Bile Salts, Hypotension and Obstructive Jaundice

Bomzon, Arieh; Finberg, J. P. M.; Tovbin, David; Naidu, Strini G.; Better, Ori S.

doi:10.1042/cs0670177

Cited by 60 publications

(42 citation statements)

References 12 publications

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“…36,37) In addition, we have found that the serum concentration of nitric oxide was also elevated in patients with obstructive jaundice. Animal studies show that obstructive jaundice or isolated cholaemia produced by choleductocaval anastomosis induces arterial hypotension due to peripheral vasodilation, and blunts peripheral pressor responses to contractile substrates, [6][7][8][9][10] which are quite similar to the hemodynamic changes observed in liver cirrhosis. Thus, it is most likely that bile acids, especially chenodeoxycholic acid (free acid and its conjugates), are responsible, at least in part, for the hemodynamic changes observed in patients with hepatobiliary diseases, in which the enhancement of endothelial nitric oxide production may be involved.…”

Section: )supporting

confidence: 53%

“…[1][2][3][4][5] Bile acids have been reported to exert vasoactive effects, such as vasodilatory effects. 6,7) Obstructive jaundice or isolated cholaemia produced by choleductocaval anastomosis induces arterial hypotension due to peripheral vasodilation, and peripheral pressor responses to contractile agonists are blunted. [8][9][10] In addition, in patients with liver cirrhosis, hemodynamic changes, such as arterial hypotension and reduced pressor effects of vasoconstrictor substrates, are commonly observed.…”

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confidence: 99%

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Enhancement of Endothelial Nitric Oxide Production by Chenodeoxycholic Acids in Patients with Hepatobiliary Diseases.

et al. 2001

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SUMMARYThe purpose of this study was to clarify whether physiological concentrations of bile acids could affect endothelial nitric oxide production. We investigated the relationships between clinical concentrations of individual bile acids observed in patients with hepatobiliary diseases and endothelial nitric oxide production induced by each bile acid.Fifteen serum bile acids were measured using high-performance liquid chromatography combined with enzymatic fluorometry in 8 patients with liver cirrhosis, obstructive jaundice, and 8 healthy subjects. The effects of individual bile acids on nitric oxide production were examined in human umbilical endothelial cells by measuring the concentration of NO 2 − in the cultured medium. NO release in the blood was also determined by measuring the NO 2 − / NO 3 − concentration in these patients.In patients with hepatobiliary diseases, the plasma concentrations of chenodeoxycholic acid, ursodeoxycholic acid and cholic acid (free acid, taurine and glycine conjugates) were markedly elevated. Incubation of cells with chenodeoxycholic acid and deoxycholic acid (free acid, taurine and glycine conjugates) enhanced NO 2 − production in a concentration-dependent manner, while cholic acid (free and its conjugates) did not. The effects of individual bile acids on nitric oxide production were additive. Patients with liver cirrhosis and obstructive jaundice had higher plasma levels of NO 2 − / NO 3 − levels than the control subjects. These results suggest that increased plasma concentrations of chenodeoxycholic acid (free, taurine and glycine conjugates) in patients with hepatobiliary diseases may induce endothelial nitric oxide production. Thus, nitric oxide production induced by bile acids may be involved in the pathogenesis of circulatory abnormalities in patients with liver diseases. (Jpn Heart J 2001; 42: 339-353)

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confidence: 53%

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confidence: 99%

Enhancement of Endothelial Nitric Oxide Production by Chenodeoxycholic Acids in Patients with Hepatobiliary Diseases.

et al. 2001

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“…These levels are within and even above the concentrations of bile acids shown here to enhance BK Ca channel activity and possibly con-tribute to systemic vasorelaxation. In fact, it has been suggested that increased levels of bile acids in plasma are associated with the hypotension of obstructive jaundice (Bomzon et al, 1984). There is a strong correlation between the magnitude of portosystemic shunting and elevations in plasma bile acid concentrations in portal hypertensive men (Ohkubo et al, 1984).…”

Section: Possible Role Of Bile Acid Activation Of Bk Ca Channels In Bmentioning

confidence: 99%

Natural Bile Acids and Synthetic Analogues Modulate Large Conductance Ca2+-activated K+ (BKCa) Channel Activity in Smooth Muscle Cells

