On the in vitro vasoactivity of bile acids

Abstract

1 We compared the vasorelaxant action of nine dierent bile acids and correlated their vasorelaxant activity with their individual indices for hydrophobicity or lipophilicity. 2 Vasorelaxant activity correlated with the relative lipid solubility of bile acids with lipophilic bile acids exhibiting the greatest vasorelaxant activity with modest to no vasorelaxant activity exhibited by hydrophilic bile acids. 3 We also investigated whether bile acid-induced vasorelaxation is mediated by antagonism of a prototypal contractile receptor, the a 1 -adrenoceptor, by stimulation of a bile acid surface membrane receptor, by the release of endothelium-derived relaxant factors, by promoting the generation of reactive oxygen species and increasing the extent of lipid peroxidation, or by modifying membranē uidity. 4 Lipophilic bile acids induce vasorelaxation possibly by antagonizing a 1 -adrenoceptors, a phenomenon that manifests itself as a lowering of the anity of vascular a 1 -adrenoceptors. Bile acid-induced vasorelaxation was not dependent upon stimulation of a bile acid surface membrane receptor or the release of endothelium-derived relaxant factors. 5 Lipophilic bile acids can also increase the extent of lipid peroxidation with a subtle reduction in the¯uidity of rat vascular smooth muscle membranes not associated with loss of membrane cholesterol or phospholipid. 6 We have concluded that lipophilic bile acids are non-selective vasorelaxants whose mechanism of action is a multifaceted process involving antagonism of contractile surface membrane receptors possibly eected by an increased extent of lipid peroxidation and/or membrane¯uidity but occurs independent of the release of endothelial-derived relaxant factors or stimulation of a surface membrane bile acid binding site.

Structural determinants of monohydroxylated bile acids to activate β1 subunit-containing BK channels

“…Among naturally occurring bile acids, the monohydroxylated LC is remarkably effective in increasing vascular myocyte BK channel activity (4), which is consistent with the powerful smooth muscle relaxant properties of hydrophobic bile acids (15). We have recently demonstrated that LC-induced vasodilation is largely endotheliumindependent, and blunted after genetic ablation of KCNMB1 (6).…”

Caveolae Depletion Contributes to Vasorelaxant Effects of Chenodeoxycholic Acid

“…It is well acknowledged that BAs can solubilize membranes extracellularly by promoting cholesterol and phospholipid clearance [6, 14]. So we hypothesized that BAs disturbed caveolae intactness on ECs membranes through diminishing cholesterol which induced vasorelaxation by facilitating eNOS phosphorylation and NO production.…”

“…Normally, hydrophobic BAs exhibit greater effect than hydrophilic ones, underlying which multiple mechanisms have been proposed [6]. For example, deoxycholic acid (DCA) or chenodeoxycholic acid (CDCA) prevents activity of contractile surface membrane receptors through lipid peroxidation [6]. CDCA promotes nitric oxide (NO) production in vascular endothelial cells (ECs) by interaction with TGR5, a plasma membrane receptor [7].…”

“…Moreover, the potency of BA-induced vasorelaxation depends much on the lipid solubility. Normally, hydrophobic BAs exhibit greater effect than hydrophilic ones, underlying which multiple mechanisms have been proposed [6]. For example, deoxycholic acid (DCA) or chenodeoxycholic acid (CDCA) prevents activity of contractile surface membrane receptors through lipid peroxidation [6].…”

β1 (KCNMB1) Subunits Mediate Lithocholate Activation of Large-Conductance Ca2+-Activated K+ Channels and Dilation in Small, Resistance-Size Arteries

“…In some of these subjects, systemic circulating levels of bile acids may reach more than 100 M (Ostrow, 1993). It has even been speculated that bile acids may serve as endogenous vasodilators (Bomzon and Ljubuncic, 1995), and bile acid relaxation of vascular smooth muscle seems to be caused by steroid actions on the smooth muscle itself (Ljubuncic et al, 2000). It is remarkable that the vasoactive properties of bile acids have not been tested in small, resistance-size arteries that develop myogenic tone; these arteries are critical to determining pressure and blood flow.…”