Effects of aminoguanidine treatment on endothelial nitric oxide synthase expression and nitric oxide levels in streptozotocin induced diabetic rats

Yıl 2016, Cilt: 3 Sayı: 5, 225 - 229, 15.05.2016

Ilker Parmaksiz Onder Sirikci Serpil Bilsel Humeyra Akdeniz Dilek Yavuz

Öz

Objective: Formation of advanced glycation end products (AGE) in Diabetes Mellitus contribute to endothelial dysfunction by permanent modifications of proteins and decrease NO concentration which regulate vascular tonicity and thus endothelial functions. We investigated the effects of AGE inhibitor aminoguanidine (AG) treatment on endothelial nitric oxide synthase (eNOS) expression and NO levels in streptozotocin induced diabetic rats.

Material and method: 38 male Sprague-Dawley rats were separated into 4 groups. Group 1 was healthy controls without any intervention (HC group). Group 2 received AG in drinking water (HC+AG group). Third and fourth groups received 65 mg/kg streptozotocin intraperitoneally to induce diabetes. Group 3 was followed without further intervention (DM group). Group 4 received aminoguanidine in drinking water (DM+AG group). After 12 weeks, glucose, HbA_1c, NO levels an eNOS expressions were determined.

Results: NO levels were significantly lower in DM and HC+AG groups compared to HC group. There was no significant difference between the NO levels of DM and DM+AG groups. eNOS protein levels in heart tissues were significantly lower in DM group than the HC group. eNOS levels were significantly higher in DM+AG than DM group. There was no significant difference in eNOS levels in kidney tissues among the groups.

Conclusion: Decreased NO levels in DM group was consistent with the literature. eNOS expression in heart tissues were decreased in DM group, their concentration were increased with AG therapy. Further studies are needed to elaboate the effects of AG in tissues and the side effects observed in some studies.

Anahtar Kelimeler

Diabetes Mellitus; Streptozotocin; Aminoguanidine; Nitric Oxide

Kaynakça

• Kılınç A, Kılınç K. Nitrik oksit: Palme Yayıncılık, 2003.
• Chatterjee A, Black SM, Catravas JD. Endothelial nitric oxide (NO) and its pathophysiologic regulation. Vascul Pharmacol. 2008;49(4-6):134-40.
• Schalkwijk CG, Stehouwer CD. Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci (Lond). 2005;109(2):143-59.
• Yavuz DG, Ersoz HO, Tuncel M, Sargon MF, Kucukkaya B, Ahiskali R, et al. Effects of aminoguanidine on glomerular basement membrane thickness and anionic charge in a diabetic rat model. Int J Exp Diabetes Res. 2001;2(3):225-32.
• Öntürk H, Özbek H. Deneysel diyabet oluşturulması ve kan şeker seviyesinin ölçülmesi. Genel tıp dergisi. 2007;17(4):231-6.
• Trinder P. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem. 1969;6:24-7.
• Recipe. Hemoglobin A1c (HbA1c) in Whole Blood (for Variant™ and Modular HPLC Systems). 2012.
• Kielbasa W, Fung HL. Nitrite inhalation in rats elevates tissue NOS III expression and alters tyrosine nitration and phosphorylation. Biochem Biophys Res Commun. 2000;275(2):335-42.
• McMurtry MS, Kim DH, Dinh-Xuan T, Archer SL. Measurement of nitric oxide, nitrite and nitrate using a chemiluminescence assay:an update for the year 2000. Analusis. 2000;28(6):455-65.
• Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-75.
• Tojo A, Kimoto M, Wilcox CS. Renal expression of constitutive NOS and DDAH: separate effects of salt intake and angiotensin. Kidney Int. 2000;58(5):2075-83.
• BIO-RAD. Opti-4CN™ Substrate Kit. Available from:
• http://www.bio-rad.com/webroot/web/pdf/lsr/literature/4100130.pdf
• Stehouwer CD, Lambert J, Donker AJ, van Hinsbergh VW. Endothelial dysfunction and pathogenesis of diabetic angiopathy. Cardiovasc Res. 1997;34(1):55-68.
• Tahara Y, Shima K. Kinetics of HbA1c, glycated albumin, and fructosamine and analysis of their weight functions against preceding plasma glucose level. Diabetes Care. 1995;18(4):440-7.
• Ahmed N. Advanced glycation endproducts--role in pathology of diabetic complications. Diabetes Res Clin Pract. 2005;67(1):3-21.
• Wautier JL, Guillausseau PJ. Advanced glycation end products, their receptors and diabetic angiopathy. Diabetes Metab. 2001;27(5 Pt 1):535-42.
• Thornalley PJ. Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts. Arch Biochem Biophys. 2003;419(1):31-40.
• Durante W, Sen AK, Sunahara FA. Impairment of endothelium-dependent relaxation in aortae from spontaneously diabetic rats. Br J Pharmacol. 1988;94(2):463-8.
• Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation. 1993;88(6):2510-6.
• Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol. 1996;27(3):567-74.
• Srinivasan S, Hatley ME, Bolick DT, Palmer LA, Edelstein D, Brownlee M, et al. Hyperglycaemia-induced superoxide production decreases eNOS expression via AP-1 activation in aortic endothelial cells. Diabetologia. 2004;47(10):1727-34.
• Cosentino F, Hishikawa K, Katusic ZS, Luscher TF. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation. 1997;96(1):25-8.
• Hoshiyama M, Li B, Yao J, Harada T, Morioka T, Oite T. Effect of high glucose on nitric oxide production and endothelial nitric oxide synthase protein expression in human glomerular endothelial cells. Nephron Exp Nephrol. 2003;95(2):e62-8.
• Pieper GM, Siebeneich W, Moore-Hilton G, Roza AM. Reversal by L-arginine of a dysfunctional arginine/nitric oxide pathway in the endothelium of the genetic diabetic BB rat. Diabetologia. 1997;40(8):910-5.
• Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, et al. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation. 2002;106(8):987-92.
• Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114(6):597-605.