Effects of Prostaglandin E 1 Metabolites on the Induction of Arterial Thromboresistance

Abstract

Prostaglandin (PG) E 1 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-PGE 1) or no (15-keto-PGE 1, 15-keto-13,14-dihydro-PGE 1) biological activity. It was the goal of this study to examine whether 13,14-dihydro-PGE 1 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-PGE 1, PGE 1, 15-keto-PGE 1, 15-keto-13,14-dihydro-PGE 1, 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-PGE 1, PGE 1, 15-keto-PGE 1, 15-keto-13,14-dihydro-PGE 1, 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-PGE 1 the thromboresistance was almost comparable to that achieved with PGE 1. 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 PGE 1 and 13,14-dihydro-PGE 1 again to be of comparable potency, while 15-keto-PGE 1 and 15-keto-13,14-dihydro-PGE 1 were only active at concentrations being several orders of magnitude higher. Not only PGE 1 but also its in vivo formed metabolite PGE 0 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.