Glycyrrhetinic acid attenuates vascular smooth muscle vasodilatory function in healthy humans

Abstract

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.

Liquorice ingestion attenuates vasodilatation via exogenous nitric oxide donor but not via β2-adrenoceptor stimulation

“…This suggests that liquorice intake impaired vasodilatation via exogenous NO in vascular smooth muscle, while the β 2 -adrenoceptor-mediated vascular relaxation was not affected. In accordance with our results, Sobieszczyk et al demonstrated that GA attenuated endothelium-independent vasodilatation in the forearm blood flow in response to verapamil, while no significant influence was observed in the endothelium-dependent vasodilatation elicited by methacholine [45]. In addition, aortas from 11β-HSD2 knockout mice demonstrated impaired vasorelaxation to both endothelium-dependent and -independent agents [46].…”

Glycyrrhetinic Acid Antagonizes Pressure-Induced Venous Remodeling in Mice

“…While not much is known of the effects of GA on ECs and SMCs in the context of their stretch-dependent activation, GA has been shown to non-specifically block gap junctions, e.g., composed of connexin-43 in vascular SMCs (Matchkov et al, 2004 ; Sobieszczyk et al, 2010 ). However, under the chosen experimental conditions, GA had only little impact on the SMC phenotype.…”

Mineralocorticoid regulation of cell function: the role of rapid signalling and gene transcription pathways

“…In the vasculature, endothelial cells can express HSD11B2 (Brem et al 1998, Christy et al 2003, Gong et al 2008, while the literature is conflicting regarding its presence in vascular smooth muscle cells (VSMCs) (Hatakeyama et al 2001, Christy et al 2003. Deficiency or inhibition of HSD11B2 impairs endothelium-mediated vasodilation, but glucocorticoid occupation of MR may not be the cause (Christy et al 2003, Sobieszczyk et al 2010. Instead, a potential mechanism may involve regulation of endothelial nitric oxide synthase (eNOS) expression.…”