Multiple Inhibition of Platelet Activation by Aurintricarboxylic Acid Prevents Vascular Stenosis after Endothelial Injury in Hamster Carotid Artery

Hiroyuki Matsuno; Osamu Kozawa; Masayuki Niwa; Kumiko Tanabe; Katsuhiro Ichimaru; Yoshiharu Takiguchi; Masayuki Yokota; Hideharu Hayashi; Toshihiko Uematsu

doi:10.1055/s-0037-1615079

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1998; 79(04): 865-871
DOI: 10.1055/s-0037-1615079

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Schattauer GmbH

Multiple Inhibition of Platelet Activation by Aurintricarboxylic Acid Prevents Vascular Stenosis after Endothelial Injury in Hamster Carotid Artery

Authors

Hiroyuki Matsuno

¹From the Department of Pharmacology, Gifu University School of Medicine, Japan
Osamu Kozawa

¹From the Department of Pharmacology, Gifu University School of Medicine, Japan
Masayuki Niwa

¹From the Department of Pharmacology, Gifu University School of Medicine, Japan
Kumiko Tanabe

¹From the Department of Pharmacology, Gifu University School of Medicine, Japan
Katsuhiro Ichimaru

²From the Department of Clinical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan
Yoshiharu Takiguchi

²From the Department of Clinical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan
Masayuki Yokota

²From the Department of Clinical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan
Hideharu Hayashi

³From the Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan
Toshihiko Uematsu

¹From the Department of Pharmacology, Gifu University School of Medicine, Japan

Abstract

Summary

Activated platelets are instrumental in restenosis due to their role in thrombus formation. Aurintricarboxylic acid (ATA) has been reported to prevent platelet activation by inhibiting von Willebrand factor binding to platelet glycoprotein (GP) Ib. We investigated the effects of ATA in vitro and in vivo in hamsters. ATA inhibited the in vitro platelet aggregation induced by ADP, botrocetin and thrombin, but not by collagen. The IC₅₀ values during the ex vivo platelet aggregation by ADP, botrocetin and thrombin were 8.2 ± 1.8 μM, 0.9 ± 0.4 μg/ml and 2.4 ± 0.8 unit/ml, respectively. The platelet retention time to collagen-coated beads of hamster blood samples was inhibited by ATA (0.1, 0.3 and 1.0 mg/kg per hour) in a dose-dependent manner. Continuous administration of ATA (0, 0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg per h) via an infusion pump produced dose-dependent antithrombotic effects: the time to occlude the carotid artery after vascular injury with a modified catheter was prolonged. Only when infused at doses of 3.0 and 10.0 mg/kg per hour, bleeding times were significantly prolonged. The continuous treatment with ATA (1.0 mg/kg per h) using a 2ML1 Alzet infusion pump for 2 weeks, resulted in a decrease in neointimal area by 22.2 ± 6.8% when measured 2 weeks after injury induction. DNA synthesis using DDT1MF2 hamster SMCs was decreased by ATA in a dose-dependent manner. ATA reduced the number of platelets adhering on the injured area, as detected by electron microscopy. These results indicated that treatment with ATA inhibited platelet adhesion but also SMC proliferation. These observations may explain the effect of ATA on neointima formation.

