benzofurans and Hypertension--Portal

To investigate the effects of Glytan on splanchnic hemodynamics and its reduction of portal pressure in portal hypertensive rats.. Glytan (Ganluotong in Chinese), is composed of salvianolic acid B and diammonium glycyrrhizinate. Portal hypertension (PHT) was induced in the rats by common bile duct ligation (BDL). Hemodynamic studies were performed using the colored microsphere method. Radioimmunoassay (RIA) was used to determine endothelin (ET)-1 levels in the mesenteric circulation. Western blotting methods were used to investigate the effect of Glytan on ET A receptor (ETAR), ET B receptor (ETBR), endothelial NO synthase (eNOS), G-protein-coupled receptor kinase (GRK)2, and β-arrestin 2 expression in the mesentery. The mRNA of ETAR and ETBR was determined using real-time polymerase chain reaction.. Treatment with Glytan reduced portal pressure (PP) and portal territory blood flow (PTBF) and increased both mean arterial pressure (MAP) and splanchnic vascular resistance (SVR). Especially at 4 wk, PP decreased by about 40%, while MAP increased by 13%, SVR increased by 12%, and PTBF decreased by about 21%. The effect of blood flow reduction was greatest in the mesentery (about 33%) at 4 wk. The mesenteric circulation ET-1 levels of BDL rats were lower and negatively correlated with PP at 4 wk. Glytan can increase mesenteric ET-1 content and inhibit ETBR, eNOS, GRK2, and β-arrestin 2 expression in the mesentery. Moreover, Glytan showed no effect on the expression of ETAR protein and mRNA.. The decreased PP and PTBF observed after Glytan treatment were related to increased mesenteric vasoconstriction and increased receptor sensitivity to vasoconstrictor.

Topics: Animals; Benzofurans; Blood Flow Velocity; Disease Models, Animal; Drugs, Chinese Herbal; Endothelin B Receptor Antagonists; Endothelin-1; G-Protein-Coupled Receptor Kinase 2; Glycyrrhetinic Acid; Hypertension, Portal; Male; Mesentery; Nitric Oxide Synthase Type III; Portal Pressure; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Receptor, Endothelin B; Signal Transduction; Splanchnic Circulation; Time Factors; Vasoconstriction; Vasoconstrictor Agents

Cirrhotic portal hypertension is characterized by increased hepatic oxidative stress, AA (arachidonic acid)-derived TXA(2) (thromboxane A(2)) release and exaggerated hepatic response to the α-adrenergic agonist MTX (methoxamine). Besides promoting hepatic fibrosis, the role of hyperleptinaemia in the modulation of vascular response in NASH (non-alcoholic steatohepatitis) rat livers remains unknown. The aim of the present study was to explore the possible links between hyperleptinaemia and the disarrangement in the hepatic microcirculation. NASH-cirrhosis with hyperleptinaemia was induced in lean rats by feeding with an HF/MCD (high-fat/methionine-choline-deficient) diet. Portal haemodynamics, various substances, protein and mRNA expression and PUFA (polyunsaturated fatty acid) composition were measured. Finally, the effects of leptin pre-infusion on TXA(2) release and concentration-PPP (portal perfusion pressure) curves in response to MTX were evaluated by simultaneously pre-treatment with the Kupffer cell inactivators GdCl(3) (gadolinium chloride) or EC (encapsulated clodronate), the TXS (TXA(2) synthase) inhibitor furegrelate, the TP receptor (TXA(2) receptor) antagonist SQ29548 and the dual TXS/TP receptor antagonist BM567. In HF/MCD+leptin-lean rats, cirrhosis-induced PPP and MTX hyper-responsiveness were associated with increased hepatic TXA(2) production, TBARS (thiobarbituric acid-reacting substances) levels and the AA (arachidonic acid)/n-3 PUFA ratio, and up-regulation of hepatic leptin, FAS (fatty acid synthase), NADPH oxidase subunits, TXS, TP receptor, TGFβ(1) (transforming growth factor β(1)) proteins and mRNAs. Pre-infusion of leptin significantly enhanced MTX-stimulated PPP elevation and TXA(2) release, which were attenuated by GdCl(3) and EC pre-treatment. Concomitantly pre-incubation with BM567, but not furegrelate or SQ29548, significantly abolished the leptin-enhanced MTX-stimulated increase in PPP in NASH-cirrhotic rats. Hyperleptinaemia plays an important role in hyper-responsiveness to MTX in NASH-cirrhotic rat livers with portal hypertension. The leptin-enhanced MTX-stimulated increase in PPP is mediated by increased oxidative stress and Kupffer-cell-activated AA-derived TXA(2) release in NASH-cirrhotic rats.

