ISSN Chin J Arterioscler, Vol 11, No 1 [ ] (2003) , ) , 2 8 ( P < ), ] R363 [ ] A

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1 22 [ ] (2003) , ( 1.,2., ) [ ] ; ; ; ;, ; ; L2 ; [ ], L2 ;,2 ( molπl molπl, P < 0. 01) 4 8 ( molπl molπl molπl molπl P < 0. 01) ; L2 ( P > 0. 05) ;, 2 8 L2 ( P < ), 2 8, [ ] R363 [ ] A The Changes in Serum Concentration of Endogenous Inhibitor of Nitric Oxide Synthase at Different Stages of Diabetic Duration in Streptozotocin Induced Diabetic Rats XIONG Yan 1, YUAN Li2Wei 1, FU Yun2Feng 1, FU Si2Hai 1, and ZHOU Hong2Hao 2 (1. Department of Pharmacology, School of Pharmaceutic Science, 2. Institute of Clinical Pharmacology, Central South University, Changsha , China) [ KEY WORDS] Diabetic Duration ; Asymmetric Dimethylarginine ; Endogenous Inhibitor of Nitric Oxide Synthase ; Endothelial Dysfunction ; L2Arginine ; Metabolic Control ; Rat [ ABSTRACT] Aim To investigate the time2dependent changes in serum concentrations of endogenous inhibitor of nitric ox2 ide synthase (NOS) asymmetric dimethylarginine (ADMA) in streptozotocin2induced diabetic rats and age2matched control rats, and to determine whether elevated endogenous ADMA is related to metabolic control and is implicated in the endothelium2depen2 dent vasodilation dysfunction of diabetic rats at different stage of diabetic duration. Methods Serum levels of ADMA and L2 arginine were measured by high2performance liquid chromatography at stages of 22, 42 and 82week diabetic duration. Thoracic aor2 tic rings from diabetic rats with different diabetic duration and their age2matched control rats were studied for endothelium2depen2 dent relaxation response to acetylcholine in vitro. Serum concentrations of glucose, glycosylated serum protein, and malondialde2 hyde, derived from lipid peroxidation were also examined to estimate metabolic control. Results Serum levels of ADMA sig2 nificantly elevated in diabetic rats with 22, 42, and 82week diabetic duration compared with their age2matched control rats( molπl vs molπl for 22week, molπl vs molπl for 42week, molπl vs molπl for 82week,n = 5 6,all P < 0. 01), whereas serum levels of L2arginine were not different between control and diabetic rats at stages of 22, 42, and 82week diabetic duration. Accordingly, the ratio of L2arginine and ADMA in diabetic rats was lower than that in their age2matched control rats. This elevation of ADMA was accompanied by impairment of relaxation response to acetylcholine of aortic rings in diabetic rats. Serum levels of glucose, glycosylated serum protein, and malondialde2 hyde were significantly increased in parallel with the elevation of ADMA in diabetic rats with 22, 42, and 82week diabetic duration compared with their age2matched control rats. Conclusion These results reveal that the extent of elevation in serum ADMA [ ] [ ] [ ] ( ) [ ],1960,,,1973,,1939,

2 CN / R in streptozotocin2induced diabetic rats with 22, 42, and 82week diabetic duration is not correlated with the length of diabetic dura2 tion. This elevation of endogenous inhibitor of NOS in diabetic rats may relate to metabolic control of the disease and may be im2 pli2cated in the endothelium2dependent vasodilation dysfunction associated with diabetes. (30 mgπkg,i. p. ), ; Krebs2Henseleit 95 %O 2 5 % ( nitric oxide CO 2 synthase,nos) (asym2 3 mm, metric dimethylarginine,adma), [124 ] 5 ml Krebs2Henseleit (streptozotocin,stz) %O 2 5 %CO min NOS ADMA, 2 g 60 min 60 mmolπl [529 ] KCl, ADMA ;, 1 molπl, molπl NOS, 10 molπl, (phenylephrine, PE) (ace2 NOS ADMA tylcholine,ach) ADMA STZ Sigma ; Fluka ; ;, (glycosylat2 ADMA ed serum protein,gsp),, 1 h, rπmin 15 min, g SD, 1 ml mg, ADMA h, ; STZ ( ph GSP ; molπl (malondialdehyde,mda) ; 100 gπl STZ ) 60 mgπkg ; STZ x s, > 16 mmolπl Student t ANOVA Turkey s t, P < molπl 1. 4

