Advertisement

Prostacyclin and thromboxane A2 biosynthesis capacities of heart, arteries and platelets at various stages of experimental atherosclerosis in rabbits

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

      Abstract

      Atherosclerosis was induced by feeding rabbits with 1 g of cholesterol and 3 g of olive oil daily for 1, 3 and 5 months. Arachidonic acid (AA)-induced generation of prostacyclin (PGI2) by perfused hearts and spontaneous generation of PGI2 by slices of mesenteric arteries and aortas were strongly suppressed after 1 and 3 months of the diet, while after 5 months a tendency for PGI2 synthesizing capacity to recover was observed. Aggregatability of blood platelets in platelet-rich plasma (PRP) by exogenous AA and endogenous thromboxane A2 (TXA2) was increased but not earlier than 3 months on the diet. On the other hand, platelet sensitivity to the pro-aggregatory action of adenosine diphosphate (ADP) and to the anti-aggregatory action of PGI2 was heightened as early as 1 month from the beginning of the experiment. These findings suggest that the first stage of experimental atherosclerosis may be causally related to the strong suppression of PGI2 generation by arteries, whereas the metabolism of AA in platelets remains unchanged. At this early stage of atherosclerosis increased susceptibility of platelets in PRP to both ADP and PG12 may be due to the lowering of cyclic AMP levels in platelets as a consequence of PGI2 deficiency. A genuine enhancement of AA metabolism in blood platelets occurs only at the second stage of experimental atherosclerosis. This stage is particularly dangerous since an increased generation of TXA2 by platelets in PRP is combined with a decreased generation of PGI2 by arteries. At the last stage of atherosclerosis observed, a slow recovery of the enzymic activity occurs in arteries.

      Keywords

      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:

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

      References

        • Gryglewski R.J.
        • Bunting S.
        • Moncada S.
        • Flower R.J.
        • Vane J.R.
        Arterial walls are protected against deposition of platelet thrombi by a substance (prostaglandin X) which they make from prostaglandin endoperoxides.
        Prostaglandins. 1976; 12: 685
        • Hamberg M.
        • Svensson J.
        • Samuelsson B.
        Thromboxanes - A new group of biologically active compounds derived from prostaglandin endoperoxides.
        in: 2nd edition. Proc. Nat. Acad. Sci. (U.S.A.). 74. 1975: 2994
        • Moncada S.
        • Gryglewski R.J.
        • Bunting S.
        • Vane J.R.
        An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation.
        Nature (Lond.). 1976; 263: 663
      1. Gryglewski, R.J., Korbut, R. and Ocetkiewicz, A., Generation of prostacyclin by lungs in vivo and its release into the arterial circulation, Nature (Lond.), In press.

