Subscribe to RSS
DOI: 10.1055/s-0038-1650305
Pentamidine Is a Specific, Non-Peptide, GPIIb/llla Antagonist
Publication History
Received 17 November 1994
Accepted after revision 22 November 1995
Publication Date:
26 July 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199603/lookinside/thumbnails/10-1055-s-0038-1650305-1.jpg)
Summary
Pentamidine was previously shown to act on glycoprotein (GP) Ilb/IIIa (Cox et al., Thromb Haemost 1992; 68: 731). In this paper we study the effect of pentamidine on other RGD-dependent receptors. In a cell adhesion assay, pentamidine was 500 times more potent than RGDS at inhibiting platelet adhesion to fibrinogen. While RGDS inhibited platelet adhesion to fibronectin, endothelial cell adhesion to vitronectin or fibronectin, 293 cell adhesion to vitronectin, IMR 32 cell adhesion to fibronectin and C32 cell adhesion to vitronectin; pentamidine failed to inhibit these interactions at doses as high as 1 mM. Resting platelets fixed in the presence of 1 mM RGDS had increased binding of fibrinogen, i.e., RGDS activated GPIMIIa, while pentamidine at 100 ΜM had no effect. Similarly, RGDS induced the binding of an anti-LIBS monoclonal antibody, while pentamidine had no effect. Pentamidine partially, but significantly, inhibited lysosome and a-granule release induced by the thrombin agonist peptide, while RGDS had no effect. Neither pentamidine nor RGDS affected ADP-induced Ca2+ influx. Pentamidine had no effect on ADP-induced intracellular pH changes while RGDS prevented the pH from returning to normal. Thus, pentamidine is a non-peptide GPIIb/IIIa antagonist that is non-activating and is specific for GPIIb/IIIa.
-
References
- 1 Ruoslahti E. Integrins. J Clin Invest 1991; 87 (01) 1-5
- 2 Cox D, Aoki T, Seki J, Motoyama Y, Yoshida K. The pharmacology of the integrins. Med Res Rev 1994; 14 (02) 195-228
- 3 Phillips DR, Charo IF, Parise LV, Fitzgerald LA. The platelet membrane glycoprotein Ilb-IIIa complex. Blood 1988; 71 (04) 831-843
- 4 Phillips DR, Charo IF, Scarborough RM. GPIIb-IIIa: the responsive integrin. Cell 1991; 65 (03) 359-362
- 5 Cheresh DA. Human endothelial cells synthesize and express an Arg-Gly-Asp-directed adhesion receptor involved in attachment to fibrinogen and von Willebrand factor. Proc Natl Acad Sci USA 1987; 84 (18) 6471-6475
- 6 Gresham HD, Goodwin JL, Allen PM, Anderson DC, Brown EJ. A novel member of the integrin receptor family mediates Arg-Gly-Asp-stimulated neutrophil phagocytosis. J Cell Biol 1989; 108 (05) 1935-1943
- 7 Senior RM, Gresham HD, Griffin GL, Brown EJ, Chung AE. Entactin stimulates neutrophil adhesion and chemotaxis through interactions between its Arg-Gly-Asp (RGD) domain and the Leukocyte Response Integrin. J Clin Invest 1992; 90 (06) 2251-2257
- 8 Cook NS, Kottirsch G, Zerwes HG. Platelet glycoprotein Ilb/IIIa antagonists. Drugs Future 1994; 19 (02) 135-159
- 9 Coller BS, Scudder LE, Beer J, Gold HK, Folts JD, Cavagnaro J, Jordan R, Wagner C, Iuliucci J, Knight D, Ghrayeb J, Smith C, Weisman HF, Berger H. Monoclonal antibodies to platelet glycoprotein Ilb/IIIa as antithrombotic agents. Ann NY Acad Sci 1991; 614: 193-213
- 10 Nicholson NS, Panzer KS, Salyers AK, Taite BB, King LW, Miyano M, Gorczynski RJ, Williams MH, Zupec ME, Tjoeng FS, Adams SP, Feigen LP. In vitro and in vivo effects of a peptide mimetic (SC-47643) of RGD as an antiplatelet and antithrombotic agent. Thromb Res 1991; 62 (05) 567-578
- 11 Imura Y, Stassen JM, Bunting S, Stockmans F, Collen D. Antithrombotic properties of L-cysteine, N-(mercaptoacetyl)-D-Tyr-Arg-Gly-Asp-sulfoxide (G4120) in a hamster platelet rich femoral vein thrombosis model. Blood 1992; 80 (05) 1247-1253
- 12 Gan ZR, Gould RJ, Jacobs JW, Friedman PA, Polokoff MA. Echistatin. A potent platelet aggregation inhibitor from the venom of the viper, Echis carinatus. J Biol Chem 1988; 263 (36) 19827-19832
- 13 Gould RJ, Polokoff MA, Friedman PA, Huang TF, Holt JC, Cook JJ, Niewiarowski S. Disintegrins: a family of integrin inhibitory proteins from viper venoms. Proc Soc Exp Biol Med 1990; 195 (02) 168-171
- 14 Du XP, Plow EF, Frelinger A, O’Toole TE, Loftus JC, Ginsberg MH. Ligands “activate” integrin alpha lib beta 3 (platelet GPIIb-IIIa). Cell 1991; 65 (03) 409-416
- 15 Cox D, Motoyama Y, Seki J, Aoki T, Dohi M, Yoshida K. Pentamidine: A nonpeptide GPIIb/IIIa antagonist - in vitro studies on platelets from humans and other species. Thromb Haemost 1992; 68 (06) 731-736
- 16 Cox D, Aoki T, Seki J, Motoyama Y. Pentamidine: A specific, non-peptide GPIIb/-Illa antagonist. Thromb Haemost 1993; 69 (06) 707