3 ( P > 0. L2 05) ;, L2 2 NOS AD2 ADMA MA, 4 ( P < 0. 01) ; L2 8 ( P < 0. 01) ; NOS ADMA L2 ADMA L2 ( P > ; 1,Table 1) 1. L2 L2 Table 1. The serum concentrations of NG, NG 2 asymmetric dimethylarginine ( ADMA), L2arginine and the ratio of L2arginine and ADMA in streptozotocin2induced diabetic rats with different duration and their age2matched control rats ( x s) L2 ADMA DM L2 ΠADMA DM b b b b b b b : P < 0. 01, 2. 2 ;,2 8 NOS, 2 8 ADMA NOS ADMA ADMA 2 8 ( 2, Table 2) Table 2. The concentrations of plasma glucose, serum glycosylated serum protein ( GSP), malondialdehyde ( MDA) and creatinine (Cr) in streptozotocin2induced diabetic rats with different duration and their age2matched control rats ( x s) GSP (MDA) (Cr) b b b b a b b b b a : P < 0. 05, b : P < 0. 01, ( molπl) ( molπ 1 molπl - L) ( 1A, Figure 1A) ; 4 8,, ( molπl) ( 1B C, Figure 1B and 1C), 10 molπl

4 CN / R x s, 5 6, 3 : P < 0. 05, 3 3 : P < Figure 1. The endothelium2dependent relaxation of thoracic aortic rings from diabetic rats with different duration and their age2 matched rats Data are expressed as x s, n = : P < 0. 05, 3 3 : P < 0. 01,compared with control group. [ ] NOS ADMA,,, NOS ADMA NOS AD2 NOS ADMA MA NOS, 2 [5, ] Ma2 NOS ADMA 4 suda 8 2 ADMA ADMA [6,7 ] Abbasi < 1 1 5,2 NOS ADMA ,

5 26 [8 ] ; NOS ADMA ADMA, NOS ADMA [ ],2 8 NOS ADMA , 17 (2) : [ 20 UΠ( kg d),b. i. d. ] [9 NOS ADMA ] Asaga2 mi [12 ] 2, NOS ADMA,, NOS ADMA ADMA [13, ADMA ] [8 ] ADMA ADMA,., 2000, 8 (3) : ADMA [14 ] ; ADMA, NOS [15 ADMA ], NOS ADMA NOS ADMA ) NOS ADMA [1 ] Yu XJ, Li YJ, Xiong Y. Increase of an endogenous inhibitor of nitric oxide syn2 thesis in serum of high cholesterol fed rabbits. Life Sci, 1994, 54 (12) : 7532 [2 ] Xiong Y, Li YJ, Yu XJ, Liu GZ, Li NS. Endogenous inhibitors of nitric oxide synthesis and lipid peroxidation in hyperlipidemic rabbits. Acta Pharmacol Sin, [3 ] Bgger RH, Bode2B? ger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, et al. Asymmetric dimethylarginine (ADMA) : a novel risk factor for endothelial dys2 function its role in hypercholesterolemia. Circulation, 1998, 98 (18) : [4 ] Surdacki A, Nowicki M, Sandmann J, Tsikas D, Boeger RH, Bode2Boeger SM, et al. Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension. J Car2 diovasc Pharmacol, 1999, 33 (4) : [5 ] Xiong Y, Lu R, Li YJ, Deng HW. Elevation of an endogenous inhibitor of ni2 tric oxide synthase in diabetic rat serum. Acta Pharmacol Sin, 1997, 18 (6) : [6 ] Masuda H, Goto M, Tamaoki S, Azuma H. Accelerated intimal hyperplasia and increased endogenous inhibitors for NO synthesis in rabbits with alloxan2induced hyperglycaemia. Br J Pharmacol, 1999, 126 (1) : [7 ],,,. 2., 2002, 10 (4) : ,,.., 2002, 10 (1) : [9 ] Abbasi F, Asagmi T, Cooke JP, Lamendola C, Mclaughlin T, Reaven GM, et al. Plasma concentrations of asymmetric dimethylarginine are increased in pa2 tients with type 2 diabetes mellitus. Am J Cardiol, 2001, 88 (10) : [10 ],,,,. [11 ]. ADMA., 2003, 19 (2) : [12 ] Asagami T, Abbasi F, Stuelinger M, Lamendola C, Mclaughlin T, Cooke JP, et al. Metformin treatment lowers asymmetric dimethylarginie concentrations in patients with type 2 diabetes. Metabolism, 2002, 51 (7) : [13 ] Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet, 1992, 339 (8793) : [14 ] Kielstein JT, B? ger RH, Bode2Bgger SM, Forlich JC, Haller H, Ritz E, et al. Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J Am Soc Nephrol, 2002, 13 (1) : [15 ] Fleck C, Janz A, Schweitzer F, Karge E, Schwertfeger M, Stein G. Serum concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in renal failure patients. Kidney Int, 2001, 78 (Suppl) : S14218 (

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