Arginine, symmetric and asymmetric dimethylarginine levels in the molsidomine treatment of experimental ischemia-reperfusion retinopathy

This study aimed to evaluate the mean changes in Arginine, Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA) levels in the ischemia/reperfusion (I/R) retinopathy and efficacy of treatment with molsidomine by these levels. Experiments were performed on the New Zealand white rabbits each weighing approximately 2.5 kg. 28 rabbits were assigned to the following 4 groups, group 1 consisted sham, group 2 consisted I/R, group 3 consisted I/R+ treatment with molsidomine, group 4 consisted prophylaxis with molsidomine +I/R. In the group 2, 3 and 4, ischemia was induced by raising the intraocular pressure to 150 mmHg for 60 minutes. After 60 min, the IOP was returned to normal pressure. 4 mg/kg/day molsidomine was administered intraperitoneally four days after I/R in group 3, one day before I/R and three days after I/R in group 4. Arginine, ADMA and SDMA levels were measured on the aqueous humor. The mean arginine levels were 12.3±4.8 μmol/L in group 1, 12.4±1.4 μmol/L in group 2, 13.2±2.4 μmol/L in group 3 and 13.7±4.3 μmol/L in group 4. No difference was present between the groups (p=0.807). The mean ADMA levels were 2.6±0.8 μmol/L, 7.3±2.7 μmol/L, 0.5±0.5 μmol/L and 2.5±1.0 μmol/L respectively. Significant increase was present in the group 2 and significant decrease was present in the group 3 (p=0.001). The mean SDMA levels were 1.0±0.3 μmol/L, 1.8±0.2 μmol/L, 0.3±0.3 μmol/L and 1.0±0.4 μmol/L respectively. Significant increase was present in the group 2 and significant decrease was present in the group 3 (p=0.001). L-Arginine levels were kept steady, ADMA and SDMA values decreased with molsidomine. Four days treatment with molsidomine after I/R may be beneficial more than prophylaxis and three days treatment


1. Schmid H, Renner M, Dick HB, et al. Loss of inner retinal neurons after retinal ischemia in rats. Invest Ophthalmol Vis Sci. 2014;55:2777-87.

2. Zhang XY, Xiao YQ, Zhang Y, et al. Protective effect of pioglitazone on retinal ischemia/reperfusion injury in rats. Invest Ophthalmol Vis Sci. 2013;54:3912-21.

3. Osborne NN, Casson RJ, Wood JP, et al. Retinal ischemia: mechanisms of damage and potential therapeutic strategies. Prog Retin Eye Res. 2004;23:91-147.

4. Riazi-Esfahani M, Kiumehr S, Asadi-Amoli F, et al. Effects of intravitreal morphine administered at different time points after reperfusion in a rabbit model of ischemic retinopathy. Retina. 2009;29:262-8.

5. Loscalzo J, Welch G. Nitricoxide and its role in the cardiovascular system. Prog Cardiovasc Dis. 1995;38:87-104.

6. Johnson G, Tsao PS, Lefer AM. Cardioprotective effects of authentic nitric oxide in myocardial ischemia with reperfusion. Crit Care Med. 1991;19:244-52.

7. Kukovetz WR, Holzmann S. Cyclic GMP as the mediator of molsidomine-induced vasodilatation. Europ J Pharmacol. 1986;122:103-9.

8. Polat N, Ozer MA, Parlakpinar H, et al. Effects of molsidomine on retinal ischemia/reperfusion injury in rabbits. Biotech Histochem. 2018;93:188-97.

9. Toda N, Nakanishi-Toda M. Nitric oxide: ocular blood flow, glaucoma, and diabetic retinopathy. Prog Retin Eye Res. 2007;26:205-38.

10. Javadiyan S, Burdon KP, Whiting MJ, et al. Elevation of serum asymmetrical and symmetrical dimethylarginine in patients with advanced glaucoma. Invest Ophthalmol Vis Sci. 2012;53:1923-7.

11. Tran CT, Leiper JM, Vallance P. The DDAH/ADMA/NOS pathway. Atheroscler Suppl. 2003;44:33-40.

12. Zinellu A, Pinna A, Sotgia S, et al. Increased plasma asymmetric dimethylarginine (ADMA) levels in retinal venous occlusive disease. Clin Chem Lab Med. 2008;46:387-92.

