Baicalin, a flavonoid from Scutellaria baicalensis Georgi, activates large-conductance Ca2+-activated K+ channels via cyclic nucleotide-dependent protein kinases in mesenteric artery

Baicalin isolated from Scutellaria baicalensis is a traditional Chinese herbal medicine used for cardiovascular dysfunction. The ionic mechanism of the vasorelaxant effects of baicalin remains unclear. We investigated whether baicalin relaxes mesenteric arteries (MAs) via large-conductance Ca2+-activated K+ (BKCa) channel activation and voltage-dependent Ca2+ channel (VDCC) inhibition. The contractility of MA was determined by dual wire myograph. BKCa channels and VDCCs were measured using whole-cell recordings in single myocytes, enzymatically dispersed from rat MAs. Baicalin (10-100μM) attenuated 80mM KCl-contracted MA in a concentration-related manner. L-NAME (30μM) and indomethacin (10μM) little affected baicalin (100μM)-induced vasorelaxations. Contractions induced by iberiotoxin (IbTX, 0.1μM), Bay K8644 (0.1μM) or PMA (10μM) were abolished by baicalin 100μM. In MA myocytes, baicalin (0.3-30μM) enhanced BKCa channel activity in a concentration-dependent manner. Increased BKCa currents were abolished by IbTX (0.1μM). Baicalin-mediated (30μM) BKCa current activation was significantly attenuated by an adenylate cyclase inhibitor (SQ 22536, 10μM), a soluble guanylate cyclase inhibitor (ODQ, 10μM), competitive antagonists of cAMP and cGMP (Rp-cAMP, 100μM and Rp-cGMP, 100μM), and cAMP- and cGMP-dependent protein kinase inhibitors (KT5720, 0.3μM and KT5823, 0.3μM). Perfusate with PMA (0.1μM) abolished baicalin-enhanced BKCa currents. Additionally, baicalin (0.3-30μM) reduced the amplitude of VDCC currents in a concentration-dependent manner and abolished VDCC activator Bay K8644-enhanced (0.1μM) currents. Baicalin produced MA relaxation by activating BKCa and inhibiting VDCC channels by endothelium-independent mechanisms and by stimulating the cGMP/PKG and cAMP/PKA pathways.