Inhibition by hydrocortisone of prostacyclin synthesis by rat aorta and its reversal with RU486

A rat aortic explant culture system was developed for the investigation of the effects of hydrocortisone (HC) and the glucocorticoid antagonist, RU486, on prostacyclin (PGI₂synthesis. HC, but not aldosterone, progesterone, 17β-estradiol, or testosterone, inhibited spontaneous, epinephrinestimulated and U46619 (an analog of thromboxane A₂)-stimulated PGI₂ synthesis by cultured aortic explants in a concentration- and time-dependent manner. Adequate inhibition of aortic explant PGI₂ synthesis by physiological concentrations of HC was achieved after an 18-h culture. An 18-h time course was employed in subsequent experiments. In contrast, HC had no effect on arachidonic acid-stimulated PGI₂ synthesis. Protein synthesis inhibitors, actinomycin D and cycloheximide, had no effect on the inhibitory action of HC on epinephrine- and U46619-induced release of PGI₂. They exerted a direct inhibitory effect on aortic PGI₂ synthesis. Arachidonic acid stimulated PGI₂ release by the explants and was unaffected either by HC or by treatment with cycloheximide or actinomycin D. RU486 blocked the inhibitory action of HC on aortic PGI₂ synthesis in a dose-dependent manner. Thus, the inhibitory effect of HC on vascular PGI₂ synthesis is probably mediated through an inhibition of phospholipase A₂ and not cycloxygenase or other PGI₂ synthase systems; furthermore, this inhibitory effect is not dependent upon de novo protein synthesis. RU486 antagonizes the inhibitory effect of HC. The inhibition of vascular PGI₂ by hydrocortisone has implications in the pathogenesis of steroidrelated hypertension and atherosclerosis and the antiinflammatory effect of steroids.