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Heart and Vessels

, Volume 28, Issue 2, pp 246–254 | Cite as

Low-dose atorvastatin, losartan, and particularly their combination, provide cardiovascular protection in isolated rat heart and aorta

  • Mojca LunderEmail author
  • Lovro Žiberna
  • Miodrag Janić
  • Aleš Jerin
  • Milan Skitek
  • Mišo Šabovič
  • Gorazd Drevenšek
Original Article

Abstract

Statins and angiotensin receptor blockers at therapeutic doses have beneficial cardiovascular effects, which can be applied for cardiovascular protection. We explored whether low doses of atorvastatin, losartan, and particularly their combination, possess important pleiotropic vasodilatory effects. Wistar rats were treated daily with low-dose atorvastatin (2 mg/kg, n = 15), low-dose losartan (5 mg/kg, n = 15), their combination (n = 15), or saline (n = 15). After 4, 6, or 8 weeks the animals were anesthetized, blood samples taken, and their hearts and thoracic aortas isolated. Two kinds of experiments were performed: the measurement of coronary flow rate after ischemia/reperfusion myocardial injury and endothelium-dependent relaxation of thoracic aorta. In both models, maximal vasodilation activity was obtained in rats treated for 6 weeks. In the ischemia/reperfusion myocardial injury model, coronary flow increased (atorvastatin or losartan 1.9-fold, P < 0.01; combination 2.4-fold, P < 0.001) compared with controls. In the thoracic aorta model, endothelium-dependent relaxation significantly increased only in the combination group compared with the control group (up to 1.4-fold; P < 0.01). Simultaneously, we detected increased anti-inflammatory activity and increased nitric oxide concentration, but no changes in lipids and blood pressure. In a rat model we showed important vasodilatory activity of low-dose atorvastatin, losartan, and particularly their combination. The effects of the low-dose combination were accompanied by, and probably at least partly achieved by, anti-inflammatory and nitric oxide pathways. Overall, these results could be valuable for the development of new vascular protective strategies focusing on a low-dose regimen of statins and sartans, and particularly their combination.

Keywords

Ischemia/reperfusion injury Endothelium-dependent relaxation Atorvastatin Losartan Chronic low-dose treatment 

Notes

Acknowledgments

The present study was supported by the Slovenian Research Agency, Ljubljana, Slovenia (research project L3-2293). The authors declare that there are no conflicts of interest.

