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 (PGI2 synthesis. HC, but not aldosterone, progesterone, 17 beta-estradiol, or testosterone, inhibited spontaneous, epinephrine-stimulated 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 cyclooxygenase 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 steroid-related hypertension and atherosclerosis and the antiinflammatory effect of steroids.
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D046508:Culture Techniques; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis*; D004963:Estrenes / Q000494:pharmacology*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors; D006854:Hydrocortisone / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D015735:Mifepristone; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D001095:Arachidonic Acids; D004963:Estrenes; D005938:Glucocorticoids; D011450:Prostaglandin Endoperoxides, Synthetic; D003609:Dactinomycin; D016718:Arachidonic Acid; D015735:Mifepristone; D003513:Cycloheximide; D011464:Epoprostenol; D006854:Hydrocortisone; D004837:Epinephrine