11 beta-Hydroxysteroid dehydrogenase antisense affects vascular contractile response and glucocorticoid metabolism

Steroids. 2002 Mar;67(3-4):195-201. doi: 10.1016/s0039-128x(01)00148-9.


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

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 2
  • 11-beta-Hydroxysteroid Dehydrogenases
  • Animals
  • Aorta, Thoracic
  • Corticosterone / analogs & derivatives*
  • Corticosterone / metabolism
  • Endothelium, Vascular / physiology
  • Glucocorticoids / metabolism*
  • Hydroxysteroid Dehydrogenases / genetics*
  • Hydroxysteroid Dehydrogenases / metabolism
  • Male
  • Muscle Contraction / drug effects*
  • Muscle, Smooth, Vascular / physiology*
  • Oligonucleotides, Antisense / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Tritium


  • Glucocorticoids
  • Oligonucleotides, Antisense
  • Tritium
  • Hydroxysteroid Dehydrogenases
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2
  • 11-beta-Hydroxysteroid Dehydrogenases
  • 11-dehydrocorticosterone
  • Corticosterone