The mechanism of glucocorticoid-induced hypertension is not known. Although glucocorticoids can exert an inhibitory effect on prostaglandin synthesis invitro, theirin vivoinfluence on this system is controversial. The goal of the present study was to determine whether dexamethasone-induced hypertension in Wistar rats is due to inhibition of the synthesis of the vasodilator prostaglandin l2(PGI2)in vivo.Dexamethasone caused a profound reduction (7 ± 1 versus 21 ± 5ng per 24 h) in the urinary excretion of PGI-M (PGI-M), a major metabolite of PGI2, and a sustained rise in systolic arterial pressure which was maximal after 5 days (144 ± 9 versus 103 ± 3mmHg). A study of the metabolism of [3H]-labeled 6-oxo-PGF1and PGI2revealed that dexamethasone exerted a dual action on the prostaglandin systemin vivo:an inhibition of PGI2biosynthesis and an alteration of its metabolism, both effects contributing to the observed reduction in urinary levels of PGI-M.Exogenous arachidonic acid induced a fourfold increase in urinary PGI-M in normal rats (from 14 ± 3 to 61 ± 6ng per 24 h). Despite a large decrease upon addition of dexamethasone, urinary PGI-M remained in the high-normal range in arachidonic acid-treated rats (21 ± 8 ng per 24 h). Arachidonic acid exerted antihypertensive effects which were marginal initially but significant in the later phase of dexamethasone-induced hypertension (124 ± 8 versus 139 ± 8mmHg in arachidonic acid-treated versus control rats after 7 days of dexamethasone). The antiglucocorticoid agent RU-486 reversed almost entirely the rise in blood pressure but only marginally reduced urinary PGI-M caused by dexamethasone. The non-steroidal anti-inflammatory agent meclofenamic acid reduced urinary PGI-M to the same extent as dexamethasone but did not cause any increase in arterial pressure.In conclusion, dexamethasone exerts a profound influence on both the biosynthesis and the metabolism of PGI2in vivoin Wistar rats. However, the mechanism initiating glucocorticoid hypertension is not dependent upon the inhibition of either PGI2biosynthesis or arachidonic acid metabolism, although such an effect may contribute to the severity of hypertension with time by preventing the moderating influence of vasodilator metabolites of arachidonic acid.