Skip to main content
SpringerLink
Log in

Temporal effects of low-dose ACE inhibition on endothelial function in Type 1 diabetic patients

  • Original Articles
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Aim: Increased asymmetrical dimethylarginine (ADMA) is known to disturb endothelial function. ACE inhibitors decrease plasma ADMA levels in diseases associated with endothelial dysfunction. The effects of ACE inhibition on endothelial function and plasma ADMA levels in Type 1 diabetic patients was evaluated in the study. Methods: Thirty Type 1 diabetic patients [29±6 yr; females (F)/males (M): 18/12] and 29 controls (30±6 yr; F/M: 16/13) were recruited. Flow-mediated dilatation (FMD), plasma ADMA and thiobarbituric acid reactive substances (TBARs) were determined at baseline, on day 15 and 90 of 0.5 mg qd trandolapril therapy. Results: Compared to controls, baseline FMD levels were lower (4.7±2.0% vs 11.2±3.9%) (p<0.001), plasma ADMA (271.1±48.1 nmol/l vs 237.5±25.1 nmol/l) (p<0.05) and TBARs levels [4517.1±2366.9 nmol/malondialdehyde (MDA) vs 1775.9±598.7 nmol/MDA] (p<0.001) were higher in diabetic patients. On day 90 of trandolapril treatment, FMD (8.6±4.1%) (p<0.01) increased, ADMA levels (229.6±42.9 nmol/l) (p<0.001) decreased and TBARs levels (1531.8±1036.0 nmol/MDA) (p<0.001) decreased significantly. FMD was negatively correlated with plasma ADMA (r=-0.228, p<0.01), and TBARs levels (r=−0.244, p=0.02), whereas ADMA and TBARs levels were correlated positively (r=0.399, p<0.0001). Conclusions: In conclusion, endothelial dysfunction is associated with elevated plasma ADMA levels in Type 1 diabetic patients. Low-dose ACE inhibition improves endothelial dysfunction and reduces ADMA levels. The antioxidant action of ACE inhibitors may play role in this process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

References

  1. Berliner JA, Navab M, Fogelman AM, et al. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation 1995, 91: 2488–96.

    Article  PubMed  CAS  Google Scholar 

  2. Myrup B, Mathiesen ER, Ronn B, Deckert T. Endothelial function and serum lipids in the course of developing microalbuminuria in insulin-dependent diabetes mellitus. Diabetes Res 1994, 26: 33–9.

    PubMed  CAS  Google Scholar 

  3. 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: 2510–6.

    Article  PubMed  CAS  Google Scholar 

  4. Mullen MJ, Clarkson P, Donald AE, et al. Effect of enalapril on endothelial function in young insulin-dependent diabetic patients: a randomized, double-blind study. J Am Coll Cardiol 1998, 31: 1330–5.

    Article  PubMed  CAS  Google Scholar 

  5. Jorgensen RG, Russo L, Mattioli L, Moore WV. Early detection of vascular dysfunction in type I diabetes. Diabetes 1988, 37: 292–6.

    Article  PubMed  CAS  Google Scholar 

  6. Calver A, Collier J, Vallance P. Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest 1992, 90: 2548–54.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  7. Elliott TG, Cockcroft JR, Groop PH, Viberti GC, Ritter JM. Inhibition of nitric oxide synthesis in forearm vasculature of insulin-dependent diabetic patients: blunted vasoconstriction in patients with microalbuminuria. Clin Sci (Lond) 1993, 85: 687–93.

    CAS  Google Scholar 

  8. Dogra G, Rich L, Stanton K, Watts GF. Endothelium-dependent and independent vasodilation studied at normoglycemia in type I diabetes mellitus with and without microalbuminuria. Diabetologia 2001, 44: 593–601.

    Article  PubMed  CAS  Google Scholar 

  9. Eid HM, Eritsland J, Larsen J, Arnesen H, Seljeflot I. Increased levels of asymmetric dimethylarginine in populations at risk for atherosclerotic disease. Effects of pravastatin. Atherosclerosis 2003,166: 279–84.

    Article  PubMed  CAS  Google Scholar 

  10. Krolewski AS, Kosinski EJ, Warram JH, et al. Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am J Cardiol 1987, 59: 750–5.

