks old) were obtained from Jackson Laboratories. Mice were housed in a pathogen-free condition. The Institutional Animal Care and Usage Committee at the University of Chicago and University of California Los Angeles approved the use of animals and experimental procedures. Diabetes was induced by tail vein injection of Streptozocin (STZ, 100 mg/Kg) dissolved in 50 μL of 0.9% saline immediately before use, once a day for three days [15, 29, 30]. Blood glucose was determined using the One Touch Ultra® blood glucose meter (Lifescan) at baseline and on day four post STZ injection for each individual mouse. On day four, STZ diabetic mice were injected with Aminoguanidine (AG)  dissolved in 0.9% saline via tail vein at 100 mg/kg/day for three days. By day seven, animals were sacrificed using CO2 inhalation and whole aorta was removed, cleared from surrounding connective tissues and cut transversely into 2 mm or 3 mm rings for subsequent experiments. Nitric oxide production and vasoreactivity measurement was performed with 2 mm of aorta segments and determination of superoxide and hydrogen peroxide level was conducted with each 3 mm of aorta. This model of diabetes is characterized by acute hyperglycemia. No renal dysfunction occurs during the study period of seven days .
Electron spin resonance measurement of aortic superoxide production
Freshly isolated aortas were placed into chilled modified Krebs/HEPES buffer (composition in mmol/L: 99.01 NaCl, 4.69 KCl, 2.50 CaCl2, 1.20 MgSO4, 1.03 KH2PO4, 25.0 NaHCO3, 20.0 Na-HEPES, and 5.6 glucose [pH 7.4]), cleaned of excessive adventitial tissue, with care taken not to injure the endothelium. The specific O2•- spin trap methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine (CMH, 500 μmol/L, Alexis) solution was prepared freshly in nitrogen gas bubbled Krebs/HEPEs buffer containing diethyldithiocarbamic acid (DETC, 5 μmol/L Sigma) and deferoxamine (25 μmol/L, Sigma). Aortic segment (~3 mm) was then mixed with the spin trap solution and loaded into glass capillary (Fisher Scientific) for analysis of O2•- signal (CM• formed after trapping O2•-) using the electron spin resonance (ESR) spectrometer (Miniscope MS200, Magnettech, Germany). Some of the intact or endothelium-denuded aortic segments were incubated in presence or absence of NSC23766 (200 nmol/L, 90 min) to detect NOX sensitive superoxide production. The ESR settings used were bio-field, 3350; field sweep, 45.00 G (1 G = 0.1 mT); microwave frequency, 9.78 GHz; microwave power 7 dB (20 mW); modulation amplitude, 3000 mG; 4,096 points of resolution; and receiver gain, 700.
Amplex-Red assay for hydrogen peroxide production
Freshly isolated aortic rings (4 × 2 mm) were used for assessment of H2O2 production using a fluorometric horseradish peroxidase assay (Amplex-Red assay, Molecular Probes). Fluorescence was measured (excitation 530 nm and emission 590 nm) after 1 hour incubation at 37°C in dark against background fluorescence of buffer. Polyethylene glycol conjugated catalase (PEG-CAT, 300 U/ml, Sigma)-inhibitable fraction reflects specific H2O2 signal. The rate of H2O2 production was presented as pmol/mg protein/min after calculation according to a standard curve generated using fresh H2O2 in reaction buffer .
Electron spin resonance of aortic nitric oxide production
Freshly isolated aortic rings (6 × 2 mm) were incubated with freshly prepared NO•-specific spin trap Fe2+(DETC)2 (0.5 mmol/L) in modified Kreb's HEPES buffer (KHB) at 37°C for 60 min [spin trap and buffer recipe see above and previous publication , in the presence or absence of calcium ionophore A23187 (10 μmol/L). After the incubation, the aorta in KHB was snap-frozen in liquid nitrogen and loaded into a finger Dewar for analysis with ESR spectrophotometer. The instrument settings were as the followings: bio-field, 3280; field sweep, 77.54 G (1 G = 0.1 mT); microwave frequency, 9.78 GHz; microwave power, 4 dB (40 mW); modulation amplitude, 10 G; 4,096 points of resolution; and receiver gain, 900.
