11β-Hydroxysteroid dehydrogenase in human vascular cells

11β-Hydroxysteroid dehydrogenase in human vascular cells. Aldosterone selectivity in mineralocorticoid target tissues is mainly due to 11β-hydroxysteroid dehydrogenase (11βHSD), which converts cortisol to its inactive metabolite cortisone in humans. The defect of dehydrogenase activity would thus allow type 1 mineralocorticoid receptor (MR) to be occupied mostly by cortisol. It has been postulated that 11βHSD type 2 (11βHSD2) plays a significant role in conferring ligand specificity on the MR. We have demonstrated the diminished dehydrogenase activity in resistance vessels of genetically hypertensive rats. However, the mechanism that could link impaired vascular 11βHSD activity and elevated blood pressure has been unclear. In this study, we showed the enzyme activity in human coronary artery smooth muscle cells. Glucocorticoids and mineralocorticoids increase vascular tone by up-regulating the receptors of pressor hormones such as angiotensin II (Ang II). Next, we found that physiological concentrations of a cortisol-induced increase in Ang II binding were significantly enhanced by the inhibition of dehydrogenase activity with an antisense DNA complementary to 11βHSD2 mRNA, and the enhancement was partially but significantly abolished by a selective aldosterone receptor antagonist. This may indicate that impaired dehydrogenase activity in vascular wall results in increased vascular tone by the contribution of cortisol, which acts as a mineralocorticoid. In congenital 11βHSD deficiency and after the administration of 11βHSD inhibitors, suppression of dehydrogenase activity in the kidney has been believed to cause renal mineralocorticoid excess, resulting in sodium retention and hypertension. These results show that vascular 11βHSD activity could influence blood pressure without invoking renal sodium retention