Bile acids increase intracellular Ca2+ concentration and nitric oxide production in vascular endothelial cells

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Abstract
The effects of bile acids on intracellular Ca2+ concentration [Ca2+]i and nitric oxide production were investigated in vascular endothelial cells. Whole‐cell patch clamp techniques and fluorescence measurements of [Ca2+]i were applied in vascular endothelial cells obtained from human umbilical and calf aortic endothelial cells. Nitric oxide released was determined by measuring the concentration of NO2−. Deoxycholic acid, chenodeoxycholic acid and the taurine conjugates increased [Ca2+]i concentration‐dependently, while cholic acid showed no significant effect. These effects resulted from the first mobilization of Ca2+ from an inositol 1,4,5‐triphosphate (IP3)‐sensitive store, which was released by ATP, then followed by Ca2+ influx. Both bile acids and ATP induced the activation of Ca2+‐dependent K+ current. Oscillations of [Ca2+]i were occasionally monitored with the Ca2+‐dependent K+ current in voltage‐clamped cells and Ca2+ measurements of single cells. The intracellular perfusion of heparin completely abolished the ATP effect, but failed to inhibit the bile acid effect. Deoxycholic acid and chenodeoxycholic acid enhanced NO2− production concentration‐dependently, while cholic acid did not enhance it. The bile acids‐induced nitric oxide production was suppressed by NG‐nitro‐L‐arginine methyl ester, exclusion of extracellular Ca2+ or N‐(6‐aminohexyl)‐5‐chloro‐l‐naphthalenesulphonamide hydrochloride (W‐7) and calmidazolium, calmodulin inhibitors. These results provide novel evidence showing that bile acids increase [Ca2+]i and subsequently nitric oxide production in vascular endothelial cells. The nitric oxide production induced by bile acids may be involved in the pathogenesis of circulatory abnormalities in liver diseases including cirrhosis. British Journal of Pharmacology (2000) 130, 1457–1467; doi:10.1038/sj.bjp.0703471