Assessment of vascular reactivity
Freshly prepared aortic rings (2 mm) were placed in organ baths containing modified Kreb's HEPES buffer(recipe see above), aerated with a mixture of 95% oxygen/5% carbon dioxide and maintained at 37°C. After being kept under 5 mN tension for 90 min to stabilize, cumulative tension was measured by a Graz Tissue Bath System (Hugo Sachs Elektronik/Harvard Apparatus GmbH, March Hugstetten, Germany) connected to a The MP100 workstations (BioPac Systems). Relaxation curve to acetylcholine (10-9 to 10-6 M) were assessed in aortic segment after contraction by phenylephrine (PE, 5 μmol/L). Data acquisition process and post-acquisition calculations were performed with AcqKnowledge software (BioPac Systems).
Differences among different groups of means were compared with unpaired t-test for two means and ANOVA for multiple means. Statistical significance was set for p < 0.05. All grouped data shown in the figures were presented as mean ± SEM.
Effect of Aminoguanidine on hyperglycemia
Diabetic mice were created by streptozotocin (STZ) administration. On day of harvest (7-8th day after initial STZ injection, same hereafter), blood glucose was elevated to 452.0 ± 15.1 mg/dl in diabetic mice vs 148.4 ± 3.2 mg/dl in the C57BL6 controls. AG (100 mg/kg/day, same hereafter) treatment since day 4 had no significant effect on STZ induction of hyperglycemia (data not shown).
Effect of Aminoguanidine on aortic superoxide production
Effect of Aminoguanidine on aortic hydrogen peroxide production
Aminoguanidine failed to restore aortic NO• production
Aminoguanidine partially restored endothelium-dependent vasorelaxation: Role of attenuation of hypercontractility?
It is important to emphasize that in the intact endothelium, uncoupled eNOS is the primary source of ROS production 7 days after STZ injection . This is presumably consequent to a transient activation of endothelial NOX based on our in vitro data from cultured aortic endothelial cells . In this earlier study we found that, via transient activation endothelial NOX, angiotensin II (Ang II) induces H2O2 dependent eNOS uncoupling. Indeed, we found that in vivo treatment with Ang II signaling attenuators candesartan or captopril completely prevented eNOS uncoupling in diabetes .
We also found that after removal of endothelium to allow sufficient spin trap penetration to the underneath VSMC, NOX-dependent O2•- production remained elevated by day 7, which was found attenuated by candesartan or captopril previously, and now by AG. Therefore we believe that although AG may not have any effects on the endothelial NOX isoform in contrast to the Ang II attenuators, it is effective in inhibiting the VSMC NOX isoform. We are working on follow-up studies to identify cell-specific NOX isoforms that are involved in the eNOS uncoupling and NOX activation in diabetic endothelial cells and VSMC. These would be however beyond the scope of the present study.
The present study systematically studied effects of AG on vascular oxidant stress, eNOS function and endothelium-dependent vasorelaxation. Whereas AG only partially reduced vascular O2•- production, it attenuated H2O2 production significantly and improved endothelium-dependent vasodilatation, likely via a reduction in NOX-linked hypercontractility. Although AG does not seem to be an effective eNOS recoupling agent like Ang II signaling attenuators , it may still exert beneficial effects via attenuating VSMC NOX activity and H2O2 production.
Oxidant stress has been implicated in micro and macrovascular complication of diabetes . Moreover, excessive generation of O2•- in endothelium by hyperglycemia has been considered one of the major factors involved in accelerating vascular complications. Recent studies have shown that eNOS uncoupling is the primary source of O2•- production in the diabetic endothelium [15, 16], whereas NAD(P)H oxidase remain active in sub-endothelial VSMC . eNOS uncoupling is a phenomenon whereby the enzyme generates O2•- rather than NO•. Previously we established that increased O2•- production in STZ-induced diabetic mice is attributed to eNOS uncoupling, which was significantly attenuated by Ang II signaling blockers . In the present study we examined effects of AGE chain breaker AG in recoupling eNOS and found AG failed to significantly reduce aortic O2•- production in diabetes. AG also failed to significantly restore aortic NO• bioavailability. AG has been used as a iNOS inhibitor because of its structure similarity with L-arginine; and it is also known as a weaker inhibitor for eNOS [27, 38]. Whether or not these are linked to the ineffectiveness of AG in restoring NO• production however, remain unclear.
