The Inhibitory Effect of GR32191, a Thromboxane Receptor Blocking Drug, on Human Platelet Aggregation, Adhesion and Secretion

E J Hornby; M R Foster; P J McCabe; L E Stratton

doi:10.1055/s-0038-1646609

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1989; 61(03): 429-436
DOI: 10.1055/s-0038-1646609

Original Article

Schattauer GmbH Stuttgart

The Inhibitory Effect of GR32191, a Thromboxane Receptor Blocking Drug, on Human Platelet Aggregation, Adhesion and Secretion

E J Hornby

The Department of Feripheral Pharmacology, Glaxo Group Research Limited, Ware, Herts, UK

,

M R Foster

The Department of Feripheral Pharmacology, Glaxo Group Research Limited, Ware, Herts, UK

,

P J McCabe

The Department of Feripheral Pharmacology, Glaxo Group Research Limited, Ware, Herts, UK

,

L E Stratton

The Department of Feripheral Pharmacology, Glaxo Group Research Limited, Ware, Herts, UK

› Author Affiliations

Abstract

PDF Download

Summary

GR32191, a potent selective thromboxane receptor antagonist, has been shown to inhibit completely prostaglandin endoperoxide and thromboxane A₂ (TxA₂)-induced platelet aggregation, [¹⁴C]-serotonin secretion and β-thromboglobulin secretion. Deposition of human platelets onto damaged rabbit aorta in vitro is reduced in the presence of GR32191 which appears to inhibit aggregation of platelets but not direct adhesion of platelets to subendothelium. The effects of non-prostanoid platelet activating agents whose mode of action requires the biosynthesis of TxA₂ are also inhibited by GR32191. Prostanoids which inhibit platelet function, such as prostacyclin or PGD₂, retain their inhibitory properties in the presence of GR32191 which does not inhibit phospholipase A₂, prostaglandin cyclooxygenase, thromboxane synthase, 12-lipoxygenase or cAMP phosphodiesterase activity. The inhibitory action of GR32191 on platelet aggregation, mural thrombus formation and platelet protein storage granule secretion suggests that it has potential in treatingthrombotic disease in man.

Keywords

GR32191 - Thromboxane receptor antagonist - Adhesion - Secretion - Platelet aggregation

PDF (457 kb)