Dopico

2002

The Journal of General Physiology

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Bile acids have been reported to produce relaxation of smooth muscle both in vitro and in vivo . The cellular mechanisms underlying bile acid-induced relaxation are largely unknown. Here we demonstrate, using patch-clamp techniques, that natural bile acids and synthetic analogues reversibly increase BK Ca channel activity in rabbit mesenteric artery smooth muscle cells. In excised inside-out patches bile acid-induced increases in channel activity are characterized by a parallel leftward shift in the activity-voltage relationship. This increase in BK Ca channel activity is not due to Ca 2 ϩ -dependent mechanism(s) or changes in freely diffusible messengers, but to a direct action of the bile acid on the channel protein itself or some closely associated component in the cell membrane. For naturally occurring bile acids, the magnitude of bile acid-induced increase in BK Ca channel activity is inversely related to the number of hydroxyl groups in the bile acid molecule. By using synthetic analogues, we demonstrate that such increase in activity is not affected by several chemical modifications in the lateral chain of the molecule, but is markedly favored by polar groups in the side of the steroid rings opposite to the side where the methyl groups are located, which stresses the importance of the planar polarity of the molecule. Bile acidinduced increases in BK Ca channel activity are also observed in smooth muscle cells freshly dissociated from rabbit main pulmonary artery and gallbladder, raising the possibility that a direct activation of BK Ca channels by these planar steroids is a widespread phenomenon in many smooth muscle cell types. Bile acid concentrations that increase BK Ca channel activity in mesenteric artery smooth muscle cells are found in the systemic circulation under a variety of human pathophysiological conditions, and their ability to enhance BK Ca channel activity may explain their relaxing effect on smooth muscle.

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“…This action can explain or at least contribute to the well-known vasodilating properties and hyperkinetic circulation induced by bile acids in human pathophysiology (7). In a wide variety of human pathological conditions (8)(9)(10)(11)(12), a significant spillover of bile acids from the portal to the systemic circulation occurs, resulting in 10-to100-fold (even close to 1 mM) higher systemic bile acid concentrations (11,13,14). These levels are within and even above the concentrations of bile acids reported to enhance vascular myocyte BK Ca channel activity (4).…”

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confidence: 99%

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

Bukiya

McMillan

Parrill

et al. 2008

Journal of Lipid Research

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Lithocholate (LC) (10-300 mM) in physiological solution is sensed by vascular myocyte large conductance, calcium-and voltage-gated potassium (BK) channel b 1 accessory subunits, leading to channel activation and arterial dilation. However, the structural features in steroid and target that determine LC action are unknown. We tested LC and close analogs on BK channel (pore-forming cbv11b 1 subunits) activity using the product of the number of functional ion channels in the membrane patch (N) and the open channel probability (Po). LC (5b-cholanic acid-3a-ol), 5a-cholanic acid-3a-ol, and 5b-cholanic acid-3b-ol increased NPo (EC 50 ?45 mM). At maximal increase in NPo, LC increased NPo by 180%, whereas 5a-cholanic acid-3a-ol and 5b-cholanic acid-3b-ol raised NPo by 40%. Thus, the a-hydroxyl and the cis A-B ring junction are both required for robust channel potentiation. Lacking both features, 5a-cholanic acid-3b-ol and 5-cholenic acid-3b-ol were inactive. Three-dimensional structures show that only LC displays a bean shape with clear-cut convex and concave hemispheres; 5a-cholanic acid-3a-ol and 5b-cholanic acid-3b-ol partially matched LC shape, and 5a-cholanic acid-3b-ol and 5-cholenic acid-3b-ol did not. Increasing polarity in steroid rings (5b-cholanic acid-3a-sulfate) or reducing polarity in lateral chain (5b-cholanic acid 3a-ol methyl ester) rendered poorly active compounds, consistent with steroid insertion between b 1 and bilayer lipids, with the steroid-charged tail near the aqueous phase. Molecular dynamics identified two regions in b 1 transmembrane domain 2 that meet unique requirements for bonding with the LC concave hemisphere, where the steroid functional groups are located.

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Bile Salts, Hypotension and Obstructive Jaundice

Cited by 60 publications

References 12 publications

Enhancement of Endothelial Nitric Oxide Production by Chenodeoxycholic Acids in Patients with Hepatobiliary Diseases.

Enhancement of Endothelial Nitric Oxide Production by Chenodeoxycholic Acids in Patients with Hepatobiliary Diseases.

Natural Bile Acids and Synthetic Analogues Modulate Large Conductance Ca2+-activated K+ (BKCa) Channel Activity in Smooth Muscle Cells

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

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