Abstract 3198: Inhibition of 11-beta Hydroxysteroid Dehydrogenase Impairs Vascular Function in Healthy Humans
Background: 11-beta hydroxysteroid dehydrogenase (11b-HSD) converts cortisol, an agonist for both mineralocorticoid and glucocorticoid receptors, to cortisone, which binds only the glucocorticoid receptor. Excess activation of the mineralocorticoid receptor has been associated with adverse cardiovascular outcomes. Accordingly, we hypothesized that increases in cortisol created by 11b-HSD inhibition would impair vascular function in intact, healthy humans.
Methods and results: This study was a randomized, double-blind, placebo-controlled crossover investigation. Fifteen healthy subjects were treated with a selective inhibitor of 11b-HSD, glycyrrhetic acid (GA), or matching placebo for 14 days prior to vascular function testing. Inactivation of 11b-HSD was determined by 24 hour urinary cortisol:cortisone ratio. Forearm blood flow (FBF) was measured using venous-occlusion, strain gauge plethysmogra-phy. Endothelium-dependent vasodilation (EDV) was measured via incremental brachial artery administration of methacholine chloride (0.3–10 mg/min). Endothelium-independent vasodila-tion (EIV) was measured with incremental administration of verapamil chloride (10–300 mg/min). Urinary cortisol was higher and cortisone lower during GA administration compared to placebo (cortisol: 30.0±22.7 vs. 20.1±11.5 mg/24hrs, p=.04 and cortisone: 46.1±19.6 vs. 36.9±19.9 mg/24hrs, p=.01). The cortisol:cortisone ratio increased from 0.44±0.18 during placebo to 0.81±0.45 during GA (p=.008). The FBF dose response to methacholine trended towards reduction during GA administration (p = 0.1 by ANOVA). The FBF dose response to verapamil was significantly reduced during GA administration (p = .04 by ANOVA).
Conclusion: Inhibition of 11b-HSD significantly increases cortisol concentration and impairs vascular smooth muscle function. These findings suggest that non-aldosterone inhibition of 11b-HSD may importantly impair vascular function in humans.