        • Johnson R.A.
        • Lincoln F.H.
        • Thompson J.L.
        • Nidy E.G.
        • Mizsak S.A.
        • Axen U.
        Synthesis and stereochemistry of prostacyclin and synthesis of 6-keto-prostaglandin Flo.
        J. Amer. Chem. Soc. 1977; 99: 12
        • Ellis E.
        • Oelez O.
        • Roberts II, J.
        • Payne N.
        • Oates J.
        Coronary arterial smooth muscle contracted by a substance released by platelets - Evidence that it is thromboxane A2.
        Science. 1976; 193: 638
        • Gorman R.
        • Bunting S.
        • Miller O.V.
        Modulation of human platelet adenylate cyclase by prostacyclin (PGX).
        Prostaglandins. 1977; 13: 377
        • Moncada S.
        • Gryglewski R.J.
        • Bunting S.
        • Vane J.R.
        A lipid peroxide inhibits the enzyme in blood vessel microsomes that generates from prostaglandin endoperoxides the substance (prostaglandin X) which prevents platelet aggregation.
        Prostaglandins. 1976; 12: 715
        • Dembiriska-Kieć A.
        • Gryglewska T.
        • Żmuda A.
        • Gryglewski R.J.
        The generation of prostacyclin by arteries and by the coronary vascular bed in reduced experimental atherosclerosis in rabbits.
        Prostaglandins. 1977; 14: 1025
        • Żmuda A.
        • Dembinska-Kiec A.
        • Chytowski A.
        • Gryglewski R.J.
        Experimental atherosclerosis in rabbits - Platelet aggregation, thromboxane A2 generation and anti-aggregatory potency of prostacyclin.
        Prostaglandins. 1977; 14: 1035
        • Proudlock J.W.
        • Day J.
        Cholesterol esterifying enzymes of atherosclerosic rabbit intima.
        Biochim. Biophys. Acta. 1972; 260: 716
        • Dusting G.J.
        • Moncada S.
        • Vane J.R.
        Prostacyclin is the endogenous metabolite of arachidonic acid which relaxes coronary arteries.
        Prostaglandins. 1977; 13: 3
        • Bunting S.
        • Moncada S.
        • Vane J.R.
        The effects of prostaglandin endoperoxides and thromboxane A2 on strips of rabbit coeliac artery and certain other smooth muscle preparations.
        Brit. J. Pharmacol. 1976; 57: 462
        • Gilmore N.
        • Vane J.R.
        • Willis J.H.
        Prostaglandins released by the spleen.
        Nature (Lond.). 1968; 218: 1935
        • Keirse M.
        • Turnbull A.
        Extraction of prostaglandins from human blood.
        Prostaglandins. 1973; 4: 607
        • Cottee F.
        • Flower R.J.
        • Salmon J.A.
        • Vane J.R.
        Synthesis of 6-keto-PGFla by ram seminal vesicle microsomes.
        Prostaglandins. 1977; 14: 413
        • Bergstrom S.
        • Danielsson H.
        • Samuelsson B.
        The enzymatic formation of prostaglandin EZ from arachidonic acid.
        Biochim. Biophys. Acts. 1964; 90: 207
        • Van Dorp D.A.
        • Beerthuis R.K.
        • Nugteren D.H.
        • Vonkeman H.
        The biosynthesis of prostaglandins.
        Biochim. Biophys. Acts. 1964; 90: 204
        • Blackwell G.J.
        • Duncombe W.G.
        • Flower R.J.
        • Parsons M.F.
        • Vane J.R.
        The distribution and metabolism of arachidonic acid in rabbit platelets and its modification by drugs.
        Brit. J. Pharmacol. 1977; 59: 353
        • Selivonchick D.P.
        • Roots B.J.
        Lipid and fatty acyl composition of rat brain capillary endothelia isolated by a new method.
        Lipids. 1976; 12: 165
        • Nugteren D.H.
        Arachidonate lipoxygenase in blood platelets.
        Biochim. Biophys. Acts. 1975; 380: 299
        • Hamberg M.
        • Samuelsson B.
        Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets.
        in: 2nd edition. Proc. Nat. Acad. Sci. (U.S.A.). 71. 1974: 3400
        • Hamberg M.
        • Samuelsson B.
        Detection and isolation of an endoperoxide intermediate in prostaglandin biosynthesis.
        in: 2nd edition. Proc. Nat. Acad. Sci. U.S.A.70. 1973: 899
        • Nugteren D.H.
        • Hazelhof E.
        Isolation and properties of intermediates in prostaglandin biosynthesis.
        Biochim. Biophys. Acts. 1973; 326: 448
        • Berberian P.A.
        • Ziboh V.A.
        • Hsia S.L.
        Prostaglandin EZ biosynthesis changes in rabbit aorta and skin during experimental atherogenesis.
        J. Lipid Res. 1976; 17: 47
        • Herman A.G.
        • Moncada S.
        • Vane J.R.
        Formation of prostacyclin (PGIZ) by different layers of the arterial wall.
        Arch. Int. Pharmacodyn. Ther. 1977; 227: 162
        • Weksler B.B.
        • Marcus A.J.
        • Jaffe E.A.
        Synthesis of prostaglandin IZ (prostacyclin) by cultured human and bovine endothelial cells.
        in: 2nd edition. Proc. Nat. Acad. Sci. U.S.A.74. 1977: 3922
        • MacIntyre D.E.
        • Pearson J.D.
        • Gordon J.L.
        Localisation and stimulation of prostacyclin production in vascular cells.
        Nature (London). 1978; 271: 549
        • Baenziger N.L.
        • Dillander M.J.
        • Majerus P.W.
        Cultured human skin fibroblasts and arterial cells produce a labile platelet-inhibitory prostaglandin.
        Biochem. Biophys. Res. Commun. 1977; 78: 294
        • Tansik R.L.
        • Namm D.H.
        • White H.L.
        Synthesis of prostaglandin 6-keto-F1a by cultured aortic smooth muscle cells and stimulation of its formation in a coupled system with platelet lysates.
        Prostaglandins. 1978; 15: 399
        • Wedt C.E.
        • Redgrave T.G.
        Reservations on the use of polyunsaturated fats in human nutrition.
        Int. Lab. March/April, 1975; : 45
        • Di Luzio N.R.
        Antioxidants, lipid peroxidation and clinical-induced liver injury.
        in: 2nd edition. Fed. Proc.32. 1973: 1875
        • Glavind J.
        • Hartman S.
        • Clemensen J.
        • Jessen K.E.
        • Dam H.
        Studies on the role of lipid peroxides in human pathology, Part 2 (The presence of peroxidized lipids in the atherosclerotic aorta).
        Acts, Pathol. Microbiol. Scand. 1952; 30: 1
        • Flipovic I.
        • Rutemöller M.
        Comparative studies on fatty acid synthesis in atherosclerotic and hypoxic human aorta.
        Atherosclerosis. 1976; 24: 457