References

References
1 Stemerman MB, Baumgartner HR, Spaet TH. The subendothelial microfibril and platelet adhesion. Lab Invest 1971; 24: 179-186
2 Baumgartner HR. The role of blood flow in platelet adhesion fibrin deposition and formation of mural thrombi. Microvase Res 1973; 5: 167-171
3 Holmsen H. Biochemistry of the platelet release reaction. Ciba Found Symp 1975; 35: 175-205
4 Niewiarowski S, Stuart RK. Thomas D R Activation of intravascular coagulation by collagen. Proc Soc Exp Biol Med 1966; 123: 196-200
5 Hamberg M, Svensson J, Samuelsson B. Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 1975; 72: 2994-2998
6 Svensson J, Hamberg M, Samuelsson B. On the formation and effects of thromboxane A₂ in human platelets. Acta Physiol Scand 1976; 98: 285-294
7 Moncada S, Vane JR. Arachidonic acid metabolites and the interactions between platelets and blood-vessel walls. N Eng J Med 1979; 300: 1142-1147
8 Ross R, Raines E, Bowen-Pope D. Growth factors from platelets, monocytes and endothelium: their role in cell proliferation. Ann NY Acad Sci 1982; 397: 18-24
9 Bowen-Pope DF, Ross R, Siefert RA. Locally acting growth factors for vascular smooth muscle cells: endogenous synthesis and release from platelets. Circulation 1985; 72: 735-740
10 Ross R, Glomset J, Kariya B, Harker L. A platelet dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci USA 1974; 71: 1207-1210
11 Like B, Massague J. The antiproliferative effect of type β transforming growth factor occurs at a level distal from receptors for growth activating factors. J Biol Chem 1986; 261: 13426-13429
12 Heimark RL, Twardzik DR, Schwarz SM. Inhibition of endothelial regeneration by type β transforming growth factor from platelets. Science 1986; 233: 1078-1080
13 Assoian RK, Grotendorst GR, Miller DM, Spom MB. Cellular transformation by co-ordinated action of three peptide growth factors from human platelets. Nature 1984; 309: 804-806
14 Lumley P, Collington EW, Hallet P, Hornby EJ, Humphrey PP A, Wallis CJ, Jack DJ, Brittain RT. The effects of GR32191, a new thromboxane receptor blocking drug, on platelets and vascular smooth muscle in vitro. Thromb Haemostas 1987; 58: 261 (Abstr 955)
15 Thomas M, Lumley P, Ballard P, O’Brien JR. Initial studies in man with a novel thromboxane receptor blocking drug GR32191. Thromb Haemostas 1987; 58: 181 (Abstr 668)
16 Born GV R. Quantitative investigations into the aggregation of blood platelets. J Physiol 1962; 162: 67 P
17 Tangen O, McKinnon EL, Berman HJ. On the fine structure and aggregation requirements of gel filtered platelets (GFP). Scand J Haematol 1973; 10: 96-105
18 Moore S, Pepper DS, Cash JD. The isolation and characterisation of a platelet specific β globulin (β thromboglobulin) and the detection of antiurokinase and antiplasmin released from thrombin-aggregated washed human platelets. Biochim Biophys Acta 1975; 379: 360-369
19 Dawes J, Clemetson KJ, Gogstad GO, McGregor J, Clezardin P, Prowse CV, Pepper DS. A radioimmunoassay for thrombospondin, used in a comparative study of thrombospondin, β thromboglobulin and platelet factor 4 in healthy volunteers. Thromb Res 1983; 29: 569-581
20 Caldwell BV, Burstein S, Brock WA, Speroff L. Radioimmunoassay of F prostaglandins. J Clin Endocrinol Metab 1971; 33: 171-175
21 Flower RJ, Cheung HS, Cushman DW. Quantitative determination of prostaglandins and malondialdehyde formed by the arachidonate oxygenase (prostaglandin synthetase) system of bovine seminal vesicles. Prostaglandins 1973; 4: 325-341
22 White HL, Glassman AT. A simple radiochemical assay for prostaglandin synthetase. Prostaglandins 1974; 7: 123-129
23 Hillier K, Dilley SR. Separation and radioimmunoassay of F prostaglandins using silica gel micro columns. Prostaglandins 1974; 5: 137-150
24 Yoshimoto T, Yamamoto S, Hayaishi O. Selective inhibition of prostaglandin endoperoxide thromboxane isomerase by 1-carboxyalkylimidazole. Prostaglandins 1978; 16: 529-540
25 Gorman RR, Sun FF, Miller OV, Johnson RA. Prostaglandins H₁and H₂. Convenient biochemical synthesis and isolation. Further biological and spectroscopic characterisation. Prostaglandins 1977; 13: 1043-1053
26 Salmon JA, Smith DR, Flower RJ, Moncada S, Vane JR. Further studies on the enzymatic conversion of prostaglandin endoperoxide into prostacyclin by porcine aorta microsomes. Biochim Biophys Acta 1978; 523: 250-262
27 Nugteren DH. Arachidonate lipoxygenase in blood platelets. Biochim Biophys Acta 1975; 380: 299-307
28 Blackwell GJ, Duncombe WG, Flower RJ, Parsons MF, Vane JR. The distribution and metabolism of arachidonic acid in rabbit platelets during aggregation and its modification by drugs. Br J Pharmacol 1977; 59: 353-366
29 Somerville AR, Rabouhans ML, Smith AA. Adenosine 3’:5’-cyclic monophosphate phosphodiesterase: kinetic and inhibition studies. Biochem J 1970; 120: 11P-12P
