Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter April 7, 2015

Therapeutic interventions using a combination of Telmisartan and omega 3-fatty acids in sodium arsenite-induced vascular endothelial dysfunction in rats: modulation through ATP-sensitive K+ channels and eNOS

  • Abhijit Nirwane , Vivek Pawar and Anuradha Majumdar EMAIL logo


Background: Effective diet/drug combinations may show additive or synergistic effects in reducing endothelial risk factors vis-à-vis monotherapies. The study evaluated the effect of combined therapy of Telmisartan and omega 3-fatty acids in sodium arsenite-induced vascular endothelial dysfunction (VED) in rats.

Methods: Forty-eight male Wistar rats (180–220 g) were randomized into eight groups; control, sodium arsenite (1.5 mg/kg/day) exposed, sodium arsenite exposure followed by treatment with Telmisartan, omega 3-fatty acids, the combination and/or endothelial modulators for 2 weeks depending on the allocated group. VED was assessed by estimating vascular reactivity. Serum thiobarbituric acid-reactive substances (TBARS), nitrite/nitrate levels, reduced glutathione (GSH) levels, superoxide dismutase (SOD) activity, serum cholesterol and triglyceride levels were also determined.

Results: Sodium arsenite produced VED by attenuating acetylcholine-induced endothelial relaxation (% Rmax= 45.36), decreasing levels of serum nitrite/nitrate (9.28 μM/mg protein), GSH (16.06 μg/mg of protein), SOD activity (30.69 units/mg protein) and increasing TBARS (0.19 µM/mg protein) compared with control group. The combined therapy with Telmisartan (10 mg/kg/day) and omega 3-fatty acids (180 mg/kg/day) (% Rmax=80.93, 13.09 µM/mg protein, 25.93 μg/mg of protein, 57.84 units/mg protein and 0.08 µM/mg protein, respectively) significantly abolished the respective derangements induced by sodium arsenite. Further, this combination significantly prevented rise in serum cholesterol and triglyceride levels that was induced by sodium arsenite. However, the ameliorative effects of this combination were abated by N-omega-nitro-L-arginine methyl ester (L-NAME) and glibenclamide.

Conclusions: Combined therapy of Telmisartan and omega 3-fatty acids attenuated VED, by activating enzyme nitric oxide synthase (eNOS) through opening of ATP-sensitive K+ channels.

Author contributions

All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding

None declared.

Employment or leadership

None declared.


None declared.

Competing interests

The funding organization(s) played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


1. RubanyiGM. The role of endothelium in cardiovascular homeostasis and diseases. J Cardiovasc Pharmacol1993;22:S114.10.1097/00005344-199322004-00002Search in Google Scholar

2. StamlerJS, LamasS, FangFC. Nitrosylation. The prototypic redox-based signaling mechanism. Cell2001;106:67583.Search in Google Scholar

3. AvogaroA, AlbieroM, MenegazzoL, de KreutzenbergS, FadiniGP. Endothelial dysfunction in diabetes the role of reparatory mechanisms. Diabetes Care2011;34:S28590.10.2337/dc11-s239Search in Google Scholar

4. LntJ. Characteristics of environmental geochemistry in the arseniasis area of the inner Mongolia of China. Sci Geogr Sin1999;19:1359.Search in Google Scholar

5. ChiouHY, ChiouST, HsuYH, ChouYL, TsengCH, WeiML, ChenCJ. Incidence of transitional cell carcinoma and arsenic in drinking water: a follow-up study of 8,102 residents in an arseniasis-endemic area in northeastern Taiwan. Am J Epidemiol2001;153:41118.10.1093/aje/153.5.411Search in Google Scholar

6. RahmanMM, MandalBK, ChowdhuryTR, SenguptaMK, ChowdhuryUK, LodhD, ChandaCR, BasuGK, MukherjeeSC, SahaKC, ChakrabartiD.. Arsenic groundwater contamination and sufferings of people in north 24-parganas, one of the nine arsenic affected districts of West Bengal, India. J Environ Sci Health Part A2003;38:2559.10.1081/ESE-120016658Search in Google Scholar

