Archives of Pharmacal Research

, Volume 35, Issue 1, pp 155–162 | Cite as

Anti-inflammatory effect of atorvastatin on vascular reactivity and insulin resistance in fructose fed rats

  • Mona F. MahmoudEmail author
  • Mohamed El-Nagar
  • Hany M. El-Bassossy
Research Article Drug Actions


We investigated the possible protective effect of atorvastatin against vascular dysfunction associated with insulin resistance (IR) in fructose-fed model rats. The effect of atorvastatin (10 mg/kg/day for 8 weeks) on vascular reactivity, glucose, cholesterol, insulin, and the IR index in a well-established model of dietary hypertriglyceridemia, the fructose-fed rat, was investigated. Fructose feeding (10% fructose in drinking water for 8 weeks) induced hypercholesterolemia and hyperinsulinemia without any change in blood glucose levels. Fructose feeding also elevated serum tumor necrosis factor-alpha (TNF-α), the insulin resistance index, leukocyte infiltration, and endothelial cell pyknosis. Fructose feeding induced hyper-responsiveness to both phenylephrine (PE), KCl, and hyporesponsiveness to acetylcholine (Ach) but not to sodium nitroprusside-induced relaxation. Atorvastatin, given concurrently with fructose, reduced hypercholesterolemia, hyperinsulinemia, TNF-α level, and the IR index. It also reduced leukocyte infiltration and endothelial cell pyknosis and decreased hyper-responsiveness to both PE and KCl but did not affect hyporesponsiveness to Ach relaxation. In conclusion, atorvastatin protected against impairment in aortic vascular reactivity associated with insulin resistance, particularly increased contractility, but not reduced endothelium-dependent relaxation, by a mechanism involving a reduction in cholesterol and IR in addition to anti-inflammatory effects.

