Download PDF
Thromb Haemost 1999; 81(05): 822-827
DOI: 10.1055/s-0037-1614576
Rapid Communication
Schattauer GmbH

Effects of Statins in Thrombosis and Aortic Lesion Development in a Dyslipemic Rabbit Model

J. Alfon
1   From the Cardiovascular Research Center, CSIC-HSCSP-UAB, Barcelona, Spain
,
C. Pueyo Palazon
1   From the Cardiovascular Research Center, CSIC-HSCSP-UAB, Barcelona, Spain
,
T. Royo
1   From the Cardiovascular Research Center, CSIC-HSCSP-UAB, Barcelona, Spain
,
L. Badimon
1   From the Cardiovascular Research Center, CSIC-HSCSP-UAB, Barcelona, Spain
› Author Affiliations
Further Information

Publication History

Received 16 March 1998

Accepted after resubmission 08 February 1999

Publication Date:
09 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

HMG-CoA reductase inhibitors (statins) are effective in primary and secondary prevention of coronary heart disease. The mechanism of action is mainly attributed to their plasma cholesterol lowering activity, although additional effects have been suggested. Our objective was to study whether atorvastatin and simvastatin exhibited an inhibitory effect on platelet deposition onto a triggering damaged vessel wall in addition to an antiatherosclerotic effect in the dyslipemic rabbit model. Statins were administered at identical doses of 2.5 mg/kg/day with a hyperlipidemic diet during 10 weeks. Both drugs similarly lowered total cholesterol and, moderately, triglycerides. Mural platelet deposition on damaged vessel wall placed in an ex-vivo flow perfusion system was reduced in atorvastatin treated animals (39.7 ± 6.2 × 106 PLT/cm2) vs. controls (94.8 ± 15.9 × 106 PLT/cm2, p <0.02). Simvastatin reduced aortic fatty streak surface coverage (31,7 ± 5.3%) vs. controls (47.9 ± 4.1%, p <0.005) and intimal thickening in thoracic aorta (0.15 ± 0.05 intima to total area ratio in simvastatin treated animals vs. 0.36 ± 0.03 in control animals, p <0.05). Atherosclerotic fatty streak coverage correlated positively with total cholesterol, tryglicerides and LDL-cholesterol levels in all groups. HMG-CoA reductase inhibitors similarly lowered plasma lipids but exhibited significantly different effects in the modulation of atherosclerotic development and platelet response at the tested dose. Therefore, the effect of statins on the progression and manifestation of cardiovascular disease might be also mediated by regulating platelet response to vessel injury.

 