- 17 Jaffe EA, Nachman RC, Becker CG, Minick CR. Culture of human endothelial cells derived form umbilical veins. J Clin Invest 1973; 52: 2745-2756
- 18 Connolly DT, Knight MB, Harakas NK, Wittwer AJ, Feder J. Determination of the number of endothelial cells in culture using an acid phosphatase assay. Anal Biochem 1986; 152: 136-140
- 19 Yatohgo T, Izumi M, Kashiwagi H, Hayashi M. Novel purification of vitronectin from human plasma by heparin affinity chromatography. Cell Structure and Function 1988; 13: 281-292
- 20 Ruoslahti E, Hayman E, Pierschbacher M, Engvall E. Fibronectin: Purification, Immunochemical properties and biological activities. Methods in Enzymology 82 1982; 803-831
- 21 Zavoico GB, Cragoe EJ, Feinstein MB. Regulation of intracellular pH in human platelets. J Biol Chem 1986; 261 (28) 13160-13167
- 22 Gartner TK, Amrani DL, Derrick JM. Characterization of adhesion of non-exogenously stimulated and resting platelets in normal plasma to fibrinogen and its fragnents. Blood Coag Fibrinol 1994; 5 (05) 747-754
- 23 Albelda SM, Daise M, Levine EM, Buck CA. Identification and characterization of cell-substratum adhesion receptors on cultured human endothelial cells. J Clin Invest 1989; 83 (06) 1992-2002
- 24 Bodary SC, McLean JW. The integrin beta 1 subunit associates with the vitronectin receptor alpha v subunit to form a novel vitronectin receptor in a human embryonic kidney cell line. J Biol Chem 1990; 265 (11) 5938-5941
- 25 Vogel BE, Tarone G, Giancotti FG, Gailit J, Ruoslahti E. A novel fibronectin receptor with an unexpected subunit composition (alpha v beta 1). J Biol Chem 1990; 265 (11) 5934-5937
- 26 Knudsen KA, Smith L, Smith S, Karczewski J, Tuszynski GP. Role of GPIIb/IIIa-like glycoproteins in cell-substratum adhesion of human melanoma cells. J Cellular Physiol 1988; 136: 471-478
- 27 Cahill MR, Macey MG, Newland AC. Fixation with formaldehyde induces expression of activation dependent platelet membrane glycoproteins, P selectin (CD62) and GP53 (CD63). Br J Haematol 1993; 84 (03) 527-529
- 28 Heynen HFG, Molero ML, de Groot PG, Nieuwenhuis HK, Sixma JJ. Absence of igands bound to glycoprotein GPIIb/IIIa on the exposed surface of a thrombus may limit thrombus growth in flowing blood. J Clin Invest 1994; 94: 1098-1112
- 29 Christie D, Sauro S, Cavanaugh A, Kaplan M. Severe thrombocytopenia in an Acquired Immunodeficiency Syndrome Patient Associated with Pentamidine-Dependent Antibodies Specific for Glycoprotein Ilb/IIIa. Blood 1993; 82: 3075-3080
- 30 Mazoyer E, Levy TS, Rendu F, Hermant L, Lu H, Fiat AM, Jolles P, Caen J. KRDS, a new peptide derived from human lactotransferrin, inhibits platelet aggregation and release reaction. Eur J Biochem 1990; 194 (01) 43-49
- 31 Goodall A, Wilson D, Lumley P. The Effect of the Fibrinogen Receptor Antagonist, GR144053, Upon Fibrinogen Binding and P-Selectin Expression in Human Platelets; Analysis Using Flow Cytometry. Thromb Haemost 1993; 69: 1071
- 32 Abrams C, Shattil SJ. Immunological detection of activated platelets in clinical disorders. Thromb Haemost 1991; 65 (05) 467-473
- 33 Simpson AW, Rink TJ. Elevation of pHi is not an essential step in calcium mobilisation in fura-2-loaded human platelets. FEBS Lett 1987; 222 (01) 144-148
- 34 Cox D, Aoki T, Seki J, Motoyama Y. FR144633: a novel platelet GPIIb/IIIa antagonist. Thromb Haemost 1993; 69: 706
- 35 Hodohara K, Fujiyama Y, Hosada S, Yasunaga K. Blood Vessel 1988; 20: 553
- 36 Foster MR, Pike NB, Hornby EJ, Porter B, Eldred CD, Ross BC, Lumley P. GR144053, a potent and specific non-peptide fibrinogen receptor antagonist on human platelets in vitro. Thromb Haemost 1993; 69: 559
- 37 Pottratz ST, Martin WJ. Role of fibronectin in Pneumocystis carinii attachment to cultured lung cells. J Clin Invest 1990; 85 (02) 351-356
- 38 Arasteh KN, Vohringer HF, Stratmann MM, Tschechne BK, Heise WS, L’Age MP. Pharmacokinetics and adverse reactions of various dosage regimens of intravenous pentamidine in the treatment of HIV-associated Pneumocystis carinii pneumonia. Drug Invest 1993; 6: 207-217
- 39 Goa K. Campoli-Richards DM. Pentamidine Isethionate: A review of its antiprotozoal activity, pharmacokinetic properties and therapeutic use in Pneumocystis carinii pneumonia. Drugs 1987; 33: 242-258
- 40 Osei K, Falko J, Nelso K, Stephens R. Diabetogenic effect of pentamidine. In vitro and in vivo studies in a patient with a malignant insulinoma. Am J Med 1984; 77: 41-46
- 41 Miller R, Semple S. Bronchial bleeding with nebulised pentamidine. Lancet 1988; ii: 1488