Key words

Insulin resistance Aorta Relaxation Contraction Atorvastatin Fructose 


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  1. Allain, C. C., Poon, L. S., Chan, C. S., Richmond, W., and Fu, P. C., Enzymatic determination of total serum cholesterol. Clin. Chem., 20, 470–475 (1974).PubMedGoogle Scholar
  2. Atsuta, J., Sterbinsky, S. A., Plitt, J., Schwiebert, L. M., Bochner, B. S., and Schleimer, R. P., Phenotyping and cytokine regulation of the BEAS-2B human bronchial epithelial cell, demonstration of inducible expression of the adhesion molecules VCAM-1 and ICAM-1. Am. J. Respir. Cell Mol. Biol., 17, 571–582 (1997).PubMedGoogle Scholar
  3. Barham, D. and Trinder, P., An improved colour reagent for the determination of blood glucose by the oxidase system. Analyst, 97, 142–145 (1972).PubMedCrossRefGoogle Scholar
  4. Bartus, M., Lomnicka, M., Lorkowska, B., Franczyk, M., Kostogrys, R. B., Pisulewski, P. M., and Chlopicki, S., Hypertriglyceridemia but not hypercholesterolemia induces endothelial dysfunction in the rat. Pharmacol. Rep., 57, 127–137 (2005).PubMedGoogle Scholar
  5. Basciano, H., Federico, L., and Adeli, K., Fructose, insulin resistance and metabolic dyslipidemia. Nutr. Metab., 2, 5 (2005).CrossRefGoogle Scholar
  6. Busija, D. W, Miller, A. W., Katakam, P., and Erdos, B., Adverse effects of reactive oxygen species on vascular reactivity in insulin resistance. Antioxid. Redox Signal., 8, 1131–1140 (2006).PubMedCrossRefGoogle Scholar
  7. Clarke, S., Protein isoprenylation and methylation at carboxyl-terminal cysteine residues. Annu. Rev. Biochem., 61, 355–386 (2006).CrossRefGoogle Scholar
  8. Corda, S., Laplace, C., Vicaut, E., and Duranteau, J., Rapid reactive oxygen species production by mitochondria in endothelial cells exposed to tumor necrosis factor-á is mediated by ceramide. Am. J. Respir. Cell Mol. Biol., 24, 762–768 (2001).PubMedGoogle Scholar
  9. Dai, S., Todd, M. E., Lee, S., and McNeill, J. H., Fructose loading induces cardiovascular and metabolic changes in nondiabetic and diabetic rats. Can. J. Physiol. Pharmacol., 72, 771–781 (1994).PubMedCrossRefGoogle Scholar
  10. Dai, S. and McNeill, J. H., Fructose-induced hypertension in rats is concentration- and duration-dependent. J. Pharmacol. Toxicol. Methods, 33, 101–107 (1995).PubMedCrossRefGoogle Scholar
  11. Dillmann, W. H., Fructose feeding increases Ca++-activated myosin ATPase activity and changes myosin isoenzyme distribution in the diabetic rat heart. Endocrinology, 114, 1678–1685 (1984).PubMedCrossRefGoogle Scholar
  12. Erdos, B., Miller, A. W., and Busija, D. W., Impaired endothelium-mediated relaxation in isolated cerebral arteries from insulin-resistant rats. Am. J. Physiol. Heart Circ. Physiol., 282, H2060–H2065 (2002).PubMedGoogle Scholar
  13. Fasolato, C., Innocenti, B., and Pozzan, T., Receptoractivated Ca2+ influx: how many mechanisms for how many channels? Trends Pharmacol. Sci., 15, 77–83 (1994).PubMedCrossRefGoogle Scholar
  14. Ferro, T. J., Hocking, D. C., and Johnson, A., Tumor necrosis factor-alpha alters pulmonary vasoreactivity via neutrophil-derived oxidants. Am. J. Physiol., 265, L462–L471 (1993).PubMedGoogle Scholar
  15. Forcillo, J., Maltais, S., Aubin, M. C., Shi, Y. F., Carrier, M., Tardif, J. C., and Perrault, L. P., Atorvastatin worsens left ventricular diastolic dysfunction and endothelial dysfunction of epicardial coronary arteries in normocholesterolemic porcine with left ventricular hypertrophy. J. Cardiovasc. Pharmacol., 58, 295–306 (2011).PubMedCrossRefGoogle Scholar
  16. Goldstein, J. L. and Brown, M. S., Regulation of the mevalonate pathway. Nature, 343, 425–430 (1990).PubMedCrossRefGoogle Scholar
  17. Goodwill, A. G., Frisbee, S. J., Stapleton, P. A., James, M. E., and Frisbee, J. C., Impact of chronic anticholesterol therapy on development of microvascular rarefaction in the metabolic syndrome. Microcirculation, 16, 667–684 (2009).PubMedCrossRefGoogle Scholar
  18. Hancock, J. F., Magee, A. I., Childs, J. E., and Marshall, C. J., All ras proteins are polyisoprenylated but only some are palmitoylated. Cell, 57, 1167–1177 (1989).PubMedCrossRefGoogle Scholar
