Glycyrrhetinic acid attenuates vascular smooth muscle vasodilatory function in healthy humans.
Abnormal glucocorticoid metabolism contributes to vascular dysfunction and cardiovascular disease. Cortisol activation of vascular mineralocorticoid and glucocorticoid receptors is regulated by two types of 11beta-HSD (11-beta hydroxysteroid dehydrogenase), namely 11beta-HSD2 and 11beta-HSD1 (type 2 and type 1 11beta-HSD respectively). We hypothesized that inhibition of 11beta-HSD would attenuate vascular function in healthy humans. A total of 15 healthy subjects were treated with the selective 11beta-HSD inhibitor GA (glycyrrhetinic acid) or matching placebo in a randomized double-blinded cross-over trial. 11beta-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 microg/min) and vascular smooth muscle function with incremental verapamil (10-300 microg/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. 11beta-HSD inhibition attenuated vascular smooth muscle vasodilatory function in healthy humans. Disturbances in cortisol activity resulting from 11beta-HSD inactivation is therefore a second plausible mechanism for mineralocorticoid-mediated hypertension in humans.
Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, U.S.A.
Piotr
P
Sobieszczyk
Barry A
BA
Borlaug
Heather L
HL
Gornik
Wesley D
WD
Knauft
Joshua A
JA
Beckman
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors / Q000502:physiology; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D003348:Cortisone / Q000652:urine; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006034:Glycyrrhetinic Acid / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D055815:Young Adult
D004791:Enzyme Inhibitors; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D006034:Glycyrrhetinic Acid; D003348:Cortisone; D006854:Hydrocortisone