References

  1. 1.
    Fuster V, Kelly BB, Vedanthan R (2011) Global cardiovascular health: urgent need for an intersectoral approach. J Am Coll Cardiol 58:1208–1210PubMedCrossRefGoogle Scholar
  2. 2.
    Mihos CG, Salas MJ, Santana O (2010) The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in cardiovascular disease: a comprehensive review. Cardiol Rev 18:298–304PubMedCrossRefGoogle Scholar
  3. 3.
    Sadowitz B, Seymour K, Costanza MJ, Gahtan V (2010) Statin therapy—part II: clinical considerations for cardiovascular disease. Vasc Endovascular Surg 44:421–433PubMedCrossRefGoogle Scholar
  4. 4.
    Tran HA, Schwartzbard A, Weintraub HS (2011) Role of RAAS inhibition in the prevention of cardiovascular disease. Curr Treat Options Cardiovasc Med 13:279–288PubMedCrossRefGoogle Scholar
  5. 5.
    Reriani MK, Dunlay SM, Gupta B, West CP, Rihal CS, Lerman LO, Lerman A (2011) Effects of statins on coronary and peripheral endothelial function in humans: a systematic review and meta-analysis of randomized controlled trials. Eur J Cardiovasc Prev Rehabil 18:704–716PubMedCrossRefGoogle Scholar
  6. 6.
    Suh JW, Choi DJ, Chang HJ, Cho YS, Youn TJ, Chae IH, Kim KI, Kim CH, Kim HS, Oh BH, Park YB (2010) HMG-CoA reductase inhibitor improves endothelial dysfunction in spontaneous hypertensive rats via down-regulation of caveolin-1 and activation of endothelial nitric oxide synthase. J Korean Med Sci 25:16–23PubMedCrossRefGoogle Scholar
  7. 7.
    Nagashima H, Endo M (2011) Pitavastatin prevents postprandial endothelial dysfunction via reduction of the serum triglyceride level in obese male subjects. Heart Vessels 26:428–434PubMedCrossRefGoogle Scholar
  8. 8.
    Skogastierna C, Luksha L, Kublickiene K, Eliasson E, Rane A, Ekstrom L (2011) Beneficial vasoactive endothelial effects of fluvastatin: focus on prostacyclin and nitric oxide. Heart Vessels 26:628–636PubMedCrossRefGoogle Scholar
  9. 9.
    Horiuchi Y, Hirayama S, Soda S, Seino U, Kon M, Ueno T, Idei M, Hanyu O, Tsuda T, Ohmura H, Miida T (2010) Statin therapy reduces inflammatory markers in hypercholesterolemic patients with high baseline levels. J Atheroscler Thromb 17:722–729PubMedCrossRefGoogle Scholar
  10. 10.
    Ghaisas MM, Dandawate PR, Zawar SA, Ahire YS, Gandhi SP (2010) Antioxidant, antinociceptive and anti-inflammatory activities of atorvastatin and rosuvastatin in various experimental models. Inflammopharmacology 18:169–177PubMedCrossRefGoogle Scholar
  11. 11.
    Sugiyama M, Ohashi M, Takase H, Sato K, Ueda R, Dohi Y (2005) Effects of atorvastatin on inflammation and oxidative stress. Heart Vessels 20:133–136PubMedCrossRefGoogle Scholar
  12. 12.
    Lee KJ, Moon JY, Choi HK, Kim HO, Hur GY, Jung KH, Lee SY, Kim JH, Shin C, Shim JJ, In KH, Yoo SH, Kang KH (2010) Immune regulatory effects of simvastatin on regulatory T cell-mediated tumour immune tolerance. Clin Exp Immunol 161:298–305PubMedCrossRefGoogle Scholar
  13. 13.
    Parizadeh SM, Azarpazhooh MR, Moohebati M, Nematy M, Ghayour-Mobarhan M, Tavallaie S, Rahsepar AA, Amini M, Sahebkar A, Mohammadi M, Ferns GA (2011) Simvastatin therapy reduces prooxidant-antioxidant balance: results of a placebo-controlled cross-over trial. Lipids 46:333–340PubMedCrossRefGoogle Scholar
  14. 14.
    Abela GS, Vedre A, Janoudi A, Huang R, Durga S, Tamhane U (2011) Effect of statins on cholesterol crystallization and atherosclerotic plaque stabilization. Am J Cardiol 107:1710–1717PubMedCrossRefGoogle Scholar
  15. 15.