  19. Heitzer, T., Schlinzig, T., Krohn, K., Meinertz, T., and Münzel, T., Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation, 104, 2673–2678 (2001).PubMedCrossRefGoogle Scholar
  20. Hwang, I. S., Ho, H., Hoffman, B. B., and Reaven, G. M., Fructose-induced insulin resistance and hypertension in rats. Hypertension, 10, 512–516 (1987).PubMedGoogle Scholar
  21. Iyer, S. N. and Katovich, M. J., Vascular reactivity to phenylephrine and angiotensin II in hypertensive rats associated with insulin resistance. Clin. Exp. Hypertens., 18, 227–242 (1996).PubMedCrossRefGoogle Scholar
  22. Laufs, U., La Fata, V., Plutzky, J., and Liao, J. K., Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation, 97, 1129–1135 (1998).PubMedGoogle Scholar
  23. Mach, F., Montecucco, F., and Steffens, S., Cannabinoid receptors in acute and chronic complications of atherosclerosis. Br. J. Pharmacol., 153, 290–298 (2008).PubMedCrossRefGoogle Scholar
  24. Marchesi, S., Lupattelli, G., Siepi, D., Schillaci, G., Vaudo, G., Roscini, A. R., Sinzinger, H., and Mannarino, E., Short-term atorvastatin treatment improves endothelial function in hypercholesterolemic women. J. Cardiovasc. Pharmacol., 36, 617–621 (2000).PubMedCrossRefGoogle Scholar
  25. Matthews, D. R., Hosker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F., and Turner, R. C., Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28, 412–419 (1985).PubMedCrossRefGoogle Scholar
  26. Maugeri, N., Rovere-Querini, P., Baldini, M., Sabbadini, M. G., and Manfredi, A. A., Translational mini-review series on immunology of vascular disease: mechanisms of vascular inflammation and remodelling in systemic vasculitis. Clin. Exp. Immunol., 156, 395–404 (2009).PubMedCrossRefGoogle Scholar
  27. McNeill, K. L., Fontana, L., Russell-Jones, D. L., Rajman, I., Ritter, J. M., and Chowienczyk, P. J., Inhibitory effects of low-density lipoproteins from men with type II diabetes on endothelium-dependent relaxation. J. Am. Coll. Cardiol., 35, 1622–1627 (2000).PubMedCrossRefGoogle Scholar
  28. Miller, A. and Adeli, K, Dietary fructose and the metabolic syndrome. Curr. Opin. Gastroenterol., 24, 204–209 (2008).PubMedCrossRefGoogle Scholar
  29. Navarro-Cid, J., Maeso, R., Perez-Vizcaino, F., Cachofeiro, V., Ruilope, L. M., Tamargo, J., and Lahera, V., Effects of losartan on blood pressure, metabolic alterations, and vascular reactivity in the fructose-induced hypertensive rat. Hypertension, 26, 1074–1078 (1995).PubMedGoogle Scholar
  30. Perticone, F., Ceravolo, R., Pujia, A., Ventura, G., Iacopino, S., Scozzafava, A., Ferraro, A., Chello, M., Mastroroberto, P., Verdecchia, P., and Schillaci, G., Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation, 104, 191–196 (2001).PubMedGoogle Scholar
  31. Piepot, H. A., Groeneveld, A. B., Van Lambalgen, A. A., and Sipkema, P., Tumor necrosis factor-alpha impairs endothelium-dependent relaxation of rat renal arteries, independent of tyrosine kinase. Shock, 17, 394–398 (2002).PubMedCrossRefGoogle Scholar
  32. Pretnar-Oblak, J., Sebestjen, M., and Sabovic, M., Statin treatment improves cerebral more than systemic endothelial dysfunction in patients with arterial hypertension. Am. J. Hypertens., 21, 674–678 (2008).PubMedCrossRefGoogle Scholar
  33. Ruegg, U. T., Wallnofer, A., Weir, S., and Cauvin, C., Receptor-operated calcium-permeable channels in vascular smooth muscle. J. Cardiovasc. Pharmacol., 14, S49–58 (1989).PubMedGoogle Scholar
  34. Shinozaki, K., Ayajiki, K., Nishio, Y., Sugaya, T., Kashiwagi, A., and Okamura, T., Evidence for a causal role of the renin-angiotensin system in vascular dysfunction associated with insulin resistance. Hypertension, 43, 255–262 (2004).PubMedCrossRefGoogle Scholar
  35. Sodha, N. R., Boodhwani, M., Ramlawi, B., Clements, R. T., Mieno, S., Feng, J., Xu, S. H., Bianchi, C., and Sellke, F. W., Atorvastatin increases myocardial indices of oxidative stress in a porcine model of hypercholesterolemia and chronic ischemia. J. Card. Surg., 23, 312–320 (2008).PubMedCrossRefGoogle Scholar