  • References

  • 1 Hunninghake DB. HMG-CoA reductase inhibitors.. Curr Opin Lipidol 1992; 3:: 22-8.
    CrossrefPubMedSearch in Google Scholar
  • 2 Endo A. The discovery and development of HMG Co A reductase inhibitors.. J Lipid Res 1992; 33: 1569-82.
    PubMedSearch in Google Scholar
  • 3 Illingworth DR, Erkeleus DW, Keller U, Thompson G, Tikkanen MJ. Defined daily doses in relation to hypolipidaemic efficacy of lovastatin, pravastatin and simvastatin.. Lancet 1994; 343: 1554-5.
    CrossrefPubMedSearch in Google Scholar
  • 4 Scandinavian Simvastatin Survival Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Group (4S).. Lancet 1994; 344:: 1383-9.
    PubMedSearch in Google Scholar
  • 5 Krause BR, Bousley R, Kieft K, Stanfield R, Newton RS. CI-981 is superior to lovastatin for lowering triglycerides in experimental animals.. FASEB J 1993; 7-A 567. Abstract.
    PubMedSearch in Google Scholar
  • 6 Bakker-Arkema RG, Davidson MH, Goldstein RJ, Davignon J, Isaacsohn JL, Weiss SR, Keilson LM, Brown WV, Miller VT, Shurzinnske LJ, Black DM. Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia.. JAMA 1996; 275: 128-33.
    CrossrefPubMedSearch in Google Scholar
  • 7 Nawrocki JW, Weiss SR, Davidson MD, Sprecher DL, Schwartz SL, Lupien P-J, Jones PH, Haber HE, Black DM. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor.. Arterioscler Thromb Vasc Biol 1995; 15: 678-82.
    CrossrefPubMedSearch in Google Scholar
  • 8 Vaugham CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol.. Lancet 1996; 348: 1079-82.
    CrossrefPubMedSearch in Google Scholar
  • 9 Van Heek M, Zilversmit DB. Mechanisms of hypertriglyceridemia in the coconut oil/cholesterol-fed rabbit. Increased secretion and decreased catabolism of very low density lipoprotein.. Arterioscler Thromb. 1991; 11: 918-27.
    CrossrefPubMedSearch in Google Scholar
  • 10 Van Heek M, Zilversmit DB. Evidence for an inverse relation between plasma triglycerides and aortic cholesterol in the coconut oil/cholesterol-fed rabbit.. Atherosclerosis 1988; 71: 185-92.
    CrossrefPubMedSearch in Google Scholar
  • 11 Bocan TMA, Mazur MJ, Mueller SB, Brown EQ, Sliskovic DR, O’Brien PM, Creswell MW, Lee H, Uhlendorf PD, Roth BD, Newton RS. Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterol-fed rabbits: a biochemical and morphological evaluation.. Atherosclerosis 1994; 111: 127-42.
    CrossrefPubMedSearch in Google Scholar
  • 12 Wagner JG.. Fundamentals of clinical pharmacokinetics. Drug Intelligence Public.. Hamilton 1979
    PubMedSearch in Google Scholar
  • 13 Manual of Laboratory Operations. Lipid Research Clinic Program.. DHEW Publ No NIH. 75-628. Washington DC: May 1994. US Government Printing Office.;
    Search in Google Scholar
  • 14 Badimon L, Badimon JJ, Lassila R, Heras M, Chesebro JH, Fuster V. Thrombin regulation of platetelet interaction with damaged vessel wall, and isolated collagen type I at arterial flow conditions in a porcine model: Effects of hirudins, heparin, and calcium chelation.. Blood 1991; 78: 423-34.
    PubMedSearch in Google Scholar
  • 15 Badimon L, Badimon JJ. Mechanism of arterial thrombosis in non parallel streamline: platelet thrombi grow on the apex of stenotic severely injured vessel wall.. J Clin Inves 1989; 84: 1134-44.
    CrossrefPubMedSearch in Google Scholar
  • 16 Badimon L, Badimon JJ, Turitto V, Vallabhajosula S, Fuster V. Platelet thrombus formation on collagen type I, a model of deep vessel injury. Influence of blood rheology, von Willebrand Factor and blood coagulation.. Circulation 1988; 78: 1431-42.
    CrossrefPubMedSearch in Google Scholar
  • 17 Prosser CL.. Liquid circulation in organisms. In Comparative animal physiology. Prosser CL, and Brown Jr. FA. eds. WB Saunders Company; Philadelphia: 1961
    Search in Google Scholar
  • 18 Badimon JJ, Badimon L, Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit.. J Clin Invest 1990; 85: 1234-41.
    CrossrefPubMedSearch in Google Scholar
  • 19 Badimon JJ, Badimon L, Galvez A, Dische R, Fuster V. High density lipoprotein plasma fraction inhibit aortic fatty streacks in cholesterol-fed rabbits.. Lab Invest 1989; 61: 455-61.
    PubMedSearch in Google Scholar
  • 20 Gurr E.. In Biological Staining Methods. Searle Diagnostic Gurr Products, Buckinghamshire. 1972; pp 46.
    PubMedSearch in Google Scholar
  • 21 Conde K, Vergara-Jimenez M, Krause BR, Newton RS, Fernandez ML.. Hypocholesterolemic actions of atorvastatin are associated with alterations on hepatic cholesterol metabolism and lipoprotein composition in the guinea pig.. J Lipid Res 1996; 37:: 2372-82.
    PubMedSearch in Google Scholar
  • 22 Ishida F, Watanabe K, Sato A, Taguchi K, Kitani K, Kamei T. Comparative effects of simvastatin (MK-733) and pravastatin (CS-514) on hypercholesterolemia induced by cholesterol feeding in rabbits.. Biochim Biophys Acta 1990; 1042: 365-73.
    CrossrefPubMedSearch in Google Scholar
  • 23 Badimon JJ, Badimon L, Turitto VT, Fuster V. Platelet deposition at high shear rates is enhanced by high plasma cholesterol levels. In vivo study in the rabbit model.. Arterioscler Thromb 1991; 11: 395-402.
    CrossrefPubMedSearch in Google Scholar
  • 24 Schror K. Platelet reactivity and arachidonic acid metabolism in type II hyperlipoproteinaemia and its modification by cholesterol-lowering agents.. Eicosanoids 1990; 3: 67-73.
    PubMedSearch in Google Scholar
  • 25 Badimon L, Fuster V, Chesebro JH, Dewanjee MK. New “ex-vivo” radioisotopic method of quantitation of platelet deposition-studies in four animal species.. Thromb Haemost 1983; 50: 639-44.
    Thieme ConnectPubMedSearch in Google Scholar
  • 26 Schootemeijer A, Gorter G, Tertoolen LG, DeLaat SW, Akkerman JW. Relation between membrane fluidity and signal transduction in the human megakaryoblastic cell line MEG-01.. Biochim Biophys Acta. 1995; 1236: 128-34.
    CrossrefPubMedSearch in Google Scholar
  • 27 Hussein O, Rosenblat M, Schlezinger S, Keidar S, Aviram M. Reduced platelet aggregation after fluvastatin therapy is associated with altered platelet lipid composition and drug binding to the platelets.. Br J Clin Pharmacol 1997; 44: 77-84.
    PubMedSearch in Google Scholar
  • 28 Coller BS.. von Willebrand Disease. In Hemostasis and Thrombosis. Basic Principles and Clinical Practice.. Colman RW, Hirsh J, Narder VJ, Salzman EW. eds. JB Lippincott Company; Philadelphia: 1982
    Search in Google Scholar
  • 29 Sakariassen KS, Nievelstein PF, Coller BS, Sixma JJ. The role of platelet membrane glycoproteins Ib and IIb-IIIa in platelet adherence to human artery subendothelium.. Br J Hematol 1986; 63: 681-91.
    CrossrefPubMedSearch in Google Scholar
  • 30 Badimon L, Badimon JJ, Rand J, Turitto VT, Fuster V. Platelet deposition on von Willebrand factor deficient vessels extracorporeal perfusion studies in swine with von Willebrand’s disease using native and heparinized blood.. J Lab Clin Med 1987; 110: 634-47.
    PubMedSearch in Google Scholar
  • 31 Badimon L, Badimon JJ, Chesebro JH, Fuster V. von Willebrand factor and cardiovascular disease.. Thromb Haemost 1993; 70: 111-8.
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 Bocan TMA, Mueller SB, Mazur MJ, Uhlendorf PD, Brown EQ, Kieft KA. The relationship between the degree of dietary-induced hypercholesterolemia in the rabbit and atherosclerotic lesion formation.. Atherosclerosis. 1993; 102: 9-22.
    CrossrefPubMedSearch in Google Scholar