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Abstract Numerous studies have demonstrated the impaired cardiovascular reactivity in cholestasis patients and bile duct ligated animals. However, the underlying mechanism remains uncertain. Transient receptor potential cation V4 (TRPV4) channels are reported to be naturally expressed in the cardiovascular system, especially on endothelial cells. However, the role of TRPV4 (transient receptor potential vanilloid 4) in regulating vascular reactivity is poorly established. In this study, we first determined that bile acids elicited endothelium-dependent vasoconstrictor hypo-activity via TRPV4 channels, which further activated cyclooxygenase 2 (COX2). Myography results demonstrated that the vascular contractile response was attenuated in BDL rats when exposed to 60 mmol/L KCl. Real time PCR and western blotting results showed that bile duct ligation (BDL) induced a time-dependent increase in TRPV4 expression levels. In addition, bile acids upregulated the expression of TRPV4 protein, which proved to be located on the cell surface of endothelial cells, and induced intracellular Ca2+ events. The relaxation response was increased while the contractile response was decreased in BDL rats, and those effects were reversed by a TRPV4 inhibitor (HC067047). Contractions induced by norepinephrine were primarily inhibited by the COX2 inhibitor, but not the NOS inhibitor, and the expression of COX2 was downregulated after TRPV4 inhibition. These data indicated that TRPV4/COX2 pathways in the endothelium are involved in vasoconstrictor hypo-activity. Our current results suggested that the TRPV4 pathway is involved in the regulation of bile acids in vasoconstrictor hypo-activity in bile duct ligation rats. [ABSTRACT FROM AUTHOR]

New and practical acid-promoted domino bicyclization between 2,2-dihydroxyindene-1,3-dione and cyclic enaminones has been established for the formation of tetracyclic isochromeno[4,3- b ]indoles under microwave heating. The present method simultaneously installs C–N, C–O, and C–C bonds, allowing direct assemble of functionalized isochromeno[4,3- b ]indole skeleton with a wide diversity in substituents. The reaction features reliable scalability, flexibility of structural modification, and wide substrate scope as well as operational simplicity, and it can avoid time-consuming and costly syntheses, tedious work-up, and isolation of intermediate. [ABSTRACT FROM AUTHOR]