  36. Taghibiglou, C., Carpentier, A., Van Iderstine, S. C., Chen, B., Rudy, D., Aiton, A., Lewis, G. F., and Adeli, K., Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. J. Biol. Chem., 275, 8416–8425 (2000).PubMedCrossRefGoogle Scholar
  37. Takagawa, Y., Berger, M. E., Hori, M. T., Tuck, M. L., and Golub, M. S., Long-term fructose feeding impairs vascular relaxation in rat mesenteric arteries. Am. J. Hypertens., 14, 811–817 (2001).PubMedCrossRefGoogle Scholar
  38. Tesfamariam, B., Frohlich, B. H., and Gregg, R. E., Differential effects of pravastatin, simvastatin, and atorvastatin on Ca2+ release and vascular reactivity. J. Cardiovasc. Pharmacol., 34, 95–101 (1999).PubMedCrossRefGoogle Scholar
  39. Torrens, C., Kelsall, C. J., Hopkins, L. A., Anthony, F. W., Curzen, N. P., and Hanson, M. A., Atorvastatin restores endothelial function in offspring of protein-restricted rats in a cholesterol-independent manner. Hypertension, 53, 661–667 (2009).PubMedCrossRefGoogle Scholar
  40. Tran, L. T, Yuen, V. G., and McNeill, J. H., The fructose-fed rat, a review on the mechanisms of fructose-induced insulin resistance and hypertension. Mol. Cell. Biochem., 332, 145–159 (2009).PubMedCrossRefGoogle Scholar
  41. Vakkilainen, J., Mäkimattila, S., Seppälä-Lindroos, A., Vehkavaara, S., Lahdenperä, S., Groop, P. H., Taskinen, M. R., and Yki-Järvinen, H., Endothelial dysfunction in men with small LDL particles. Circulation, 102, 716–721 (2000).PubMedGoogle Scholar
  42. Van Etten, R. W., De Koning, E. J., Honing, M. L., Stroes, E. S., Gaillard, C. A., and Rabelink, T. J., Intensive lipid lowering by statin therapy does not improve vasoreactivity in patients with type 2 diabetes. Arterioscler. Thromb. Vasc. Biol., 22, 799–804 (2002).PubMedCrossRefGoogle Scholar
  43. Van Venrooij, F. V., van de Ree, M. A., Bots, M. L., Stolk, R. P., Huisman, M. V., and Banga, J. D., Aggressive lipid lowering does not improve endothelial function in type 2 diabetes, the Diabetes Atorvastatin Lipid Intervention (DALI) Study, a randomized, Double blind, placebo-controlled trial. Diabetes Care, 25, 1211–1216 (2002).PubMedCrossRefGoogle Scholar
  44. Verma, S., Bhanot, S., Yao, L., and McNeill, J. H., Defective endothelium-dependent relaxation in fructose-hypertensive rats. Am. J. Hypertens., 9, 370–376 (1996).PubMedCrossRefGoogle Scholar
  45. Viswanad, B., Srinivasan, K., Kaul, C. L., and Ramarao, P., Effect of tempol on altered angiotensin II and acetylcholine-mediated vascular responses in thoracic aorta isolated from rats with insulin resistance. Pharmacaol. Res., 53, 209–215 (2006).CrossRefGoogle Scholar
  46. Weyand, C. M., Ma-Krupa, W., and Goronzy, J. J., Immunopathways in giant cell arteritis and polymyalgia rheumatica. Autoimmun. Rev., 3, 46–53 (2004).PubMedCrossRefGoogle Scholar
  47. Yki-Järvinen, H., Prediction and prevention of non-insulindependent diabetes mellitus, In Williams, G. and Pickup, J. (Eds.). Textbook of Diabetes. Blackwell, Oxford, pp. 83.1–83.13, (2001).Google Scholar
  48. Yoshino, G., Iwai, M., Kazumi, T., Matsushita, M., Morita, M., Matsuba, K., Iwatani, I., and Baba, S., Effect of dietary fructose on triglyceride turnover in streptozotocin-diabetic rats. Atherosclerosis, 79, 41–46 (1989).PubMedCrossRefGoogle Scholar
  49. Zeng, Z. H., Zhang, Z. H., Luo, B. H., He, W. K., Liang, L. Y., He, C. C., and Su, C. J., The functional changes of the perivascular adipose tissue in spontaneously hypertensive rats and the effects of atorvastatin therapy. Clin. Exp. Hypertens., 31, 355–363 (2009).PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea and Springer Netherlands 2012

Authors and Affiliations

  • Mona F. Mahmoud
    • 1
    Email author
  • Mohamed El-Nagar
    • 2
  • Hany M. El-Bassossy
    • 1
    • 3
  1. 1.Department of Pharmacology, Faculty of PharmacyUniversity of ZagazigZagazigEgypt
  2. 2.Department of Pharmacology, Faculty of PharmacyUniversity of MiniaMiniaEgypt
  3. 3.Hypertension CenterWake Forest University Baptist Medical CenterWinston-SalemUSA

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