7. Navas-AcienA, SharrettAR, SilbergeldEK, SchwartzBS, NachmanKE, BurkeTA, GualiarE. Arsenic exposure and cardiovascular disease: a systematic review of the epidemiologic evidence. Am J Epidemiol2005;162:103749.10.1093/aje/kwi330Search in Google Scholar

8. WangCH, HsiaoCK, ChenCL, HsuLI, ChiouHY, ChenSY, HsuehYM, WuMM, ChenCJ. A review of the epidemiologic literature on the role of environmental arsenic exposure and cardiovascular diseases. Toxicol Appl Pharmacol2007;222:31526.10.1016/j.taap.2006.12.022Search in Google Scholar

9. SantraA, MaitiA, ChowdhuryA, Guha MazumderDN. Oxidative stress in liver of mice exposed to arsenic-contaminated water. Ind J Gastroenterol2000;19:11215.Search in Google Scholar

10. AposhianHV. Enzymatic methylation of arsenic species and other new approaches to arsenic toxicity. Annu Rev Pharmacol Toxicol1997;27:397419.10.1146/annurev.pharmtox.37.1.397Search in Google Scholar

11. BoyerJL. Arsenic: an endothelial cell toxin in the liver?Ind J Gastroenterol1999;18:1412.Search in Google Scholar

12. BeresJ. Interactive relations between Cu, FC, Zn, as, Cd & Pb in the liver in sheep after experimental poisoning with copper oxide. Vet Med Praka1989;34:66574.Search in Google Scholar

13. GhoshA, GhatakS, DattaS, DhaliGK, ChoudhuryA, SantraA. Dimethyl arsenic acid induced apoptosis of hepatocytes is mediated through mitochondria. An Vitro Study. Ind J Gastroenterol2007;26:487.Search in Google Scholar

14. DizikM, ChristmasJK, WenatonE. Alternatives in expression and methylation of specific genes in livers of rats fed a cancer promoting methyl deficient diet. Carcinogenesis1991;12:130312.10.1093/carcin/12.7.1307Search in Google Scholar

15. ZapisekWF, CroninGM, Lyn-CookBD, PoirierLA. The onset of oncogene hypomethylation in the livers of rats fed methyl-deficient, amino acid-defined diets. Carcinogenesis1992;13:186972.10.1093/carcin/13.10.1869Search in Google Scholar

16. MuellerPD, BenowitzNL. Toxicologic causes of acute abdominal disorders. Emerg Med Clin North Am1989;7:66782.10.1016/S0733-8627(20)30760-4Search in Google Scholar

17. MaillardMP, PerregauxC, CentenoC, StangierJ, WienenW, BrunnerHR, BurnierM. In vitro and in vivo characterization of the activity of telmisartan: an insurmountable angiotensin ii receptor antagonist. J Pharmacol Exp Ther2002;302:108995.10.1124/jpet.102.036772Search in Google Scholar

18. FukudaD, EnomotoS, HirataY, NagaiR, SataM. The angiotensin receptor blocker, telmisartan, reduces and stabilizes atherosclerosis in ApoE and AT1aR double deficient mice. Biomed Pharmacother2010;64:71217.10.1016/j.biopha.2010.09.014Search in Google Scholar

19. FukudaD, SataM. Expanded roles of the renin-angiotensin system. Hypertens Res2013;36:5867.10.1038/hr.2013.27Search in Google Scholar

20. OnoY, NakayaY, BandoS, SoekiT, ItoS, SataM. Telmisartan decreases plasma levels of asymmetrical dimethyl-l-arginine and improves lipid and glucose metabolism and vascular function. Int Heart J2009;50:738310.1536/ihj.50.73Search in Google Scholar

21. EspositoK, MarfellaR, CiotolaM, Di PaloC, GiuglianoF, GiuglianoG, D‘ArmientoM, D‘AndreaF, GiuglianoD. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. J Am Med Assoc2004;292:14406.10.1001/jama.292.12.1440Search in Google Scholar