Despite lack of significant impacts on O2•-/NO• pathway, AG significantly attenuated aortic H2O2 production in diabetic mice. It also significantly, though modestly, improved endothelium-dependent vasodilatation, which is likely consequent to a reduction in hypercontractility that is associated with attenuation of VSMC NOX activity. Ineffective eNOS recoupling agent that is, AG proved to be highly effective in attenuating diabetes-induced aortic hypercontractility.
There have been controversial observations of diabetic hypercontracility given species, age, diabetic type, diabetic stage, and vessel types [14, 39–43]. For instance, a recent study by Su et al., showed that acetylcholine dependent dilation was decreased in diabetes whereas there was no difference between control and diabetic group in response to PE, concluding no specific role of VSMC contraction in type 2 diabetes . Not in agreement with our data, they observed that AG did not alter vasocontraction to PE, indicating that AGE formation is not associated with muscle contraction in type 2 diabetic mesenteric arteries . On the other hand, other studies demonstrated hypercontractility to PE in aortas of STZ-induced diabetes [44, 45]. In agreement with our results, AG normalized the response to PE in STZ diabetic mice without affecting plasma glucose levels . Taken together, our results are consistent with previous observations regarding effect of AG on vascular hypercontraction in conduit vessels of early stage type 1 diabetes, hence indicating a potential beneficial effect of AG for prevention of cardiovascular complication for this particular diabetic type and stage.
It has been hypothesized that the basal hypercontractility is dependent on O2•- in STZ induced diabetic mice . In the denuded aortas of human diabetes, O2•- production was also found elevated . Indeed we have observed that in the endothelium-denuded aortas, AG completely attenuated NOX dependent O2•- production from VSMC (Fig. 5). Theoretically this reduction in O2•- could feed back to the endothelium to partially contribute to preservation of NO• bioavailability. On the other hand, loss of O2•- in VSMC may directly modulate VSMC contractility via undefined mechanisms. It is interesting to speculate that loss of NOX-derived O2•- in diabetic VSMC might underlie AG reduction of hypercontractility.
In summary, AG has been examined systematically for its effects on vascular oxidant stress, eNOS function and endothelium-dependent vasorelaxation. To our knowledge these are first endeavors. This agent was ineffective in reducing plasma glucose levels, partially effective in inhibiting total O2•-, and insignificantly effective in improving NO• bioavailability in diabetes. However, it reduced aortic H2O2 production and improved endothelium-dependent vasorelaxation while diminished hypercontractility of aortas. Whether this is attributed to AG-dependent significant reduction in VSMC NOX activity remains to be further elucidated.
The authors' work is supported by National Heart, Lung and Blood Institute Grants HL-077440, HL-081571, an American Heart Association Grant 0435189N, an American Diabetes Association Award 7-04-RA-16, a Career Development Award from the Schweppe Foundation, and start-up funds from the University of Chicago and University of California Los Angeles (all to H. Cai).
