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.
Bourgain
R H
RH
Laboratory of Physiology and Physiopathology, University of Brussels, VUB, Belgium.
Andries
R
R
Esanu
A
A
Braquet
P
P
D000123:Acetyltransferases / Q000037:antagonists & inhibitors; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation; D006168:Guinea Pigs; D006861:Hydrogen Peroxide / Q000633:toxicity; D006867:Hydrolases / Q000037:antagonists & inhibitors; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D058924:Thienopyridines; D013927:Thrombosis / Q000209:etiology* / Q000517:prevention & control; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D010972:Platelet Activating Factor; D058924:Thienopyridines; D014230:Triazoles; D010664:Phenylmethylsulfonyl Fluoride; D006861:Hydrogen Peroxide; D000123:Acetyltransferases; D006867:Hydrolases; C067429:Setipafant