    Hamada M, Sugimoto M, Matsui H, Mizuno T, Shida Y, Doi M, Fukushima H, Nishio K, Yoshioka A, Shima M (2011) Antithrombotic properties of pravastatin reducing intra-thrombus fibrin deposition under high shear blood flow conditions. Thromb Haemost 105:313–320PubMedCrossRefGoogle Scholar
  16. 16.
    Nemati F, Rahbar-Roshandel N, Hosseini F, Mahmoudian M, Shafiei M (2011) Anti-inflammatory effects of anti-hypertensive agents: influence on interleukin-1β secretion by peripheral blood polymorphonuclear leukocytes from patients with essential hypertension. Clin Exp Hypertens 33:66–76PubMedCrossRefGoogle Scholar
  17. 17.
    Honjo T, Yamaoka-Tojo M, Inoue N (2011) Pleiotropic effects of ARB in vascular metabolism—focusing on atherosclerosis-based cardiovascular disease. Curr Vasc Pharmacol 9:145–152PubMedCrossRefGoogle Scholar
  18. 18.
    Yokota T, Osanai T, Hanada K, Kushibiki M, Abe N, Oikawa K, Tomita H, Higuma T, Yokoyama J, Hanada H, Okumura K (2010) Effects of telmisartan on markers of ventricular remodeling in patients with acute myocardial infarction: comparison with enalapril. Heart Vessels 25:460–468PubMedCrossRefGoogle Scholar
  19. 19.
    Chen HQ, Tan HY, Yang YW, Qiu L, Liu XQ (2010) Effects of ramipril on serum monocyte chemoattractant protein 1, interleukin-18, and interleukin-10 in elderly patients with acute coronary syndrome. Heart Vessels 25:77–81PubMedCrossRefGoogle Scholar
  20. 20.
    Miyoshi T, Doi M, Hirohata S, Kamikawa S, Usui S, Ogawa H, Sakane K, Izumi R, Ninomiya Y, Kusachi S (2011) Olmesartan reduces arterial stiffness and serum adipocyte fatty acid-binding protein in hypertensive patients. Heart Vessels 26:408–413PubMedCrossRefGoogle Scholar
  21. 21.
    Fujita H, Sakamoto T, Komatsu K, Fujishima H, Morii T, Narita T, Takahashi T, Yamada Y (2011) Reduction of circulating superoxide dismutase activity in type 2 diabetic patients with microalbuminuria and its modulation by telmisartan therapy. Hypertens Res 34:1302–1308PubMedCrossRefGoogle Scholar
  22. 22.
    Landmesser U, Drexler H (2006) Effect of angiotensin II type 1 receptor antagonism on endothelial function: role of bradykinin and nitric oxide. J Hypertens Suppl 24:S39–S43PubMedCrossRefGoogle Scholar
  23. 23.
    Barrios V, Escobar C, Calderon A, Barrios S, Navarro-Cid J, Ferrer E, Echarri R (2010) Gender differences in the diagnosis and treatment of left ventricular hypertrophy detected by different electrocardiographic criteria. Findings from the SARA study. Heart Vessels 25:51–56PubMedCrossRefGoogle Scholar
  24. 24.
    Hussein O, Shneider J, Rosenblat M, Aviram M (2002) Valsartan therapy has additive anti-oxidative effect to that of fluvastatin therapy against low-density lipoprotein oxidation: studies in hypercholesterolemic and hypertensive patients. J Cardiovasc Pharmacol 40:28–34PubMedCrossRefGoogle Scholar
  25. 25.
    Horiuchi M, Cui TX, Li Z, Li JM, Nakagami H, Iwai M (2003) Fluvastatin enhances the inhibitory effects of a selective angiotensin II type 1 receptor blocker, valsartan, on vascular neointimal formation. Circulation 107:106–112PubMedCrossRefGoogle Scholar
  26. 26.
    Liu L, Zhao SP, Zhou HN, Li QZ, Li JX (2007) Effect of fluvastatin and valsartan, alone and in combination, on postprandial vascular inflammation and fibrinolytic activity in patients with essential hypertension. J Cardiovasc Pharmacol 50:50–55PubMedCrossRefGoogle Scholar
  27. 27.
    Koh KK, Han SH, Oh PC, Shin EK, Quon MJ (2010) Combination therapy for treatment or prevention of atherosclerosis: focus on the lipid–RAAS interaction. Atherosclerosis 209:307–313PubMedCrossRefGoogle Scholar
