Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cardiovascular Pharmacology

C16, a novel advanced glycation endproduct breaker, restores cardiovascular dysfunction in experimental diabetic rats



Advanced glycation endproducts (AGE) have been implicated in the pathogenesis of diabetic complications, including diabetic cardiovascular dysfunction. 3-[2-(4-Bromo-phenyl)-1-methyl-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazol-3-ium bromide (C16), a novel AGE breaker, was investigated for its effects on the development of cardiovascular disease in diabetic rats.


Rats that had streptozotocin-induced diabetes for 12 weeks were divided into groups receiving C16 or vehicle by gavage.


In hemodynamic studies of the left ventricle, C16 treatment (25 or 50 mg/kg) for 4 weeks resulted in a significant increase in left ventricular systolic pressure, +dp/dtmax, and -dp/dtmax as compared with vehicletreated diabetic rats. Furthermore, in hemodynamic studies of the cardiovascular system, C16 (12.5, 25, or 50 mg/kg) treatment for 4 weeks resulted in a dosedependent and significant increase in cardiac output, a reduction of total peripheral resistance, and an increase in systemic arterial compliance when compared with vehicle-treated diabetic rats. Biochemical studies showed that C16 treatment also resulted in a significant decrease in immunoglobulin G-red blood cell surface crosslink content and an increase in collagen solubility. Morphological and immunohistochemical examinations indicated that C16 was able to prevent increases of the collagen type III/I ratio in the aorta and decrease the accumulation of AGE in the aorta.


C16 has the ability to reduce AGE accumulation in tissues in vivo, and can restore diabetes-associated cardiovascular disorders in rats. This provides a potential therapeutic approach for cardiovascular disease associated with diabetes and aging in humans.


  1. 1

    Brownlee M, Cerami A, Vlassara H . Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 1988; 318: 1315–21.

    CAS  Article  Google Scholar 

  2. 2

    Kass DA . Getting better without AGE: new insights into the diabetic heart. Circ Res 2003; 92: 704–6.

    CAS  Article  Google Scholar 

  3. 3

    Brownlee M . Lilly Lecture 1993. Glycation and diabetic complications. Diabetes 1994; 43: 836–41.

    Google Scholar 

  4. 4

    Singh R, Barden A, Mori T, Beilin L . Advanced glycation endproducts: a review. Diabetologia 2001; 44: 129–46.

    CAS  Article  Google Scholar 

  5. 5

    Brownlee M . The pathological implications of protein glycation. Clin Invest Med 1995; 18: 275–81.

    CAS  PubMed  Google Scholar 

  6. 6

    Bucala R, Cerami A . Advanced glycosylation: chemistry, biology, and implications for diabetes and aging. Adv Pharmacol 1992; 23: 1–34.

    CAS  Article  Google Scholar 

  7. 7

    Sims TJ, Rasmussen LM, Oxlund H, Bailey AJ . The role of glycation cross-links in diabetic vascular stiffening. Diabetologia 1996; 39: 946–51.

    CAS  Article  Google Scholar 

  8. 8

    Avendano GF, Agarwal RK, Bashey RI, Lyons MM, Soni BJ, Jyothirmayi GN, et al. Effects of glucose intolerance on myocardial function and collagen-linked glycation. Diabetes 1999; 48: 1443–7.

    CAS  Article  Google Scholar 

  9. 9

    Rahbar S, Figarola JL . Novel inhibitors of advanced glycation endproducts. Arch Biochem Biophys 2003; 419: 63–79.

    CAS  Article  Google Scholar 

  10. 10

    Vasan S, Foiles P, Founds H . Therapeutic potential of breakers of advanced glycation end product-protein crosslinks. Arch Biochem Biophys 2003; 419: 89–96.

    CAS  Article  Google Scholar 

  11. 11

    Dukic-Stefanovic S, Schinzel R, Riederer P, Munch G . AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs? Biogerontology 2001; 2: 19–34.

    CAS  Article  Google Scholar 

  12. 12

    Li YM, Steffes M, Donnelly T, Liu C, Fuh H, Basgen J, et al. Prevention of cardiovascular and renal pathology of aging by the advanced glycation inhibitor aminoguanidine. Proc Natl Acad Sci USA 1996; 93: 3902–7.

    CAS  Article  Google Scholar 

  13. 13

    Brownlee M, Vlassara H, Kooney A, Ulrich P, Cerami A . Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science 1986; 232: 1629–32.

    CAS  Article  Google Scholar 

  14. 14

    Wolffenbuttel BH, Boulanger CM, Crijns FR, Huijberts MS, Poitevin P, Swennen GN, et al. Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc Natl Acad Sci USA 1998; 95: 4630–4.

    CAS  Article  Google Scholar 

  15. 15

    Asif M, Egan J, Vasan S, Jyothirmayi GN, Masurekar MR, Lopez S, et al. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci USA 2000; 97: 2809–13.