- Laing SP, Swerdlow AJ, Slater SD, Burden AC, Morris A, Waugh NR, Gatling W, Bingley PJ, Patterson CC: Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes. Diabetologia. 2003, 46 (6): 760-765. 10.1007/s00125-003-1116-6.View ArticlePubMedGoogle Scholar
- Paterson AD, Rutledge BN, Cleary PA, Lachin JM, Crow RS: The effect of intensive diabetes treatment on resting heart rate in type 1 diabetes: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Diabetes Care. 2007, 30 (8): 2107-2112. 10.2337/dc06-1441.PubMed CentralView ArticlePubMedGoogle Scholar
- Goth L, Eaton JW: Hereditary catalase deficiencies and increased risk of diabetes. Lancet. 2000, 356 (9244): 1820-1821. 10.1016/S0140-6736(00)03238-4.View ArticlePubMedGoogle Scholar
- Rosen P, Nawroth PP, King G, Moller W, Tritschler HJ, Packer L: The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society. Diabetes Metab Res Rev. 2001, 17 (3): 189-212. 10.1002/dmrr.196.View ArticlePubMedGoogle Scholar
- Sakai K, Matsumoto K, Nishikawa T, Suefuji M, Nakamaru K, Hirashima Y, Kawashima J, Shirotani T, Ichinose K, Brownlee M: Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic beta-cells. Biochem Biophys Res Commun. 2003, 300 (1): 216-222. 10.1016/S0006-291X(02)02832-2.View ArticlePubMedGoogle Scholar
- Ceriello A: New insights on oxidative stress and diabetic complications may lead to a "Causal" antioxidant therapy. Diabetes Care. 2003, 26 (5): 1589-1596. 10.2337/diacare.26.5.1589.View ArticlePubMedGoogle Scholar
- Schmidt AM, Yan SD, Wautier JL, Stern D: Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res. 1999, 84 (5): 489-497.View ArticlePubMedGoogle Scholar
- Cai H, Harrison DG: Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 2000, 87 (10): 840-844.View ArticlePubMedGoogle Scholar
- Feener EP, King GL: Endothelial dysfunction in diabetes mellitus: role in cardiovascular disease. Heart Fail Monit. 2001, 1 (3): 74-82.PubMedGoogle Scholar
- Natarajan R, Gerrity RG, Gu JL, Lanting L, Thomas L, Nadler JL: Role of 12-lipoxygenase and oxidant stress in hyperglycaemia-induced acceleration of atherosclerosis in a diabetic pig model. Diabetologia. 2002, 45 (1): 125-133. 10.1007/s125-002-8253-x.View ArticlePubMedGoogle Scholar
- Cai H, Griendling KK, Harrison DG: The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci. 2003, 24 (9): 471-478. 10.1016/S0165-6147(03)00233-5.View ArticlePubMedGoogle Scholar
- Aliciguzel Y, Ozen I, Aslan M, Karayalcin U: Activities of xanthine oxidoreductase and antioxidant enzymes in different tissues of diabetic rats. J Lab Clin Med. 2003, 142 (3): 172-177. 10.1016/S0022-2143(03)00110-0.View ArticlePubMedGoogle Scholar
- Ouslimani N, Mahrouf M, Peynet J, Bonnefont-Rousselot D, Cosson C, Legrand A, Beaudeux JL: Metformin reduces endothelial cell expression of both the receptor for advanced glycation end products and lectin-like oxidized receptor 1. Metabolism. 2007, 56 (3): 308-313. 10.1016/j.metabol.2006.10.010.View ArticlePubMedGoogle Scholar
- Su J, Lucchesi PA, Gonzalez-Villalobos RA, Palen DI, Rezk BM, Suzuki Y, Boulares HA, Matrougui K: Role of advanced glycation end products with oxidative stress in resistance artery dysfunction in type 2 diabetic mice. Arterioscler Thromb Vasc Biol. 2008, 28 (8): 1432-1438. 10.1161/ATVBAHA.108.167205.PubMed CentralView ArticlePubMedGoogle Scholar
- Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl RA, Warnholtz A: Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res. 2001, 88 (2): E14-22.View ArticlePubMedGoogle Scholar
- Oak JH, Cai H: Attenuation of angiotensin II signaling recouples eNOS and inhibits nonendothelial NOX activity in diabetic mice. Diabetes. 2007, 56 (1): 118-126. 10.2337/db06-0288.View ArticlePubMedGoogle Scholar
