Effects of prostaglandin E1 metabolites on the induction of arterial thromboresistance.
Prostaglandin (PG) E1 has been shown to induce arterial thromboresistance in experimental animals and in man. It is known to be degraded in vivo to metabolites which have comparable (13,14-dihydro-PGE1) or no (15-keto-PGE1, 15-keto-13,14-dihydro-PGE1) biological activity. It was the goal of this study to examine whether 13,14-dihydro-PGE1 and its derivatives might share biological activity in rendering the arterial wall less thrombogenic. Using a cross-perfusion technique the aorta and iliac artery surface were exposed to a donor rabbits' blood. We examined the intact endothelial lining and a surface which had been deendothelialized before by means of a Fogarty catheter. Donor animals and/or receiver animals were treated daily for 1 week with 13,14-dihydro-PGE1, PGE1, 15-keto-PGE1, 15-keto-13,14-dihydro-PGE1, or the vehicle only, respectively. From the group of the receiver animals, a subgroup of 6 animals each was treated for the same period of time with either 13,14-dihydro-PGE1, PGE1, 15-keto-PGE1, 15-keto-13,14-dihydro-PGE1, or the vehicle. Immediately after the last administration of the respective PG or solvent, native blood from a donor rabbit was circulated [30 mL/min. under in vivo flow conditions (60 Hz)] over an arterial segment of a receiver animal. Deposition of 111Indium-oxine labeled autologous platelets per surface unit was quantitatively assessed. In vitro perfusion data were morphometrically analysed. In animals pretreated with 13,14-dihydro-PGE1 the thromboresistance was almost comparable to that achieved with PGE1. In contrast, pretreatment of the donor animals (platelet) had only minor effects on the thromboresistance. The other compounds showed no effects. In vitro perfusion of human saphenous vein segments revealed PGE1 and 13,14-dihydro-PGE1 again to be of comparable potency, while 15-keto-PGE1 and 15-keto-13,14-dihydro-PGE1 were only active at concentrations being several orders of magnitude higher. Not only PGE1 but also its in vivo formed metabolite PGE0 may play an important role in inducing improvement of haemostatic balance via the vascular wall rather than the platelets. The other metabolites, however, are unlikely to exhibit an effect at biologically relevant concentrations.
Sinzinger
H
H
Wilhelm Auerswald-Atherosclerosis Research Group, Vienna, Austria.
Neumann
I
I
O'Grady
J
J
Rogatti
W
W
Peskar
B A
BA
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001158:Arteries / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D007083:Iliac Artery / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D010477:Perfusion; D011817:Rabbits; D013927:Thrombosis / Q000517:prevention & control*
C069881:13,14-dihydroprostaglandin E1; C011008:15-ketoprostaglandin E; C036808:13,14-dihydro-15-ketoprostaglandin E1; D000527:Alprostadil