13. Colak C, Parlakpınar H. Hayvan Deneyleri: In vivo Denemelerin Bildirimi: ARRIVE Kılavuzu-Derleme. J Turgut Ozal Med Cent. 2012;19:128-31.

14. Bentli R, Parlakpinar H, Polat A, et al. Molsidomine Prevents Cisplatin-induced Hepatotoxicity. Arch Med Res. 2013;4:521-8.

15. Narayanan SP, Rojas M, Suwanpradid J, et al. Arginase in retinopathy. Prog Retin Eye Res. 2013;36:260-80.

16. Romero MJ, Platt DH, Tawfik HE, et al. Diabetes-induced coronary vascular dysfunction involves increased arginase activity. Circ Res. 2008;102:95-102.

17. White AR, Ryoo S, Li D, et al. Knockdown of arginase I restores NO signaling in the vasculature of old rats. Hypertension. 2006;47:245-51.

18. Kaesemeyer WH, Ogonowski AA, Jin L, et al. Endothelial nitric oxide synthase is a site of superoxide synthesis in endothelial cells treated with glyceryl trinitrate. Br J Pharmacol. 2000;131:1019-23.

19. Morris SM Jr. Regulation of enzymes of urea and arginine synthesis. Annu Rev Nutr. 1992;12:81-101.

20. Thengchaisri N, Hein TW, Wang W, et al. Upregulation of arginase by H2O2 impairs endothelium-dependent nitric oxide-mediated dilation of coronary arterioles. Arterioscler Thromb Vasc Biol. 2006;26:2035-42.

21. El-Remessy AB, Tawfik HE, Matragoon S, et al. Peroxynitrite mediates diabetes-induced endothelial dysfunction: possible role of Rho kinase activation. Exp Diabetes Res. 2010;2010:247861.

22. Chen YH, Xu X, Sheng MJ, et al. Effects of asymmetric dimethylarginine on bovine retinal capillary endothelial cell proliferation, reactive oxygen species production, permeability, intercellular adhesion molecule-1, and occludin expression. Mol Vis. 2011;17:332-40.

23. Sugai M, Ohta A, Ogata Y, et al. Asymmetric dimethylarginine (ADMA) in the aqueous humour of diabetic patients. Endocr J. 2007;54:303-9.

24. Yoshida Y, Yamagishi S, Ueda S, et al. Aqueous humour levels of asymmetric dimethylarginine (ADMA) are correlated with pigment epithelium-derived factor (PEDF) in patients with uveitis. J Int Med Res. 2007;35:892-5.

25. Yoshida Y, Yamagishi S, Ueda S, et al. Aqueous humor levels of asymmetric dimethylarginine (ADMA) are positively associated with monocyte chemoattractant protein-1 (MCP-1) in patients with uveitis. Br J Ophthalmol. 2008;92:93-4.

26. Tosun M, Erdurmus M, Bugdayci G, et al. Aqueous humour and serum concentration of asymmetric dimethyl arginine in pseudoexfoliation syndrome. Br J Ophthalmol. 2012;96:1137-40.

27. Abhary S, Kasmeridis N, Burdon KP, et al. Diabetic retinopathy is associated with elevated serum asymmetric and symmetric dimethylarginines. Diabetes Care. 2009;32:2084-6.

28. Chen S, Li N, Deb-Chatterji M, et al. Asymmetric dimethyarginine as marker and mediator in ischemic stroke. Int J Mol Sci. 2012;13:15983-6004.

29. Martín-Sanz P, Olmedilla L, Dulin E, et al. Presence of methylated arginine derivatives in orthotopic human liver transplantation: relevance for liver function. LiverTranspl. 2003;9:40-8.

30. Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethyl arginine: dimethylarginine dimethyl amino hydrolase pathway. Arterioscler Thromb Vasc Biol. 2004;24:1023-30.

31. Sydow K, Munzel T. ADMA and oxidative stress. Atheroscler Suppl. 2003;4:41-51

32. Yonem A, Duran C, Unal M, et al.. Plasma apelin and asymmetric dimethylarginine levels in type 2 diabetic patients with diabetic retinopathy. Diabetes Res Clin Pract. 2009;84:219-23.

Kaynak Göster