PAF-Acether Induced Arterial Thrombosis and the Effect of Specific Antagonists
Platelet-vessel wall interactions and local thrombosis are investigated in vivo in a branch of the mesenteric artery of the guinea pig, using optoelectronic registration and ultrastructural control. Following an electrical challenge resulting in changes of cell membrane polarization, subsequent superfusion by PAF-acether or a stable analogue, (1-O-alkyl-2-N-methylcarbamyl-sn-glycero-3-phosphocholine, 10-8 M focal concentration (f.c.)) for a restricted period results in endothelial cell retraction and bleb formation followed by platelet adhesion and the development of a thrombus which over time becomes invaded by leukocytes and eventually occludes the vascular lumen. It was demonstrated in a previous investigation that these phenomena are triggered by the generation of endogenous PAF-acether by the endothelial cells.
Specific PAF-acether-antagonists, such as BN 52021 a ginkgolide, but also synthetic molecules, derivatives of the triazolo-pyridino-diazepine group (BN 50727, BN 50755 and BN 50789), significantly inhibit platelet-vessel wall interactions and thrombosis, but not the formation of blebs in the endothelial cells. Hydrogen peroxide (10-5 M f.c.) not only primes the effect of PAF-acether, but is by itself capable of inducing thrombosis through a PAF-acether-mediated mechanism.
Inhibition of acetyl hydrolase by PMSF (phenyl-methyl-sulfonyl-fluoride, 10-5 M f.c.) invariably results in a significant enhancement of thrombosis, while conversely, inhibition of acetyl transferase by 27584 RP (4-(naphtylvinyl)pyridine hydrochloride, 10-6 M f.c.) inhibits thromboformation indicating that the remodeling pathway is involved.
KeywordsArterial Thrombosis Platelet Content Stable Analogue Pyridine Hydrochloride Remodel Pathway
Unable to display preview. Download preview PDF.
- Bourgain, R. H., Vermariën, H., Andries, R., Vereecke, F., Jacqueloot, J., Rennies, J., Blockeel, E., and Six, F., 1984, A standardized ‘in vivo’ model for the study of experimental arterial thrombosis. Description of a method, Adv. exp. Med. Biol.. 180: 635.Google Scholar
- Bourgain, R. H., Maes, L., Braquet, P., Andries, R., Touqui, L., Braquet, M., 1985, The effect of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF-acether) on the arterial wall, Prostaglandins, 30: 185.Google Scholar
- Bourgain, R. H., Andries, R., Braquet, P., Xie, Z. W., Sedivy, P., Decuyper, K., and Vargaftig, B. B., 1988, PAF-acether autogenerated in the guinea pig arterial wall may account for local thromboformation, Prostaglandins, 35: 809.Google Scholar
- Demopoulos, C. A, Pinckard, R. N., and Hanahan, D. J., 1979, Platelet-activating factor. Evidence for 1-O-alkyl-2-acetyl-sn-glycerol-3-phosphorylcholine as the active component (a new class of lipid mediators), J. Biol. Chem., 254: 9355.Google Scholar
- Desquand, S., Touvay, C., Randon, J., Lagente, V., Maridonneau-Parini, I., Etienne, A., Lefort, J., Braquet, P., and Vargaftig, B. B., 1986, Interference of BN 52021 with the bronchopneumonial effects of PAF-acether in the guinea pig, Eur. J. Pharmacol., 127: 83.Google Scholar
- Duval, D. L., Didisheim, P., Titus, J. L., Spitell, J. A., and Owen, C. A., 1970, Experimental arterial thrombosis: description of a method, Mayo Clin. Proc., 45: 388.Google Scholar
- Joly, F., Bessou, G., Benveniste, J., and Ninio, E., 1987, Ketotifen inhibits PAF-acether biosynthesis and ß-hexosaminidase release in mouse mast cells stimulated with antigen, Eur. J. Paharmacol., 144: 133.Google Scholar
- Lewis, M. S., Whatley, R. E., Cain, P., McIntyre, T. M., Prescott, S. M., and Zimmerman, G. A., 1988, Hydrogen peroxide stimulates the synthesis of platelet-activating factor by endothelium and induces endothelium cell-dependent neutrophil adhesion, J. Clin. Invest., 82: 2045.Google Scholar
- Stem, P., 1971, Phannakologische analyse eines specifischem cholinacetylase-inhibitors, Arzneim. Forsch., 7: 991.Google Scholar
- Vargaftig, B. B., Chignard, M., Benveniste, J., Lefort, J., and Wal, F., 1981, Background and present status of research on platelet-activating factor (PAF-acether), Ann. N.Y. Acad. Sci., 370: 119.Google Scholar