  28. 28.
    Lunder M, Janic M, Habjan S, Sabovic M (2011) Subtherapeutic, low-dose fluvastatin improves functional and morphological arterial wall properties in apparently healthy, middle-aged males—a pilot study. Atherosclerosis 215:446–451PubMedCrossRefGoogle Scholar
  29. 29.
    Lunder M, Janic M, Sabovic M (2011) Reduction of age-associated arterial wall changes by low-dose valsartan. Eur J Cardiovasc Prev Rehabil. doi: 10.1177/1741826711423104
  30. 30.
    Lunder M, Janic M, Jug B, Sabovic M (2011) The effects of low-dose fluvastatin and valsartan combination on arterial function: a randomized clinical trial. Eur J Intern Med. doi: 10.1016/j.ejim.2011.11.011
  31. 31.
    Kuhar P, Lunder M, Drevensek G (2007) The role of gender and sex hormones in ischemic-reperfusion injury in isolated rat hearts. Eur J Pharmacol 561:151–159PubMedCrossRefGoogle Scholar
  32. 32.
    Ziberna L, Lunder M, Tramer F, Drevensek G, Passamonti S (2011) The endothelial plasma membrane transporter bilitranslocase mediates rat aortic vasodilation induced by anthocyanins. Nutr Metab Cardiovasc Dis. doi: 10.1016/j.numecd.2011.02.005
  33. 33.
    Ziberna L, Zorman T, Drevensek G (2009) Characterization of histamine-induced relaxation in pre-contracted rat aorta. Inflamm Res 58(Suppl 1):63–65PubMedCrossRefGoogle Scholar
  34. 34.
    Hirota T, Nonaka A, Matsushita A, Uchida N, Ohki K, Asakura M, Kitakaze M (2011) Milk casein-derived tripeptides, VPP and IPP induced NO production in cultured endothelial cells and endothelium-dependent relaxation of isolated aortic rings. Heart Vessels 26:549–556PubMedCrossRefGoogle Scholar
  35. 35.
    Garcia-Villalon AL, Amezquita YM, Monge L, Fernandez N, Climent B, Sanchez A, Dieguez G (2005) Effect of ischemia duration and nitric oxide on coronary vasoconstriction after ischemia–reperfusion. Eur J Pharmacol 509:165–170PubMedCrossRefGoogle Scholar
  36. 36.
    Flynn JD, Akers WS (2003) Effects of the angiotensin II subtype 1 receptor antagonist losartan on functional recovery of isolated rat hearts undergoing global myocardial ischemia–reperfusion. Pharmacotherapy 23:1401–1410PubMedCrossRefGoogle Scholar
  37. 37.
    Xu HC, Qian LB, Ru XC, Miao HF, Ye ZG, Wang HP (2010) Electrophysiological effect of atorvastatin on isolated rat hearts injured by ischemia/reperfusion. Zhejiang Da Xue Xue Bao Yi Xue Ban 39:589–593PubMedGoogle Scholar
  38. 38.
    Spurney CF, Sali A, Guerron AD, Iantorno M, Yu Q, Gordish-Dressman H, Rayavarapu S, van der Meulen J, Hoffman EP, Nagaraju K (2011) Losartan decreases cardiac muscle fibrosis and improves cardiac function in dystrophin-deficient mdx mice. J Cardiovasc Pharmacol Ther 16:87–95PubMedCrossRefGoogle Scholar
  39. 39.
    Schmechel A, Grimm M, El-Armouche A, Hoppner G, Schwoerer AP, Ehmke H, Eschenhagen T (2009) Treatment with atorvastatin partially protects the rat heart from harmful catecholamine effects. Cardiovasc Res 82:100–106PubMedCrossRefGoogle Scholar
  40. 40.
    Filusch A, Buss S, Hardt S, Katus HA, Kuecherer HF, Hansen A (2008) Evaluation cardioprotective effects of atorvastatin in rats by real time myocardial contrast echocardiography. Echocardiography 25:974–981PubMedCrossRefGoogle Scholar
  41. 41.
    Li D, Xia K, Li NS, Luo D, Wang S, Jiang DJ, Deng HW, Li YJ (2007) Reduction of asymmetric dimethylarginine involved in the cardioprotective effect of losartan in spontaneously hypertensive rats. Can J Physiol Pharmacol 85:783–789PubMedCrossRefGoogle Scholar