- Johansen JS, Harris AK, Rychly DJ, Ergul A: Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice. Cardiovasc Diabetol. 2005, 4 (1): 5-10.1186/1475-2840-4-5.PubMed CentralView ArticlePubMedGoogle Scholar
- Potenza MA, Gagliardi S, Nacci C, Carratu MR, Montagnani M: Endothelial dysfunction in diabetes: from mechanisms to therapeutic targets. Curr Med Chem. 2009, 16 (1): 94-112. 10.2174/092986709787002853.View ArticlePubMedGoogle Scholar
- Stadler K, Jenei V, Somogyi A, Jakus J: Beneficial effects of aminoguanidine on the cardiovascular system of diabetic rats. Diabetes Metab Res Rev. 2005, 21 (2): 189-196. 10.1002/dmrr.501.View ArticlePubMedGoogle Scholar
- Ara C, Karabulut AB, Kirimlioglu H, Yilmaz M, Kirimliglu V, Yilmaz S: Protective effect of aminoguanidine against oxidative stress in an experimental peritoneal adhesion model in rats. Cell Biochem Funct. 2006, 24 (5): 443-448. 10.1002/cbf.1245.View ArticlePubMedGoogle Scholar
- Chowdhury P, Soulsby ME, Scott JL: Effects of aminoguanidine on tissue oxidative stress induced by hindlimb unloading in rats. Ann Clin Lab Sci. 2009, 39 (1): 64-70.PubMedGoogle Scholar
- Szabo C, Ferrer-Sueta G, Zingarelli B, Southan GJ, Salzman AL, Radi R: Mercaptoethylguanidine and guanidine inhibitors of nitric-oxide synthase react with peroxynitrite and protect against peroxynitrite-induced oxidative damage. J Biol Chem. 1997, 272 (14): 9030-9036. 10.1074/jbc.272.14.9030.View ArticlePubMedGoogle Scholar
- Ihm SH, Yoo HJ, Park SW, Ihm J: Effect of aminoguanidine on lipid peroxidation in streptozotocin-induced diabetic rats. Metabolism. 1999, 48 (9): 1141-1145. 10.1016/S0026-0495(99)90128-2.View ArticlePubMedGoogle Scholar
- Giardino I, Fard AK, Hatchell DL, Brownlee M: Aminoguanidine inhibits reactive oxygen species formation, lipid peroxidation, and oxidant-induced apoptosis. Diabetes. 1998, 47 (7): 1114-1120. 10.2337/diabetes.47.7.1114.View ArticlePubMedGoogle Scholar
- Bolton WK, Cattran DC, Williams ME, Adler SG, Appel GB, Cartwright K, Foiles PG, Freedman BI, Raskin P, Ratner RE: Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol. 2004, 24 (1): 32-40. 10.1159/000075627.View ArticlePubMedGoogle Scholar
- Thornalley PJ: Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts. Arch Biochem Biophys. 2003, 419 (1): 31-40. 10.1016/j.abb.2003.08.013.View ArticlePubMedGoogle Scholar
- Alderton WK, Cooper CE, Knowles RG: Nitric oxide synthases: structure, function and inhibition. Biochem J. 2001, 357 (Pt 3): 593-615. 10.1042/0264-6021:3570593.PubMed CentralView ArticlePubMedGoogle Scholar
- Rosca MG, Mustata TG, Kinter MT, Ozdemir AM, Kern TS, Szweda LI, Brownlee M, Monnier VM, Weiss MF: Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am J Physiol Renal Physiol. 2005, 289 (2): F420-430. 10.1152/ajprenal.00415.2004.View ArticlePubMedGoogle Scholar
- Kuttler B, Schneider E: Diabetes mellitus in mice induced by multiple subdiabetogenic doses of streptozotocin: age and sex dependence. Acta Biol Med Ger. 1982, 41 (12): 1199-1202.PubMedGoogle Scholar
- Rees DA, Alcolado JC: Animal models of diabetes mellitus. Diabet Med. 2005, 22 (4): 359-370. 10.1111/j.1464-5491.2005.01499.x.View ArticlePubMedGoogle Scholar
- Shen KP, Lo YC, Yang RC, Liu HW, Chen IJ, Wu BN: Antioxidant eugenosedin-A protects against lipopolysaccharide-induced hypotension, hyperglycaemia and cytokine immunoreactivity in rats and mice. J Pharm Pharmacol. 2005, 57 (1): 117-125. 10.1211/0022357055137.View ArticlePubMedGoogle Scholar
- Tay YC, Wang Y, Kairaitis L, Rangan GK, Zhang C, Harris DC: Can murine diabetic nephropathy be separated from superimposed acute renal failure?. Kidney Int. 2004, 68 (1): 391-398. 10.1111/j.1523-1755.2005.00405.x.View ArticleGoogle Scholar
