deoxycholic-acid and Ischemia

Refined Qing-Kai-Ling (QKL), a modified Chinese medicine, consists of three main ingredients (Baicalin, Jasminoidin and Desoxycholic acid), plays a synergistic effect on the treatment of the acute stage of ischemic stroke. However, the rules of the combination and synergism are still unknown. Based on the ischemic stroke mice model, all different kinds of combination of Baicalin, Jasminoidin, and Desoxycholic acid were investigated by the methods of neurological examination, microarray, and genomics analysis. As a result, it confirmed that the combination of three drugs offered a better therapeutical effect on ischemic stroke than monotherapy of each drug. Additionally, we used Ingenuity pathway Analysis (IPA) and principal component analysis (PCA) to extract the dominant information of expression changes in 373 ischemia-related genes. The results suggested that 5 principal components (PC1-5) could account for more than 95% energy in the gene data. Moreover, 3 clusters (PC1, PC2+PC5, and PC3+PC4) were addressed with cluster analysis. Furthermore, we matched PCs on the drug-target networks, the findings demonstrated that Baicalin related with PC1 that played the leading role in the combination; Jasminoidin related with PC2+PC5 that played a compensatory role; while Desoxycholic acid had the least performance alone which could relate with PC3+PC4 that played a compatible role. These manifestations were accorded with the principle of herbal formulae of Traditional Chinese Medicine (TCM), emperor-minister-adjuvant-courier. In conclusion, we firstly provided scientific evidence to the classic theory of TCM formulae, an initiating holistic viewpoint of combination therapy of TCM. This study also illustrated that PCA might be an applicable method to analyze the complicated data of drug combination.

Topics: Animals; Cluster Analysis; Computational Biology; Deoxycholic Acid; Disease Models, Animal; Drug Combinations; Drugs, Chinese Herbal; Enzyme Inhibitors; Flavonoids; Gene Expression Profiling; Gene Expression Regulation; Iridoids; Ischemia; Male; Mice; Models, Statistical; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Principal Component Analysis; Stroke

We have previously shown rapid in vitro recovery of barrier function in porcine ischemic-injured ileal mucosa, attributable principally to reductions in paracellular permeability. However, these experiments did not take into account the effects of luminal contents, such as bile salts. Therefore, the objective of this study was to evaluate the role of physiological concentrations of deoxycholic acid in recovery of mucosal barrier function. Porcine ileum was subjected to 45 min of ischemia, after which mucosa was mounted in Ussing chambers and exposed to varying concentrations of deoxycholic acid. The ischemic episode resulted in significant reductions in transepithelial electrical resistance (TER), which recovered to control levels of TER within 120 min, associated with significant reductions in mucosal-to-serosal (3)H-labeled mannitol flux. However, treatment of ischemic-injured tissues with 10(-5) M deoxycholic acid significantly inhibited recovery of TER with significant increases in mucosal-to-serosal (3)H-labeled mannitol flux, whereas 10(-6) M deoxycholic acid had no effect. Histological evaluation at 120 min revealed complete restitution regardless of treatment, indicating that the breakdown in barrier function was due to changes in paracellular permeability. Similar effects were noted with the application of 10(-5) M taurodeoxycholic acid, and the effects of deoxycholic acid were reversed with application of the Ca(2+)-mobilizing agent thapsigargin. Deoxycholic acid at physiological concentrations significantly impairs recovery of epithelial barrier function by an effect on paracellular pathways, and these effects appear to be Ca(2+) dependent.

Topics: Animals; Bile Acids and Salts; Calcium; Deoxycholic Acid; Female; Ileum; Ischemia; Male; Microscopy, Electron; Osmolar Concentration; Permeability; Recovery of Function; Swine; Taurodeoxycholic Acid

O2 extraction during progressive ischemia in canine skeletal muscle, J. Appl. Physiol. 79(4): 1351-1360, 1995.--O2 uptake (VO2) is defended during decreased O2 delivery (QO2) by an increase in the O2 extraction ratio (O2ER, VO2/QO2), presumably by recruitment of capillaries. This study tested the hypothesis that activity of the microvascular endothelium plays a necessary role in achievement of maximal O2ER. We pump perfused the vascularly isolated hindlimbs of 24 anesthetized and paralyzed dogs at progressively lower flows over a 90-min period. In eight dogs, hindlimb vascular endothelium was removed by injection of deoxycholate (DOC) into the perfusing artery before the ischemic challenge. DOC treatment resulted in loss of normal in vivo and in vitro endothelium-dependent dilatory responses to acetylcholine, but endothelium-independent vascular smooth muscle responses were intact. Eight other dogs were pretreated with nitro-L-arginine methyl ester plus indomethacin (L+I group) to block the synthesis of the vasodilators nitric oxide and prostacyclin. L+I and DOC treatment were associated with increases in hindlimb vascular resistance of 168 +/- 17 and 63 +/- 12%, respectively. O2ER at critical QO2 (QO2 at which VO2 begins to decrease) was 81 +/- 2% in eight control dogs, 66 +/- 6% in L+I, and 42 +/- 4% in DOC, indicating a significant O2 extraction defect in the two treatment groups. These data suggest that products of the vascular endothelium play an important role in the matching of O2 supply to demand during supply limitation in skeletal muscle.

Topics: Acetylcholine; Animals; Blood Gas Analysis; Cyclooxygenase Inhibitors; Deoxycholic Acid; Dogs; Endothelium, Vascular; Female; Hindlimb; Immunohistochemistry; Ischemia; Male; Microscopy, Electron; Muscle, Skeletal; Nitric Oxide Synthase; Norepinephrine; Oxygen Consumption; Regional Blood Flow; Vascular Resistance; Vasoconstrictor Agents

Although recent clinical reports suggest that greater than normal amounts of dihydroxy secondary bile acids appear in the gastric content of patients with postoperative alkaline reflux gastritis, the pathophysiologic significance of these observations is unclear. We addressed this problem by usiong chambered ex vivo wedges of proximal canine gastric wall. The effects of 1 and 2 mM concentrations of the dihydroxy secondary bile acid, taurodeoxycholic, were compared with those of its parent trihydroxy primary bile acid, taurocholic. The parameters of mucosal function evaluated included the net flux of hydrogen ion, the transmural electrical potential difference, mucosal blood flow determined by radiolabeled microsphere embolization, and the severity of mucosal damage induced in mucosa rendered ischemic by wedge-specific intra-arterial low-dose vasopressin infusin. The results indicate that at each concentration in both ischemic and nonischemic mucosa the dihydroxy secondary bile acid induced a greater depression in potential difference, a more profound increase in mucosal permeability to hydrogen ion, and in ischemic mucosa a more severe degree of gross mucosal damage than did the trihydroxy primary bile acid. These effects may be related to a greater lipid solubility and consequent capacity to disrupt cell membranes.

Topics: Animals; Deoxycholic Acid; Dogs; Female; Gastric Mucosa; Ischemia; Male; Stomach Ulcer; Taurocholic Acid; Taurodeoxycholic Acid