Abnormal glucocorticoid metabolism contributes to vascular dysfunction and cardiovascular disease. Cortisol activation of vascular mineralocorticoid and glucocorticoid receptors is regulated by two types of 11β-HSD (11-β hydroxysteroid dehydrogenase), namely 11β-HSD2 and 11β-HSD1 (type 2 and type 1 11β-HSD respectively). We hypothesized that inhibition of 11β-HSD would attenuate vascular function in healthy humans. A total of 15 healthy subjects were treated with the selective 11β-HSD inhibitor GA (glycyrrhetinic acid) or matching placebo in a randomized double-blinded cross-over trial. 11β-HSD activity was assessed by the urinary cortisol/cortisone ratio, and vascular function was measured using strain-gauge plethysmography. Endothelial function was measured through incremental brachial artery administration of methacholine (0.3–10 μg/min) and vascular smooth muscle function with incremental verapamil (10–300 μg/min). GA increased the 24-h urinary cortisol/cortisone ratio compared with placebo (P=0.008). GA tended to reduce the FBF (forearm blood flow) response to methacholine (P=0.09) and significantly reduced the FBF response to verapamil compared with placebo (P=0.04). MAP (mean arterial pressure) did not differ between the study conditions. 11β-HSD inhibition attenuated vascular smooth muscle vasodilatory function in healthy humans. Disturbances in cortisol activity resulting from 11β-HSD inactivation is therefore a second plausible mechanism for mineralocorticoid-mediated hypertension in humans.

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