    Article  PubMed  CAS  Google Scholar 

  11. Mittermayer F, Pleiner J, Krzyzanowska K, Wiesinger GF, Francesconi M, Wolzt M. Regular physical exercise normalizes elevated asymmetrical dimethylarginine concentrations in patients with type 1 diabetes mellitus. Wien Klin Wochenschr 2005,117: 816–20.

    Article  PubMed  CAS  Google Scholar 

  12. Ito A, Egashira K, Narishige T, Muramatsu K, Takeshita A. Angiotensin-converting enzyme activity is involved in the mechanism of increased endogenous nitric oxide synthase inhibitor in patients with type 2 diabetes mellitus. Circ J 2002, 66: 811–5.

    Article  PubMed  CAS  Google Scholar 

  13. Fard A, Tuck CH, Donis JA, et al. Acute elevations of plasma asymmetric dimethylarginine and impaired endotheial function in response to a high-fat meal in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol 2000, 20: 2039–44.

    Article  PubMed  CAS  Google Scholar 

  14. Abbasi F, Asagmi T, Cooke JP, et al. Plasma concentrations of asymmetric dimetyhlarginine are increased in patients with type 2 diabetes mellitus. Am J Cardiol 2001, 88: 1201–3.

    Article  PubMed  CAS  Google Scholar 

  15. O’Driscoll G, Green D, Rankin J, Stanton K, Taylor R. Improvement in endothelial function by angiotensin converting enzyme inhibition in insulin-dependent diabetes melitus. J Clin Inves 1997,100: 678–84.

    Article  Google Scholar 

  16. Arcaro G, Zenere BM, Saggiani F, et al. ACE inhibitors improve endothelial function in type 1 diabetic patients with normal arterial pressure and microalbuminuria. Diabetes Care 1999, 22: 1536–42.

    Article  PubMed  CAS  Google Scholar 

  17. O’Driscoll G, Green D, Maiorana A, Stanton K, Colreavy F, Taylor R. Improvement in endothelial function by angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1999, 33: 1506–11.

    Article  PubMed  Google Scholar 

  18. Chen JW, Hsu NW, Wu TC, Lin SJ, Chang MS. Long term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X. Am J Cardiol 2002, 90: 974–82.

    Article  PubMed  CAS  Google Scholar 

  19. Corretti MC, Anderson, TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery. A report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002, 39: 257–65.

    Article  PubMed  Google Scholar 

  20. Teerlink T, Nijveldt RJ, de Jong S, van Leeuwen PA. Determination of arginine, asymmetric dimethylarginine and symmmetric dimethylarginine in human plasma and other biological samples by high performance liquid chromatography. Anal Biochem 2002, 303: 131–7.

    Article  PubMed  CAS  Google Scholar 

  21. Nijveldt RJ, Teerlink T, Siroen MP, van Lambalgen AA, Rauwerda JA, van Leeuwen PA. The liver is an important organ in the metabolism of asymmetrical dimethylarginine (ADMA). Clin Nutr 2003, 22: 17–22.

    Article  PubMed  CAS  Google Scholar 

  22. Haklar G, Ersahin C, Moini H, et al. Involvement of free radicals in the cardioprotective effect of defibrotide. Arzneimittelforschung 1996, 46: 381–4.

    PubMed  CAS  Google Scholar 

  23. Yagi K. Assay for blood plasma or serum. Methods Enzymol 1984,105: 328–31.

    Article  PubMed  CAS  Google Scholar 

  24. Grisham MB, Johnson GG, Lancaster JR Jr. Quantitation of nitrate and nitrite in extracellular fluids. Methods Enzymol 1996, 268: 237–46.

    Article  PubMed  CAS  Google Scholar 

  25. Anderson TJ. Assessment and treatment of endothelial dysfunction in humans. J Am Coll Cardiol 1999, 34: 631–8.

    Article  PubMed  CAS  Google Scholar 

  26. Faulx MD, Wright AT, Hoit BD. Detection of endothelial dysfunction with brachial artery ultrasound scanning. Am Heart J 2003,145: 943–51.

    Article  PubMed  Google Scholar 

  27. Clarkson P, Celermajer DS, Donald AE, et al. Impaired vascular reactivity in insulin-dependent diabetes melitus is related to disease duration and low-density lipoprotein cholesterol levels. J Am Coll Cardiol 1996, 28: 573–9.