    CAS  Article  Google Scholar 

  16. 16

    Vaitkevicius PV, Lane M, Spurgeon H, Ingram DK, Roth GS, Egan JJ, et al. A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys. Proc Natl Acad Sci USA 2001; 98: 1171–5.

    CAS  Article  Google Scholar 

  17. 17

    Liu J, Masurekar MR, Vatner DE, et al. Glycation end-product cross-link breaker reduces collagen and improves cardiac function in aging diabetic heart. Am J Physiol Heart Circ Physiol 2003; 285: H2587–91.

    CAS  Article  Google Scholar 

  18. 18

    Susic D, Varagic J, Ahn J, Frohlich ED . Cardiovascular and renal effects of a collagen cross-link breaker (ALT 711) in adult and aged spontaneously hypertensive rats. Am J Hypertens 2004; 17: 328–33.

    CAS  Article  Google Scholar 

  19. 19

    Kass DA, Shapiro EP, Kawaguchi M, Capriotti AR, Scuteri A, deGroof RC, et al. Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation 2001; 104: 1464–70.

    CAS  Article  Google Scholar 

  20. 20

    Vasan S, Zhang X, Zhang X, Kapurniotu A, Bernhagen J, Teichberg S, et al. An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. Nature 1996; 382: 275–8.

    CAS  Article  Google Scholar 

  21. 21

    Li S, Cui H, Wang LL, Inventors. New substituted penta azacyclo salt kind compound and its use in treating protein ageing related disease. CN patent 1534027. 2004 Oct 6.

  22. 22

    Yamamoto K, Masuyama T, Sakata Y, Nishikawa N, Mano T, Yoshida J, et al. Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart. Cardiovasc Res 2002; 55: 76–82.

    CAS  Article  Google Scholar 

  23. 23

    Levy BI, Duriez M, Phillipe M, Poitevin P, Michel JB . Effect of chronic dihydropyridine (isradipine) on the large arterial walls of spontaneously hypertensive rats. Circulation 1994; 90: 3024–33.

    CAS  Article  Google Scholar 

  24. 24

    Yin FC, Guzman PA, Brin KP, et al. Effect of nitroprusside on hydraulic vascular loads on the right and left ventricle of patients with heart failure. Circulation 1983; 67: 1330–9.

    CAS  Article  Google Scholar 

  25. 25

    Kochakian M, Manjula BN, Egan JJ . Chronic dosing with aminoguanidine and novel advanced glycosylation end productformation inhibitors ameliorates cross-linking of tail tendon collagen in STZ-induced diabetic rats. Diabetes 1996; 45: 1694–700.

    CAS  Article  Google Scholar 

  26. 26

    Stegemann, H, Stalder, K . Determination of hydroxyproline. Clin Chim Acta 1967; 18: 267–73.

    CAS  Article  Google Scholar 

  27. 27

    Junqueira LC, Cossermelli W, Brentani R . Differential staining of collagens type I, II and III by Sirius Red and polarization microscopy. Arch Histol Jpn 1978; 41: 267–74.

    CAS  Article  Google Scholar 

  28. 28

    Whittaker P, Kloner RA, Boughner DR, Pickering JG . Quantitative assessment of myocardial collagen with picrosirius red staining and circularly polarized light. Basic Res Cardiol 1994; 89: 397–410.

    CAS  Article  Google Scholar 

  29. 29

    Brownlee M, Cerami A, Vlassara H . Advanced products of nonenzymatic glycosylation and the pathogenesis of diabetic vascular disease. Diabetes Metab Rev 1988; 4: 437–51.

    CAS  Article  Google Scholar 

  30. 30

    Cooper ME . Importance of advanced glycation end products in diabetes-associated cardiovascular and renal disease. Am J Hypertens 2004; 17: 31S–8S.

    CAS  Article  Google Scholar 

  31. 31

    Shimizu M, Umeda K, Sugihara N, Yoshio H, Ino H, Takeda R, et al. Collagen remodelling in myocardia of patients with diabetes. J Clin Pathol 1993; 46: 32–6.

    CAS  Article  Google Scholar 

  32. 32

    Bruel A, Oxlund H . Changes in biomechanical properties, composition of collagen and elastin, and advanced glycation end products of the rat aorta in relation to age. Atherosclerosis 1996; 127: 155–65.

    CAS  Article  Google Scholar 

Download references

Author information



Corresponding authors

Correspondence to Li-li Wang or Song Li.

Additional information

Project supported by the National High Technology Research and Development Program of China (863 Program, No 2001AA35031).

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cheng, G., Wang, Ll., Qu, Ws. et al. C16, a novel advanced glycation endproduct breaker, restores cardiovascular dysfunction in experimental diabetic rats. Acta Pharmacol Sin 26, 1460–1466 (2005).

Download citation


  • C16
  • advanced glycation endproduct
  • cardiovascular dysfunction
  • hemodynamics
  • diabetes
  • collagen

Further reading


Quick links