22. EstruchR, Martínez-GonzálezMA, CorellaD, Salas-SalvadóJ, Ruiz-GutiérrezV, CovasMI, FiolM, Gómez-GraciaE, López-SabaterMC, VinyolesE, ArósF, CondeM, LahozC, LapetraJ, SáezG, RosE. Effects of a Mediterranean-style diet on cardiovascular risk factors a randomized trial. Ann Intern Med2006;145:111.10.7326/0003-4819-145-1-200607040-00004Search in Google Scholar

23. DinJN, NewbyDE, FlapanAD. Omega 3 fatty acids and cardiovascular disease fishing for a natural treatment. BMJ2004;328:305.10.1136/bmj.328.7430.30Search in Google Scholar

24. MittraS, SinghM. Possible mechanism of captopril induced endothelium-dependent relaxation in isolated rabbit aorta. Mol Cell Biochem1998;183:637.Search in Google Scholar

25. SongD, ArikawaE, GalipeauDM, YehJH, BattellML, YuenVG, McNeillJHChronic estrogen treatment modifies insulin-induced insulin resistance and hypertension in ovariectomized rats. Am J Hypertens2005;18:118994.10.1016/j.amjhyper.2005.04.003Search in Google Scholar

26. WongCM, YaoX, AuCL, TsangSY, FungKP, LaherI, VanhouttePM, HuangY. Raloxifene prevents endothelial dysfunction in aging ovariectomized female rats. Vasc Pharmacol2006;44: 2908.10.1016/j.vph.2005.12.005Search in Google Scholar

27. MaFX, LiuLY, XiongXM. Protective effects of lovastatin on vascular endothelium injured by low density lipoprotein. Acta Pharmacol Sin2003;24:102732.Search in Google Scholar

28. MisraHP, FridovichI. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem1972;247:31705.10.1016/S0021-9258(19)45228-9Search in Google Scholar

29. MoronMS, DepierreJW, MannervikB. Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta1979;582:6778.10.1016/0304-4165(79)90289-7Search in Google Scholar

30. CortasNK, WakidNW. Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. Clin Chem1990;36:14403.10.1093/clinchem/36.8.1440Search in Google Scholar

31. AllainCC, PoonLS, ChenCS, RichmondW, FuPC. Enzymatic determination of total serum cholesterol. Clin Chem1974;20:4705.10.1093/clinchem/20.4.470Search in Google Scholar

32. McGowanMW, ArtissJD, StrandberghDR, ZakB. A peroxidase-coupled method for the colorimetric determination of serum triglycerides. Clin Chem1983;29:53842.10.1093/clinchem/29.3.538Search in Google Scholar

33. AndersonTJ, UehataA, GerhardMD, MeredithIT, KnabS, DelagrangeD, LiebermanEH, GanzP, CreagerMA, YeungAC. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol1995;26:12354110.1016/0735-1097(95)00327-4Search in Google Scholar

34. KinlayS, GanzP. Role of endothelial dysfunction in coronary artery disease and implications for therapy. Am J Cardiol1997;80:11-I16-I.10.1016/S0002-9149(97)00793-5Search in Google Scholar

35. AmbringA, FribergP, AxelsenM, LaffrenzenM, TaskinenMR, BasuS, JohanssonM. Effects of a Mediterranean-inspired diet on blood lipids, vascular function and oxidative stress in healthy subjects. Clin Sci2004;106:51926.10.1042/CS20030315Search in Google Scholar PubMed

36. VaradyKA, BhutaniS, KlempelMC, PhillipsSA. Improvements in vascular health by a low-fat diet, but not a high-fat diet, are mediated by changes in adipocyte biology. Nutr J2011;10:8.10.1186/1475-2891-10-8Search in Google Scholar PubMed PubMed Central

