Bilobalide increases SKCa current via 5-HT2BR-PLC–PKC pathway, causing hyperpolarization and enhanced EET production in human coronary artery endothelial cells

Ginkgo biloba extract and its active component bilobalide induce endothelium-dependent vasodilation in coronary and other vascular beds. This effect is associated with increased Ca2+-activated K+ channel activity in endothelial cells. We aimed to identify ion channels targeted by bilobalide in human coronary artery endothelial cells (HCAECs) and to explore the underlying mechanisms. Whole-cell patch-clamp recordings were performed on cultured HCAECs. Epoxyeicosatrienoic acids (EETs) and prostacyclin were quantified with enzyme-linked immunosorbent assays; nitric oxide and hydrogen peroxide were assessed with commercial kits. Bilobalide dose-dependently increased whole-cell current through activation of the small-conductance Ca2+-activated K+ (SKCa) channel, but not through Cl−, transient receptor potential, or other K+ channels. The current increase persisted when all channels except SKCa were blocked and was abolished by apamin, a selective SKCa blocker; additionally, apamin prevented bilobalide-stimulated current. Bilobalide also induced HCAEC hyperpolarization, which was inhibited by apamin. The bilobalide-induced current increase was blocked by antagonists of 5-hydroxytryptamine (5-HT)1/2 and 5-HT2B receptors, phospholipase C, and protein kinase C, but not by inhibitors of 5-HT1B receptors, cytochrome P450, or Gi/o proteins. Furthermore, bilobalide stimulated EET production but not nitric oxide, prostacyclin, or hydrogen peroxide production; this effect was also apamin-sensitive. Bilobalide increases HCAEC current and induces hyperpolarization by activating SKCa via the 5-HT2B receptor–phospholipase C–protein kinase C signaling pathway, leading to EET generation. These findings provide insights into bilobalide’s endothelial mechanisms and highlight its potential as an alternative therapy for coronary artery disease.