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.
KeywordsPeroxide Ischemia Phenyl Pyridine Prostaglandin
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