37. SpenceJD. Importance of diet in vascular prevention: vastly underestimated. Circulation2002;106:e133.10.1161/01.CIR.0000035930.42911.B4Search in Google Scholar PubMed

38. Kris-EthertonPM, HarrisWS, AppelLJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation2002;106:274757.10.1161/01.CIR.0000038493.65177.94Search in Google Scholar

39. ChungJY, YuSD, HongYS. Environmental source of arsenic exposure. J Prev Med Public Health2014;47:2537.10.3961/jpmph.14.036Search in Google Scholar PubMed PubMed Central

40. SinghAP, GoelRK, KaurT. Mechanisms pertaining to arsenic toxicity. Toxicol Int2011;18:8793.10.4103/0971-6580.84258Search in Google Scholar PubMed PubMed Central

41. HaghighiMK, PollockD. The possible involvement of nitric oxide/endothelium derived relaxing factor in atropine-induced vasorelaxation. Iran Biomed J2001;5:1339.Search in Google Scholar

42. StiusoP, ScognamiglioI, MuroloM, FerrantiP, De SimoneC, RizzoMR, ConcettaT, CaragliaM, Federico, A. Serum oxidative stress markers and lipidomic profile to detect NASH patients responsive to an antioxidant treatment: a pilot study. Oxid Med Cell Longev2014;18.10.1155/2014/169216Search in Google Scholar PubMed PubMed Central

43. DursunB, DursunE, SuleymanlarG, OzbenB, CaprazI, ApaydinA, OzbenT. Carotid artery intima-media thickness correlates with oxidative stress in chronic haemodialysis patients with accelerated atherosclerosis. Nephrol Dial Transplant2008;23:1697703.10.1093/ndt/gfm906Search in Google Scholar PubMed

44. PadovaniAM, MolinaMF, MannKK. Inhibition of liver x receptor/retinoid x receptor-mediated transcription contributes to the proatherogenic effects of arsenic in macrophages in vitro. Arterioscler Thromb Vasc Biol2010;30:122836.10.1161/ATVBAHA.110.205500Search in Google Scholar PubMed

45. BensonSC, PershadsinghHA, HoCI, ChittiboyinaA, DesaiP, PravenecM, QiN, WangJ, AveryMA, KurtzTW. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension2004;43:9931002.10.1161/01.HYP.0000123072.34629.57Search in Google Scholar PubMed

46. CalderPC. N-3 fatty acids and cardiovascular disease: evidence explained and mechanisms explored. Clin Sci2004;107:111.10.1042/CS20040119Search in Google Scholar PubMed

47. GrossiniE, MolinariC, CaimmiPP, UbertiF, VaccaG. Levosimendan induces NO production through P38 MAPK, ERK and Akt in porcine coronary endothelial cells: role for mitochondrial K(ATP) channel. Br J Pharmacol2009;156:25061.10.1111/j.1476-5381.2008.00024.xSearch in Google Scholar PubMed PubMed Central

48. ZongF, ZuoXR, WangQ, ZhangSJ, XieWP, WangH. Iptakalim rescues human pulmonary artery endothelial cells from hypoxia-induced nitric oxide system dysfunction. Exp Ther Med2012;3:5359.10.3892/etm.2011.414Search in Google Scholar PubMed PubMed Central

49. KaurJ, ReddyK, BalakumarP. The novel role of fenofibrate in preventing nicotine and sodium arsenite-induced vascular endothelial dysfunction in the rat. Cardiovasc Toxicol2010;10:22738.10.1007/s12012-010-9086-7Search in Google Scholar PubMed

50. TomaiF, CreaF, GaspardoneA, VersaciF, De PaulisR, de PeppoAP, ChiarielloL, GioffrèPA. Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Circulation1994;90:7005.10.1161/01.CIR.90.2.700Search in Google Scholar

Received: 2015-2-13
Accepted: 2015-3-12
Published Online: 2015-4-7
Published in Print: 2015-6-1

©2015 by De Gruyter

Downloaded on 9.12.2023 from
Scroll to top button