    Article  PubMed  CAS  Google Scholar 

  28. Böger RH, Bode-Böger SM, Szuba A, et al. Asymmetric dimethylarginine (ADMA): A novel risk factor for endotheial dysfunction: Its role in hypercholesterolemia. Circulation 1998, 98: 1842–7.

    Article  PubMed  Google Scholar 

  29. Miyazaki H, Matsuoka H, Cooke JP, et al. Endogenous nitric oxide inhibitor: a novel marker of atherosclerosis. Circulation 1999, 99: 1141–6.

    Article  PubMed  CAS  Google Scholar 

  30. McDermott JR. Studies on the catabolism of Ng-methylarginine, Ng, Ng-dimethylarginine and Ng, Ng-dimethylarginine in the rabbit. Biochem J 1976,154: 179–84.

    PubMed Central  PubMed  CAS  Google Scholar 

  31. Kimoto M, Whitley GS, Tsuji H, Ogawa T. Detection of NG, NG-dimethylarginine dimethylaminohydrolase in human tissues using a monoclonal antibody. J Biochem (Tokyo) 1995,117: 237–8.

    Article  CAS  Google Scholar 

  32. MacAllister RJ, Fickling SA, Whitley GS, Vallance P. Metaboism of methylarginines by human vasculature; implications for the regulation of nitric oxide synthesis. Br J Pharmacol 1994, 112: 43–8.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  33. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 1994, 74: 1141–8.

    Article  PubMed  CAS  Google Scholar 

  34. Rajagopalan S, Kurz S, Münzel T, et al. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 1996, 97: 1916–23.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 1999, 99: 3092–5.

    Article  PubMed  CAS  Google Scholar 

  36. Ito A, Egashira K, Narishige T, Muramatsu K, Takeshita A. Renin angiotensin system is involved in the mechanism of increased serum asymmetric dimethylarginine in essential hypertension. Jpn Circ J 2001, 65: 775–8.

    Article  PubMed  CAS  Google Scholar 

  37. Vaughan DE, Rouleau JL, Ridker PM, Arnold JM, Menapace FJ, Pfeffer MA. Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. HEART Study Investigators. Circulation 1997, 96: 442–7.

    Article  PubMed  CAS  Google Scholar 

  38. Hamsten A, de Faire U, Walldius G, et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987, 2: 3–9.

    Article  PubMed  CAS  Google Scholar 

  39. Kleber FX, Sabin GV, Winter UJ, et al. Angiotensin-converting enzyme inhibitors in preventing remodeling and development of heart failure after acute myocardial infarction: results of the German multicenter study of the effects of captopril on cardiopulmonary exercise parameters (ECCE). Am J Cardiol 1997, 80: 162A–7A.

    Article  PubMed  CAS  Google Scholar 

  40. Hartnett ME, Stratton RD, Browne RW, Rosner BA, Lanham RJ, Armstrong D. Serum markers of oxidative stress and severity of diabetic retinopathy. Diabetes Care 2000, 23: 234–40.

    Article  PubMed  CAS  Google Scholar 

  41. Farkas K, Jermendy G, Herold M, Ruzicska E, Sasvari M, Somogyi A. Impairment of the NO/cGMP pathway in the fasting and postprandial state in type 1 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2004, 112: 258–63.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Endocrinology and Metabolism, Marmara University Medical School, Istanbul, Turkey

    D. Yazıcı MD, D. Gogas Yavuz, O. Deyneli, H. Aydın & S. Akalın

  2. Department of Pharmaceutical Chemistry, Marmara University Medical School, Istanbul, Turkey

    S. Ünsalan & S. Rollas

  3. Department of Cardiology, Marmara University Medical School, Istanbul, Turkey

    A. Toprak & H. Tezcan

  4. Marmara University Vocational School of Health Related Sciences, Istanbul, Turkey

    M. Yüksel

Authors
  1. D. Yazıcı MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Gogas Yavuz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Ünsalan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Toprak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Yüksel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. O. Deyneli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H. Aydın
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H. Tezcan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S. Rollas
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S. Akalın
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D. Yazıcı MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yazıcı, D., Gogas Yavuz, D., Ünsalan, S. et al. Temporal effects of low-dose ACE inhibition on endothelial function in Type 1 diabetic patients. J Endocrinol Invest 30, 726–733 (2007). https://doi.org/10.1007/BF03350809

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03350809

Key-words

Search

Navigation