11β-hydroxysteroid dehydrogenase antisense affects vascular contractile response and glucocorticoid metabolism

Glucocorticoids (GC's) are metabolized in vascular tissue by two isoforms of 11beta-hydroxysteroid dehydrogenase (1beta-HSD). 11beta-HSD2 is unidirectional and metabolizes GC's to their respective inactive 11-dehydro derivatives. 11beta-HSD1 is bi-directional, also possessing reductase activity and thus the ability to regenerate active GC from the I I-dehydro derivatives. In vascular tissue, GC's amplify the pressor responses to catecholamines and angiotensin 11 and may down-regulate certain depressor systems such as nitric oxide and prostaglandins. We hypothesize that both 11beta-HSD2 and 11beta-HSD1 regulate GC levels in vascular tissue and are part of additional mechanisms that control vascular tone. We examined the effects of specific antisense oligomers to 11beta-HSD2 and 11beta-HSD1 on GC metabolism and contractile response to phenylephrine (PE) in rat aortic rings. In aortic rings incubated (24 h) with corticosterone (13) (10 nmol/1) and 11beta-HSD2 antisense (3 mumol/l). the contractile response to graded concentrations of PE (PE: 10 nmol/l - 1 mumol/l) were significantly (P < 0.05) increased compared to rings incubated with B and 11beta-HSD2 nonsense. 11beta-HSD1 antisense oligomers also enhanced the ability of B to amplify the contractile response to PE. In addition, 11beta-HSD2 and 11beta-HSD1 antisense also decreased the metabolism of B to 11-dehydro-B. 11-Dehydro-B (100 nmol/l) also amplified the contractile response to PE in aortic rings (P < 0.01), most likely due to the generation of active corticosterone by 11beta-HSD1-reductase; this effect was significantly attenuated by 11beta-HSD1 antisense. 11beta-HSD1 antisense also caused a marked decrease in the metabolism of 11-dehydro-B back to B by 11beta-HSD1-reductase. These findings underscore the importance of 11beta-HSD2 and 11beta-HSD1 in regulating local concentrations of GC's in vascular tissue. They also indicate that decreased 11beta-HSD2 activity may be a possible mechanism in hypertension and that 11beta-HSD1-reductase may be a possible target for anti-hypertensive therapy. (C) 2002 Elsevier Science Inc. All rights reserved.