- Cai H, McNally JS, Weber M, Harrison DG: Oscillatory shear stress upregulation of endothelial nitric oxide synthase requires intracellular hydrogen peroxide and CaMKII. J Mol Cell Cardiol. 2004, 37 (1): 121-125. 10.1016/j.yjmcc.2004.04.012.View ArticlePubMedGoogle Scholar
- Chalupsky K, Cai H: Endothelial dihydrofolate reductase: critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase. Proc Natl Acad Sci USA. 2005, 102 (25): 9056-9061. 10.1073/pnas.0409594102.PubMed CentralView ArticlePubMedGoogle Scholar
- Fleischhacker E, Esenabhalu VE, Spitaler M, Holzmann S, Skrabal F, Koidl B, Kostner GM, Graier WF: Human diabetes is associated with hyperreactivity of vascular smooth muscle cells due to altered subcellular Ca2+ distribution. Diabetes. 1999, 48 (6): 1323-1330. 10.2337/diabetes.48.6.1323.View ArticlePubMedGoogle Scholar
- Chang KC, Chung SY, Chong WS, Suh JS, Kim SH, Noh HK, Seong BW, Ko HJ, Chun KW: Possible superoxide radical-induced alteration of vascular reactivity in aortas from streptozotocin-treated rats. J Pharmacol Exp Ther. 1993, 266 (2): 992-1000.PubMedGoogle Scholar
- El-Remessy AB, Abou-Mohamed G, Caldwell RW, Caldwell RB: High glucose-induced tyrosine nitration in endothelial cells: role of eNOS uncoupling and aldose reductase activation. Invest Ophthalmol Vis Sci. 2003, 44 (7): 3135-3143. 10.1167/iovs.02-1022.View ArticlePubMedGoogle Scholar
- Brooks BA, Heffernan S, Thomson S, McLennan SV, Twigg SM, Yue DK: The effects of diabetes and aminoguanidine treatment on endothelial function in a primate model of type 1 diabetes. Am J Primatol. 2008, 70 (8): 796-802. 10.1002/ajp.20550.View ArticlePubMedGoogle Scholar
- Rodriguez-Manas L, Angulo J, Vallejo S, Peiro C, Sanchez-Ferrer A, Cercas E, Lopez-Doriga P, Sanchez-Ferrer CF: Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature. Diabetologia. 2003, 46 (4): 556-566.PubMedGoogle Scholar
- Pieper GM: Enhanced, unaltered and impaired nitric oxide-mediated endothelium-dependent relaxation in experimental diabetes mellitus: importance of disease duration. Diabetologia. 1999, 42 (2): 204-213. 10.1007/s001250051140.View ArticlePubMedGoogle Scholar
- Hopfner RL, McNeill JR, Gopalakrishnan V: Plasma endothelin levels and vascular responses at different temporal stages of streptozotocin diabetes. Eur J Pharmacol. 1999, 374 (2): 221-227. 10.1016/S0014-2999(99)00316-7.View ArticlePubMedGoogle Scholar
- Schofield I, Malik R, Izzard A, Austin C, Heagerty A: Vascular structural and functional changes in type 2 diabetes mellitus: evidence for the roles of abnormal myogenic responsiveness and dyslipidemia. Circulation. 2002, 106 (24): 3037-3043. 10.1161/01.CIR.0000041432.80615.A5.View ArticlePubMedGoogle Scholar
- Bagi Z, Koller A, Kaley G: PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes. Am J Physiol Heart Circ Physiol. 2004, 286 (2): H742-748. 10.1152/ajpheart.00718.2003.View ArticlePubMedGoogle Scholar
- El-Khatib AS, Moustafa AM, Abdel-Aziz AA, Al-Shabanah OA, El-Kashef HA: Effects of aminoguanidine and desferrioxamine on some vascular and biochemical changes associated with streptozotocin-induced hyperglycaemia in rats. Pharmacol Res. 2001, 43 (3): 233-240. 10.1006/phrs.2000.0772.View ArticlePubMedGoogle Scholar
- Dewhurst M, Stevens EJ, Tomlinson DR: Effects of aminoguanidine and N(G)-nitro-L-arginine methyl ester on vascular responses of aortae and lungs from streptozotocin-diabetic rats. Prostaglandins Leukot Essent Fatty Acids. 1997, 56 (4): 317-324. 10.1016/S0952-3278(97)90576-7.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.