VASODILATATION AND INHIBITION OF MEDIATOR RELEASE REPRESENT 2 DISTINCT MECHANISMS FOR PROSTAGLANDIN MODULATION OF ACUTE MAST CELL-DEPENDENT INFLAMMATION

Intravital microscopy of the hamster cheek pouch was used to examine the influence of vasodilator prostanoids (prostaglandin E2 (PGE2), PGI2), forskolin, and nitroprusside on the microvascular changes during acute inflammation induced by antigen or histamine. The results extend our previous finding that PGE2 modulates allergic inflammation and histamine release in the cheek pouch model. The microvascular actions of arachidonic acid and different cyclo-oxygenase products (PGE2, PGD2, PGI2, PGF(2α), and the thromboxane A2 (TXA2)-analogue U-44069) were first compared with respect to their effects on arteriolar tone. Of the prostaglandins, only PGE2 and PGI2 were potent vasodilators and markedly increased local blood flow. Nitroprusside and forskolin also caused vasodilatation and increased blood flow, but were somewhat less potent than PGE2 and PGI2. Topically applied PGE2 and PGI2 in vasodilator concentrations suppressed the antigen-induced plasma leakage. On the other hand, although the antigen response was predominantly mediated by histamine, both prostaglandins enhanced the plasma leakage evoked by exogeneous histamine. In contrast, the vasodilator nitroprusside, in a dose causing an increase in blood flow equal to that of PGE2 and PGI2, potentiated both the histamine-induced plasma leakage, as well as the plasma and leukocyte extravasation after antigen challenge, indicating that the anti-inflammatory actions of the prostaglandins were unrelated to their vasodilator properties per se. Because forskolin, a specific activator of adenylate cyclase, mimicked the actions of PGE2 and PGI2, i.e. inhibition of the antigen-induced plasma extravasation and enhancement of the histamine response, it is possible that the observed antiallergic effects of the prostaglandins were related to accumulation of intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP). Taken together, there appears to be a competition between pro- and anti-inflammatory effects of PGE2 and PGI2 in reactions involving release of endogeneous inflammatory mediators in vivo, i.e. enhancement of inflammatory mediator target action on one hand ('two mediator synergism'), and suppression of mediator release on the other. Moreover, the observations indicate that vasodilatation and inhibition of mediator release are two distinct actions of PGE2 and PGI2.