  42. 42.
    Garjani A, Andalib S, Biabani S, Soraya H, Doustar Y, Maleki-Dizaji N (2011) Combined atorvastatin and coenzyme Q10 improve the left ventricular function in isoproterenol-induced heart failure in rat. Eur J Pharmacol 666:135–141PubMedCrossRefGoogle Scholar
  43. 43.
    Manickavasagam S, Ye Y, Lin Y, Perez-Polo RJ, Huang MH, Lui CY, Hughes MG, McAdoo DJ, Uretsky BF, Birnbaum Y (2007) The cardioprotective effect of a statin and cilostazol combination: relationship to Akt and endothelial nitric oxide synthase activation. Cardiovasc Drugs Ther 21:321–330PubMedCrossRefGoogle Scholar
  44. 44.
    Rosanio S, Ye Y, Atar S, Rahman AM, Freeberg SY, Huang MH, Uretsky BF, Birnbaum Y (2006) Enhanced cardioprotection against ischemia–reperfusion injury with combining sildenafil with low-dose atorvastatin. Cardiovasc Drugs Ther 20:27–36PubMedCrossRefGoogle Scholar
  45. 45.
    Sonmez Uydes-Dogan B, Topal G, Takir S, Ilkay Alp F, Kaleli D, Ozdemir O (2005) Relaxant effects of pravastatin, atorvastatin and cerivastatin on isolated rat aortic rings. Life Sci 76:1771–1786PubMedCrossRefGoogle Scholar
  46. 46.
    Matsumoto T, Ishida K, Taguchi K, Kobayashi T, Kamata K (2010) Losartan normalizes endothelium-derived hyperpolarizing factor-mediated relaxation by activating Ca2+-activated K+ channels in mesenteric artery from type 2 diabetic GK rat. J Pharmacol Sci 112:299–309PubMedCrossRefGoogle Scholar
  47. 47.
    Torrens C, Kelsall CJ, Hopkins LA, Anthony FW, Curzen NP, Hanson MA (2009) Atorvastatin restores endothelial function in offspring of protein-restricted rats in a cholesterol-independent manner. Hypertension 53:661–667PubMedCrossRefGoogle Scholar
  48. 48.
    Yu XL, Zhang HJ, Ren SD, Geng J, Wu TT, Chen WQ, Ji XP, Zhong L, Ge ZM (2011) Effects of loading dose of atorvastatin before percutaneous coronary intervention on periprocedural myocardial injury. Coron Artery Dis 22:87–91PubMedCrossRefGoogle Scholar
  49. 49.
    Amin KA, Abd El-Twab TM (2009) Oxidative markers, nitric oxide and homocysteine alteration in hypercholesterolemic rats: role of atorvastatin and cinnamon. Int J Clin Exp Med 2:254–265PubMedGoogle Scholar
  50. 50.
    Huisamen B, Perel SJ, Friedrich SO, Salie R, Strijdom H, Lochner A (2011) ANG II type I receptor antagonism improved nitric oxide production and enhanced eNOS and PKB/Akt expression in hearts from a rat model of insulin resistance. Mol Cell Biochem 349:21–31PubMedCrossRefGoogle Scholar
  51. 51.
    Mensah K, Mocanu MM, Yellon DM (2005) Failure to protect the myocardium against ischemia/reperfusion injury after chronic atorvastatin treatment is recaptured by acute atorvastatin treatment: a potential role for phosphatase and tensin homolog deleted on chromosome ten? J Am Coll Cardiol 45:1287–1291PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2012

Authors and Affiliations

  • Mojca Lunder
    • 1
    • 2
    Email author
  • Lovro Žiberna
    • 1
  • Miodrag Janić
    • 2
  • Aleš Jerin
    • 3
  • Milan Skitek
    • 3
  • Mišo Šabovič
    • 2
  • Gorazd Drevenšek
    • 1
  1. 1.Institute of Pharmacology and Experimental Toxicology, Faculty of MedicineUniversity of LjubljanaLjubljanaSlovenia
  2. 2.Department of Vascular DiseaseUniversity of Ljubljana Medical CentreLjubljanaSlovenia
  3. 3.Institute of Clinical Chemistry and BiochemistryUniversity of Ljubljana Medical CentreLjubljanaSlovenia

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