11 beta-hydroxysteroid dehydrogenase in human vascular cells

Aldosterone selectivity in mineralocorticoid target tissues is mainly due t o 11 beta-hydroxysteroid dehydrogenase (11 beta HSD), which converts cortis ol to its inactive metabolite cortisone in humans. The defect of dehydrogen ase activity would thus allow type 1 mineralocorticoid receptor (MR) to be occupied mostly by cortisol. It has been postulated that 11 beta HSD type 2 (11 beta HSD2) plays a significant role in conferring ligand specificity o n the MR. We have demonstrated the diminished dehydrogenase activity in res istance vessels of genetically hypertensive rats. However. the mechanism th at could link impaired vascular 11 beta HSD activity and elevated blood pre ssure has been unclear. In this study, we showed the enzyme activity in hum an coronary artery smooth muscle cells. Glucocorticoids and mineralocortico ids increase vascular tone by up-regulating the receptors of pressor hormon es such as angiotensin II (Ang II). Next, we found that physiological conce ntrations of a cortisol-induced increase in Ang II binding were significant ly enhanced by the inhibition of dehydrogenase activity with an antisense D NA complementary to 11 beta HSD2 mRNA, and the enhancement was partially bu t significantly abolished by a selective aldosterone receptor antagonist. T his may indicate that impaired dehydrogenase activity in vascular wall resu lts in increased vascular tone by the contribution of cortisol, which acts as a mineralocorticoid. In congenital 11 beta HSD deficiency and after the administration of 11 beta HSD inhibitors, suppression of dehydrogenase acti vity in the kidney has been believed to cause renal mineralocorticoid exces s, resulting in sodium retention and hypertension. These results show that vascular 11 beta HSD activity could influence blood pressure without invoki ng renal sodium retention.