Full Text

References

References
1 Phillips MD, Moake JL, Nolasco L, Turner N. Aurintricarboxylic acid: a novel inhibitor of the association of von Willebrand factor and platelets. Blood 1988; 72: 1898-903.
2 Strony J, Phillips M, Brands D, Moake J, Adelman B. Aurintricarboxylic acid in a canine model of coronary artery thrombosis. Circulation 1990; 81: 1106-14.
3 Takiguchi Y, Shimazawa M, Nakashima M. A comparative study of the antithrombotic effect of aurintricarboxylic acid on arterial thrombosis in rats and guinea-pigs. Br J Pharmacol 1996; 118: 1633-8.
4 Kawasaki T, Kaku S, Kohinata T, Sakai Y, Taniuchi Y, Kawamura K, Yano S, Takenaka T, Fujimura Y. Inhibition by aurintricarboxylic acid of von Willebrand factor binding to platelet GPIb, platelet retention, and thrombus formation in vivo. Am J Hematol 1994; 47: 6-15.
5 Coller BS, Peerschke EI, Scudder LE, Sullivan CA. Studies with a murine monoclonal antibody that abolishes ristocetin-induced binding of von Willebrand factor to platelets: additional evidence in support of GPIb as a platelet receptor for von Willebrand factor. Blood 1983; 61: 99-110.
6 Ikeda Y, Handa M, Kawano K, Kamata T, Murata M, Araki Y, Anbo H, Kawai Y, Watanabe K, Itagaki I. The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress. J Clin Invest 1991; 87: 1234-40.
7 Miller JL, Thiam-Cisse M, Drouet LO. Reduction in thrombus formation by PG-1 F(ab’)2, an anti-guinea pig platelet glycoprotein Ib monoclonal antibody. Arterioscler Thromb 1991; 11: 1231-6.
8 Gagliardi AR, Collins DC. Inhibition of angiogenesis by aurintricarboxylic acid. Anticancer Research 1994; 14: 475-9.
9 Matsuno H, Kozawa O, Niwa M, Uematsu T. Inhibition of von Willebrand factor binding to platelet GP Ib by a fractionated aurintricarboxylic acid prevents restenosis after vascular injury in hamster carotid artery. Circulation 1998; 96: 1299-304.
10 Kerins DM, Roy L, Fitzgerald GA, Fitzgerald DJ. Platelet and vascular function during coronary thrombolysis with tissue-type plasminogen activator. Circulation 1989; 80: 1718-25.
11 Fuster V, Chesebro JH. Mechanism of unstable angina. N Engl J Med 1986; 315: 1023-5.
12 Willerson JT, Hillis LD, Winniford M, Buja LM. Speculation regarding mechanisms responsible for acute ischemic heart disease syndromes. J Am Coll Cardiol 1986; 8: 245-50.
13 Coller BS, Folts JD, Scudder LE, Smith SR. Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model. Blood 1986; 68: 783-6.
14 Fingerle J, Johnson R, Clowes AW, Majesky MW, Reidy MA. Role of platelets in smooth muscle cell proliferation and migration after vascular injury in rat carotid artery. Proc Natl Acad Sci 1989; 86: 8412-61.
15 Kiss RG, Stassen JM, Deckmyn H, Roskams T, Gold HK, Plow EF, Collen D. Contribution of platelets and the vessel wall to the antithrombotic effects of a single bolus injection of Fab fragments of the antiplatelet GPIIb/IIIa antibody 7E3 in a canine arterial eversion graft preparation. Arteriosclerosis Thrombosis 1994; 14: 375-80.
16 Konstantopoulos K, Kamat SG, Schafer AI, Banez EJ, Jordan R, Kleiman NS, Hellums JD. Shear-induced platelet aggregation is inhibited by in vivo infusion of an anti-glycoprotein IIb/IIIa antibody fragment, c7E3Fab, in patients undergoing coronary angioplasty. Circulation 1995; 91: 1427-31.
17 Matsuno H, Stassen JM, Vermylen J, Deckmyn H. Inhibition of integrin function by a cyclic RGD-containing peptide prevents neointima formation. Circulation 1994; 90: 2203-6.
18 Fujimura Y, Titani K, Usami Y, Suzuki M, Oyama R, Matsui T, Fukui H, Sugimoto M, Ruggeri ZM. Isolation and chemical characterization of two structurally and functionally distinct forms of botrocetin, the platelet coagglutinin isolated from the venom of Bothrops jararaca. Biochemistry 1991; 30: 1957-64.
19 Tomita T, Umegaki K, Hayashi E. Basic properties of washed platelets: correlation between aggregation, phospho lipid degradation, malondialde-hyde, and thromboxane formation. J Pharmacol Methods 1983; 10: 31-44.
20 Matsuno H, Stassen JM, Hoylaerts MF, Vermylen J, Deckmyn H. Fast and reproducible vascular neointima formation in the hamster carotid artery: effects of trapidil and captopril. Thromb Haemost 1995; 74: 1591-6.
21 Matsuno H, Uematsu T, Umemura K, Takiguchi Y, Wada K, Nakashima M. Effects of vapiprost, a novel thromboxane receptor antagonist, on thrombus formation and vascular patency after thrombolysis by tissue-type plasminogen activator. Br J Pharmacol 1992; 106: 533-8.
22 Collen D, Lu HR, Stassen JM, Vreys I, Yasuda T, Bunting S, Gold HK. Antithrombotic effects and bleeding time prolongation with synthetic platelet GPIIb/IIIa inhibitors in animal models of platelet-mediated thrombosis. Thromb Haemost 1994; 71: 95-102.
23 Matsuno H, Uematsu T, Nagashima S, Nakashima M. Photochemically induced thrombosis model in rat femoral artery and evaluation of effects of heparin and tissue-type plasminogen activator with use of this model. J Pharmacol Methods 1991; 25: 303-17.
24 Coller BS, Seligsohn U, West SM, Scudder LE, Norton KJ. Platelet fibrinogen and vitronectin in Glanzmann thrombasthenia: evidence consistent with specific roles for glycoprotein IIb/IIIa and αvβ3 integrins in platelet protein trafficking. Blood 1991; 78: 2603-10.
25 Gold HK, Gimple LW, Yasuda T, Leinbach RC, Werner W, Holt R, Jordan R, Berger H, Collen D, Coller BS. Pharmacodynamic study of F(ab’)2 fragments of murine monoclonal antibody 7E3 directed against human platelet glycoprotein IIb/IIIa in patients with unstable angina pectoris. J Clin Invest 1990; 86: 651-9.
26 Ferns GA, Raines EW, Sprugel KH, Motani AS, Reidy MA, Ross R. Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science 1991; 253: 1129-32.
27 Kang SS, Gosselin C, Ren D, Greisler HP. Selective stimulation of endothelial cell proliferation with inhibition of smooth muscle cell proliferation by fibroblast growth factor-1 plus heparin delivered from fibrin glue suspensions. Surgery 1995; 118: 280-7.
28 Kaida T, Matsuno H, Niwa M, Kozawa O, Miyata H, Uematsu T. Antiplatelet effect of FK633, a platelet glycoprotein IIb/IIIa antagonist, on thrombus formation and vascular patency after thrombolysis in the injured hamster carotid artery. Thromb Haemost 1998; 77: 562-7.
29 Umemura K, Nishiyama H, Kikuchi S, Kondo K, Nakashima M. Inhibitory effect of a novel orally active GPIIb/IIIa inhibitor, SC-54684A on intimal ticketing in the guinea pig femoral artery. Thromb Hamost 1996; 76: 799-806.
30 Matsuno H, Stassen JM, Moons L, Vermylen J, Hoylaerts MF. Neointima formation in injured hamster carotid artery is effectively prevented by the combination G4120 and quinapril. Thromb Haemost 1996; 76: 263-9.
31 Golino P, Ambrosio G, Ragni M, Cirillo P, Esposito N, Willerson JT, Rothlein R, Petrucci L, Condorelli M, Chiariello M, Buja LM. Inhibition of leukocyte and platelet adhesion reduced neointima hyperplasia after injury. Thromb Haemost 1998; 77: 783-8.