Research Article| Volume 103, ISSUE 1, P93-105, October 1993

Antiatherosclerotic effects of oral cicaprost in experimental hypercholesterolemia in rabbits

      This paper is only available as a PDF. To read, Please Download here.


      The efficacy of the oral prostacyclin mimetic cicaprost in preventing atheromatous plaque formation was studied in an in vivo model of experimental hypercholesterolemia. New Zealand white rabbits were fed either standard chow or a cholesterol-enriched (1%) diet for 12 weeks. Cicaprost was added to the drinking water in a non-hypotensive dose (5 μg/kg/day) and withdrawn 3 days prior to studying platelet, leukocyte and endothelial function. In cholesterol-fed rabbits, oral cicaprost reduced the aortic intimal surface covered by atheromatous lesions from 84 to 63% (P < 0.05). There was no major difference in serum lipid composition between cicaprost- and vehicle-treated animals. In hypercholesterolemic rabbits there was a significant impairment of endothelium-dependent relaxations. Cicaprost treatment considerably improved this endothelial function but had no effect in rabbits receiving standard diet. In addition, platelet and leukocyte hyperreactivity, as seen in hypercholesterolemic rabbits, were largely reduced by cicaprost treatment. These data are the first to demonstrate marked antiatherosclerotic effects of long-term oral prostacyclin treatment. The mechanism may be related to improved endothelial function and subsequent prevention of secondary platelet and neutrophil hyperreactivity.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Ross R.
        The pathogenesis of atherosclerosis — an update.
        N. Engl. J. Med. 1986; 314: 488
        • Lefer A.M.
        • Sedar A.W.
        Endothelial alterations in hypercholesterolaemia and atherosclerosis.
        Pharmacol. Res. 1991; 23: 1
        • Zeiher A.M.
        • Drexler H.
        • Wollschla¨ger H.
        • Just H.
        Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis.
        Circulation. 1991; 83: 391
        • Ridker P.M.
        • Manson J.E.
        • Buring J.E.
        • Goldhaber S.Z.
        • Hennekens C.H.
        The effect of chronic platelet inhibition with low-dose aspirin on atherosclerotic progression and acute thrombosis: clinical evidence from the Physicians' Health study.
        Am. Heart J. 1991; 122: 1588
        • Willis A.L.
        • Smith D.L.
        Therapeutic impact of eicosanoids in atherosclerotic disease.
        Eicosanoids. 1989; 2: 69
        • Akopov S.E.
        • Orekhov A.X.
        • Tertov V.V.
        • Khashimov H.A.
        • Gabrielyan E.S.
        • Smirnov V.N.
        Stable analogues of prostacyclin and throm☐ane AZ display contradictory influences on atherosclerotic properties of cells cultured from human aorta.
        Atherosclerosis. 1988; 72: 245
        • Shirotani M.
        • Yui Y.
        • Hattori R.
        • Kawai C.
        U-61, 413F, a stable prostacyclin analogue, inhibits the proliferation of bovine vascular smooth muscle cells with little antiproliferative effect on endothelial cells.
        Prostaglandins. 1991; 41: 97
        • Hajjar D.P.
        • Pomerantz K.B.
        Eicosanoids and their role in atherosclerosis.
        Arch. Mal. Coeur Vaiss. 1989; 82: 21
        • Jellinek H.
        • Stock G.
        • Taka´csm E.
        Lipofundin arteriosclerosis and iloprost treatment.
        in: Gryglewski R. Stock G. Prostacyclin and its Stable Analogue Iloprost. Springer, Heidelberg1987: 269
        • Dong Y.J.
        • Jones R.L.
        • Wilson N.H.
        Prostaglandin E receptor subtypes in smooth muscle: agonist activities of stable prostacyclin analogues.
        Br. J. Pharmacol. 1986; 87: 97
        • Hildebrand M.
        • Staks T.
        • Schutt A.
        • Matthes H.
        Pharmacokinetics of 3H-cicaprost in healthy volunteers.
        Prostaglandins. 1989; 37: 259
        • Lo¨bel P.
        • Schro¨r K.
        Stimulation of vascular prostacyclin and inhibition of platelet function by oral defibrotide in cholesterol-fed rabbits.
        Atherosclerosis. 1989; 80: 69
        • Schro¨r K.
        • Seidel H.
        Blood-vessel wall arachidonate metabolism and its pharmacological modification in a new in vitro assay system.
        Naunyn-Schmiedeberg's Arch. Pharmacol. 1988; 337: 177
        • Tono-Oka T.