30 Coleman RA, Humphrey PP A, Kennedy I, Levy GP, Lumley P. Comparison of the actions of U46619, a prostaglandin H₂ analogue, with those of prostaglandin H₂ and thromboxane A₂ on some isolated smooth muscle preparations. Br J Pharmacol 1981; 73: 773-778
31 Humphrey PP A, Lumley P, White BP. The agonist action of AH23848 at guinea-pig vascular and airways smooth muscle TP receptors in vivo. Br J Pharmacol 1986; 89: 820 P
32 Authi KS, Hornby EJ, Evenden BJ, Crawford N. Inositol 1,4,5- triphosphate (IP₃) induced rapid formation of thromboxane B₂ in saponin-permeabilised human platelets: mechanism of IP₃ action. FEBS Letts 1987; 213: 95-101
33 Cross PE, Dickinson RP, Parry MJ, Randall MJ. 3-(1-imidazolyl methyl) indoles: Potent and selective inhibitors of human blood platelet thromboxane synthetase. Agents Actions 1981; 11: 274-280
34 Hornby EJ, Skidmore IF. Evidence that prostaglandin endoperoxides can induce platelet aggregation in the absence of thromboxane A₂production. Biochem Pharmacol 1982; 31: 1158-1160
35 Heptinstall S, Bevan J, Cockbill SR, Hanley SP, Parry MJ. Effect of a selective inhibitor of thromboxane synthetase on human blood platelet behaviour. Thromb Res 1980; 20: 219-230
36 Hornby EJ, Skidmore IF. Reduction in TxB₂ production as a consequence of thromboxane receptor blockade in human platelet rich plasma. Br J Pharmacol 1984; Proc Suppl (Suppl. 38) 432
37 Best LC, McGuire MB, Martin TJ, Preston FE, Russell RG. Effects of epoxymethano analogues of prostaglandin endoperoxides on aggregation, on release of 5-hydroxytryptamine and on metabolism of 3’, 5’-cyclic AMP and cyclic GMP in human platelets. Biochim Biophys Acta 1979; 583: 344-351
38 Stratton L, Hornby E. Inhibition of human platelet aggregation by the thromboxane mimetic, U46619. Thromb Haemostas 1987; 58: 470 (Abstr 1741)
39 Armstrong RA, Jones RL, Peesapati V, Will SG, Wilson NH. Competitive antagonism at thromboxane receptors in human platelets. Br J Pharmacol 1985; 84: 595-607
40 Armstrong RA, Jones RL, Wilson NH. Ligand binding to thromboxane receptors on human platelets: correlation with biological activity. Br J Pharmacol 1983; 79: 953-964
41 Thompson NT, Scrutton MC, Wallis RB. Synergistic responses in human platelets. Comparison between aggregation, secretion and cytosolic Ca²⁺ concentration. Eur J Biochem 1986; 161: 399-408
42 Smith JB, Ingerman CM, Silver MJ. Platelet prostaglandin production and its implications. Adv Prostaglandin Thromboxane Res 1976; 2: 747-753
43 Sturk A, Asyee GM, Schaap MC, van Maanen M, ten-Cate JW. Synergistic effects of platelet-activating factor and other platelet agonists in human platelet aggregation and release. The role of ADP and products of the cyclooxygenase pathway. Thromb Res 1985; 40: 359-372
44 Higgs EA, Moncada S, Vane JR, Caen JP, Michel H, Tobelem G. Effects of prostacyclin (PGI₂) on platelet adhesion to rabbit arterial subendoethelium. Prostaglandins 1978; 16: 17-22
45 McCabe PJ, Stratton LE, Hornby EJ, Foster M. Inhibition of guinea-pig platelet function in vivo and ex vivo using the thromboxane A₂ antagonists AH23848 and GR32191. Thromb Haemostas 1987; 58: 182 (Abstr 669)
46 McCollum CN, Harper RA, Lane IF, Meek AC. A specific thromboxane A₂ antagonist GR32191, reduces platelet deposition in PTFE grafts. Thromb Haemostas 1987; 58: 261 (Abstr 954)
47 Kinlough-Rathbone RL, Cazenave JP, Packham MA, Mustard JF. Effects of inhibitors of the arachidonate pathway on the release of granule contents from rabbit platelets adherent to collagen. Lab Invest 1980; 42: 28-34
48 Brittain RT, Boutal L, Carter MC, Coleman RA, Collington EW, Geisow HP, Hallet P, Hornby EJ, Humphray PP, Jack D. et al AH23848 a thromboxane receptor blocking drug that can clarify the pathophysiological role of thromboxane A₂ . Circulation 1985; 72: 1208-1218
49 Lewis Jr HD. Unstable angina: status of aspirin and other forms of therapy. Circulation 1985; 72 P V155-V160
50 Cairns JA, Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, Jablonsky G, Kostuk WJ, Melendez LJ, Myers M-G. et al Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N tngl J Med 1985; 313: 1369-1375
51 Hennekens CH, Peto R, Hutchison GB, Doll R. An overview of the British and American aspirin studies (letter). N Engl J Med 1988; 318: 923-924
52 ISIS-2 (Second International Study of Infarct Survival Collaborative Group). Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349-360
53 Janssens WJ, Deckmyn H, Gresele P, Vermylen J. BM13.177 selectively inhibits endoperoxide analogue induced vascular contractions. Arch Int Pharmacodyn Ther 1985; 276: 28-34
54 Jessup CL, Jessup R, Wayne M. ICI 185282, a potent thromboxane receptor antagonist on platelets. Br J Pharmacol 1980; 90: 229 P
55 Ogletree ML, Harris DN, Greenberg R, Haslanger MF, Nakane M. Pharmacological actions of SQ29548, a novel selective thromboxane antagonist. J Pharmacol Exp Ther 1985; 234: 435-441