Glabridin-induced vasorelaxation: Evidence for a role of BKCa channels and cyclic GMP

Background and purpose: Glabridin is a major flavonoid in Glycyrrhiza glabra (licorice) root, a traditional Asian medicine. Glabridin is reported to have anti-atherogenic, anti-inflammatory and anti-nephritic properties; however its effects on vascular tone remain unexplored. Experimental approach: We examined the effect of glabridin on rat main mesenteric artery using isometric myography and also ELISA to measure cGMP levels. Key results: Glabridin (30 mu M) relaxed arteries pre-constricted with the thromboxane A(2) analog U46619 (0.2 mu M) by similar to 60% in an endothelium-independent manner. Relaxation to 30 mu M glabridin was abolished by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (1 mu M) and by the BKCa channel blocker tetraethyammonium (1 mM) but was unaffected by the estrogen receptor antagonist ICI182780. The concentration-response curve to glabridin (0.1 to 30 mu M) was downshifted by the K-ATP channel blocker glibenclamide (10 mu M), the K-V channel blocker 4-aminopyridine (300 mu M), and the K-IR blocker BaCl2 (30 mu M). In U46619 contracted arteries partially relaxed by 0.1 mu M sodium nitroprusside, application of 10 and 30 nM glabridin caused additional vasorelaxation. Glabridin (30 mu M) approximately doubled tissue [cyclic GMP]. Application of the phosphodiesterase inhibitor isobutylmethylxanthine caused a much larger rise in [cyclic GMP], and glabridin failed to cause vasorelaxation or a further rise in [cGMP] when co-applied with IBMX. Conclusions and implications: Vasorelaxation to glabridin is dependent on the opening of K+ channels, particularly BKCa, probably caused by a rise in cellular [cyclic GMP] owing to phosphodiesterase inhibition. In the presence of sodium nitroprusside an effect of glabridin is observed at nM concentrations, similar those measured in plasma following human ingestion of licorice flavonoid oil. (C) 2016 The Authors. Published by Elsevier Inc.