Topics: Analysis of Variance; Animals; Arachidonic Acid; Benzofurans; Choline; Clodronic Acid; Diet, High-Fat; DNA Primers; Fatty Acids, Unsaturated; Fatty Liver; Gadolinium; Hemodynamics; Hypertension, Portal; Insulin Resistance; Kupffer Cells; Leptin; Methionine; Methoxamine; Microcirculation; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Rats; Receptors, Thromboxane A2, Prostaglandin H2; RNA, Messenger; Sulfonylurea Compounds; Thiobarbituric Acid Reactive Substances; Thromboxane A2

To study the relaxant effects of glycyrrhizinate and salvianolic acid B on rat portal vein in vitro.. Healthy female Wistar rats were canalized from hepatic artery, portal vein and hepatic vein in vitro. Remained blood in liver was eliminated with heparinized Krebs-Henseleit solution through hepatic artery, then the liver was isolated under infusing manner. Being constricted with phenylephrine and relaxed with acetylcholine, and infused with glycyrrhizinate or salvianolic acid B, the portal pressures of infused rat livers were consistently monitored by BL-420S physiological experiment system. The median effective concentration (EC50) of the two agents were analyzed with non-linear various slope regression using Prism-4 software.. EC50 of glycyrrhizinate in relaxing the phenylephrine-contracted portal was 1.5556 x 10(-9) mol/L, suggesting one of the mechanism of action of diammonium glycyrhizinate for the treatment of portal hypertension was direct relaxation. Salvianolic acid B showed constrictive action on the phenylephrine-retracted portal vein, the EC50 was 1.4639 x 10(-9) mol/L, indicating that its indirect control action was took part in the portal hypertension therapy synergistically.. Under the mode with both controlled-velocity and monitored pressure, glycyrrhizinate showed relaxation and salvianolic acid B showed constriction on portal pressure in vitro.

Topics: Animals; Benzofurans; Blood Pressure; Female; Glycyrrhizic Acid; Hypertension, Portal; Phenylephrine; Portal Vein; Rats; Rats, Wistar; Vasoconstrictor Agents; Vasodilator Agents; Vasomotor System

To observe the effects of Salviae miltiorrhizae and its component, salvianolic acid B (SA-B), on the microcirculation of liver in mice with portal hypertension induced by endothelin-1 (ET-1).. Eighty-four Kunming mice were randomly divided into 7 groups: untreated group, endothelin A receptor (ETAR) blocker group, Astragali mongolici group, Astragalus polysaccharides (APS) group, Corydalis Yanhusuo group, Salviae miltiorrhizae group and SA-B group. There were 12 mice in each group. Mice were pretreated with a corresponding equivalent volume of drug or distilled water for 3 days, and then the portal hypertension in mice was induced by continuous injection of ET-1 into coccygeal vein using a micro-injection pump. Six mice in each group were used to observe the average liver blood flow volume by laser-Doppler flow instrument before and after injection of ET-1, and the other six rats were used to observe the hepatic microcirculation velocity in vivo by an inverted microscope.. The average blood flow of liver in mice decreased in each group after ET-1 injection. But the changes of average blood flow in the SA-B group and the ETAR blocker group were less than that in the untreated group (P<0.01). The changes of average blood volume in the Astragali mongolici group and the APS group were similar to that in the untreated group, but more than that in the SA-B group after injection of ET-1. The change of average blood flow in the SA-B group showed no significant difference when compared with the ETAR blocker group. The microcirculatory flow velocity in liver also decreased in each group after ET-1 injection. But the changes of microcirculatory flow velocity in the SA-B group and the ETAR blocker group were less than that in the untreated group (P<0.05, P<0.01). There were no significant differences in the changes of microcirculatory flow velocity among the Salviae miltiorrhizae group, the SA-B group and the ETAR blocker group.. Salviae miltiorrhizae and SA-B can decrease the average blood flow and microcirculatory flow velocity in liver in mice with portal hypertension, which may be one of the mechanisms of Salviae miltiorrhizae and SA-B in decreasing portal hypertension.

Topics: Animals; Benzofurans; Hypertension, Portal; Liver; Male; Mice; Mice, Inbred Strains; Microcirculation; Salvia miltiorrhiza

To investigate the effects of salvianolic acid B (SA-B) on portal hypertension induced by endothelin-1 in rats.. Twenty-eight Sprague-Dawley rats were randomly divided into four groups: ET-1 group, ET-1+SA-B group, ET-1+ET(A)R blocker (BQ-123) group and ET-1+ET(B)R blocker (BQ-788) group. The rats of ET-1+SA-B group underwent intragastrical administration of salvianolic acid B for five days before ET-1 injection, while in three other groups' drinking water was given. In BQ-123 group or BQ-788 group, an intravenous injection of BQ-123 or BQ-788 via femoral vein was administered 30 minutes prior to ET-1 injection. Then changes of portal pressure, cervical artery pressure and heart rate were monitored continuously.. After ET-1 injection, the portal pressure of all rats in the ET-1 group increased significantly, while slightly in groups that pretreated with SA-B, BQ-123 or BQ-788.. SA-B can attenuate the elevated portal pressure induced by ET-1 with effect similar to ETR blocker.

Topics: Animals; Antihypertensive Agents; Benzofurans; Drugs, Chinese Herbal; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Portal; Injections, Intravenous; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Portal Pressure; Random Allocation; Rats; Rats, Sprague-Dawley