DDAVP Stimulates Prostacyclin Production

Abstract

SummaryDes-amino-D-arginine vasopressin (DDAVP) stimulates the release of factor VIII and plasminogen activator from the vascular endothelium. An infusion of exogenous factor VIII given to haemophiliacs causes an increase in platelet activation. This activation does not occur after stimulating a rise in the patient's own factor VIII level caused by DDAVP infusion. We hypothesised therefore that DDAVP could also cause the endothelial release of prostacyclin (PGI2), a potent anti-platelet agent which would counteract the aggregating effect of factor VIII. To examine this possibility we studied the effect of DDAVP on prostacyclin release, as measured by its stable metabolite 6-oxo-PGFla, in vitro and in vivo. Rabbit aortic rings were incubated with different concentrations of DDAVP using saline as control. The supernatant was assayed for 6-oxo-PGFlct by radioimmunoassay. All concentrations of DDAVP gave a significant release of 6-oxo-PGF1α. Vasopressin was much less potent. When DDAVP was infused into haemophilic patients there was a significant increase in circulating 6-oxo-PGF1α levels immediately after the infusion. The facial flushing observed as a side-effect of DDAVP could therefore be prostacyclin-mediated. We confirmed this by abolishing the DDAVP induced flushing seen in normal subjects by prior treatment with aspirin which inhibits PGI2 formation.

Endothelial Stimulation by DDAVP in von Willebrand’s Disease and Haemophilia

“…These results confirm our previous find ings [7] that DDAVP stimulates PGI2 pro duction in normal and haemophilic patients. This finding has been questioned by D'An gelo et al [15] who could find no effect of DDAVP on PGI2 production, but this may have been due to differences in the method ology [16].…”

“…The mechanism for the action of DDAVP on PGI2 production is not en tirely clear. Previous in vitro studies have shown DDAVP to have a direct stimulatory effect on PGI2 production from arterial tissue [7], while there is mounting evidence that the effect of DDAVP on FVIIR:Ag release is mediated via a secondary messenger [20,21]. In the absence of any change in TxB2 levels following DDAVP, the stimulatory effect on PGI2 production may be mediated through an endothelial cell receptor rather than a gen eral activation of the arachidonic acid cas cade.…”

“…The failure of the vWd subjects to flush is also of interest, since this general vasodila tion is seen in normal and haemophilic sub jects and has been shown to be abolished by aspirin [7], It is likely therefore to be due to the potent vasodilator action of PGI2. This lack of flushing in vWd suggests either a vas cular insensitivity to PGI2 or failure to reach a 'flush threshold', as the vWd subjects had lower post-DDAVP levels of PGI2 than nor mal subjects.…”

“…Prostacyclin (PGI2) is a prostaglan din produced by vascular endothelium, and is a potent vasodilator and antiplatclct agent [6]. PGG levels have been shown to increase following DDAVP infusions in normal and haemophilic subjects [7,8], The aim of this study was to determine the effect of DDAVP on PGD, FV1II and plasminogen activator production in vWd, and to compare this with the response to DDAVP in haemophilic and normal subjects. Thromboxane A2, the ma jor product of arachidonic acid in platelets with actions directly opposed to PGI2, namely vasoconstriction and platelet aggre gation, was also measured as its stable hydra tion product thromboxane B2 (TxB2).…”

Platelet‐activating factor secreted by DDAVP‐treated monocytes mediates von willebrand factor release from endothelial cells

“…Since anephric patients respond normally to DDAVP (Mannucci et al, 1975), the site of the V, receptors involved in the hemostatic properties of DDAVP is not in the kidney. DDAVP is without effect on platelets (Yang et al, 1990;Belch et al, 1982;D'Angelo et al, 1983). However, platelets possess V,- (Pollock and MacIntyre, 1986) but not V,-receptors (Seiss et al, 1986;Yang et al, 1990) and DDAVP is a specific V2-receptor agonist (Jard, 1988).…”