        • Uena N.
        • Matsumoto N.
        • Ohkawa M.
        • Matsumoto S.
        Chemiluminescence of whole blood. A simple and rapid method for the estimation of phagocytic function of granulocytes and opsonic activity in whole blood.
        Clin. Immunol. Immunopathol. 1983; 36: 66
        • Myers S.I.
        • Russel D.H.
        • Parks L.
        • Reed M.K.
        Triphasic response of prostacyclin in rabbit thoracic aorta in early atherosclerosis.
        Prostagl. Leukotr. Essent. Fatty Acids. 1991; 44: 31
        • Rolland P.H.
        • Jouve R.
        • Pellegrin E.
        • Mercier C.
        • Serradimigni A.
        Alteration in prostacyclin and prostaglandin E2 production. Correlation with changes in human aortic atherosclerotic disease.
        Arteriosclerosis. 1984; 4: 70
        • Minor R.L.
        • Myers P.R.
        • Guerra R.
        • Bates J.N.
        • Harrison D.C.
        Diet-induced atherosclerosis increases the release of nitrogen oxides from rabbit aorta.
        J. Clin. Invest. 1990; 86: 2109
        • Woditsch I.
        • Hohlfeld Th.
        • Schro¨r K.
        Reduced endothelium-dependent relaxation in hypercholesterolaemic rabbits is not due to diminished forma tion of nitric oxide.
        in: Moncada S. Biology of Nitric Oxide. Portland Press, London1992: 196
        • Takahashi M.
        • Yui Y.
        • Yasumoto H.
        • Aoyama T.
        • Morishita H.
        • Hattori R.
        • Kawai C.
        Lipoproteins are inhibitors of endothelium-dependent relaxation of rabbit aorta.
        Am. J. Physiol. 1990; 258: H1
        • Simon B.C.
        • Cunningham L.D.
        • Cohen R.A.
        Oxidized low density lipoproteins cause contraction and inhibit endothelium-dependent relaxation in the pig coronary artery.
        J. Clin. Invest. 1990; 86: 75
        • Mu¨gge A.
        • Elwell J.H.
        • Peterson T.E.
        • Hofmeyer T.G.
        • Heistad D.D.
        • Harrison D.G.
        Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits.
        Circ. Res. 1991; 69: 1293
        • Tagawa H.
        • Tomoike H.
        • Nakamura M.
        Putative mechanisms of the impairment of endothelium-dependent relaxation of the aorta with atheromatous plaque in heritable hyperlipidemic rabbits.
        Circ. Res. 1991; 68: 330
        • Wautier J.L.
        • Setiadi H.
        • Vilette D.
        • Weill D.
        • Wautier M.P.
        Leukocyte adhesion to endothelial cells.
        Biorheology. 1990; 27: 425
        • Croft K.D.
        • Beilin L.J.
        • Vandongen R.
        • Rouse I.
        • Masarei J.
        Leukocyte and platelet function and eicosanoid production in subjects with hypercholesterolemia.
        Atherosclerosis. 1990; 83: 101
        • Carvalho A.C.A.
        • Colman R.W.
        • Lees R.S.
        Platelet function in hyperlipoproteinemia.
        N. Engl. J. Med. 1974; 290: 434
        • Tremoli E.
        • Maderna P.
        • Colli S.
        • Morazzoni G.
        • Sirtori M.
        • Sirtori C.R.
        Increased platelet sensitivity and throm☐ane B2 formation in type Ila hyperlipoproteinaemic patients.
        Eur. J. Clin. Invest. 1984; 14: 329
        • Dalal K.B.
        • Ebbe S.
        • Mazoyer E.
        • Carpenter D.
        • Yee T.
        Biochemical and functional abnormalities in hypercholesterolemic rabbit platelets.
        Lipids. 1990; 25: 86
        • Schro¨r K.
        • Lo¨bel P.
        • Steinhagen-Thiessen E.
        Simvastatin reduces platelet throm☐ane formation and restores normal sensitivity against prostacyclin in type Ila hypercholesterolemia.
        Eicosanoids. 1989; 2: 39
        • Strano A.
        • Davi G.
        • Averna M.
        • Rini G.B.
        • Novo S.
        • DiFede G.
        • Mattini A.
        • Notarbartolo A.
        Platelet sensitivity to prostacyclin and throm☐ane production in hyperlipidemic patients.
        Thromb. Haemostasis. 1982; 48: 18
        • Fredrich M.
        • Muller B.
        Prostacyclin and atherosclerosis.
        in: Rubanyi G.M. Vane J. Prostacyclin: New Perspectives for Basic Research and Novel Therapeutic Indications. Elsevier, Amsterdam1992: 169
        • Garg U.C.
        • Hassid A.
        Nitric-oxide generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells.
        J. Clin. Invest. 1989; 83: 1774