bq-123 and Hypertension--Portal

Increased endothelin (ET)-1 activity may contribute to the complications of cirrhosis and portal hypertension. The aim of this study was to assess the systemic and portal haemodynamic effects of selective ET-A and ET-B receptor antagonism in patients with cirrhosis.. Sixteen patients with cirrhosis and portal hypertension (aged 52 (1) years, Pugh score 6.2 (0.3)) underwent 24 studies with infusions of: (A) selective ET-A antagonist, BQ-123 (n = 8), at 1000 and 3000 nmol/min; (B) selective ET-B antagonist, BQ-788 (n = 8), at 100 and 300 nmol/min; or (C) matched saline placebo (n = 8) in a double blind randomised manner. Haemodynamic measurements were performed through pulmonary artery, hepatic venous, and femoral artery catheters.. Baseline patient characteristics were well matched. Compared with placebo, BQ-123 decreased mean arterial pressure (MAP -15 (11) mm Hg (-18%); p<0.02) and pulmonary vascular resistance index (PVRI -81 (54) dyn x s x m2/cm5 (-64%); p<0.05), with no effect on hepatic venous pressure gradient (HVPG), cardiac index (CI), or systemic vascular resistance index (SVRI). Compared with placebo, BQ-788 increased MAP (+11 (3) mm Hg (+12%); p<0.03) and SVRI (+1101 (709) dyn x s x m2/cm5 (+50%); p<0.05), reduced CI (-1.0 (0.4) l/min/m2 (-29%); p = 0.05) with no effect on HVPG or PVRI.. ET-1 contributes to maintenance of systemic and pulmonary haemodynamics without acutely affecting HVPG in patients with early cirrhosis. In this group of patients, the use of selective ET-A and ET-B antagonists for the management of variceal haemorrhage is likely to be limited.

Topics: Adult; Aged; Double-Blind Method; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Female; Hemodynamics; Humans; Hypertension, Portal; Liver Circulation; Liver Cirrhosis; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Circulation

The effect of an endothelin (ET) A receptor antagonist on hepatic hemodynamics in cirrhotic rats was examined.. Portal pressure and hepatic tissue blood flow in cirrhotic rats were measured. Plasma ET-1 levels were determined by radioimmunoassay. BQ-123 was infused to these rats at a rate of 10 nmol/min. The sinusoids were observed by scanning electron microscopy. The localization of ET-1 and ETA receptors was examined using the indirect immunoperoxidase method.. In cirrhotic rats, the portal pressure significantly increased to 16.6 ± 1.5 cm H2O, and the hepatic tissue blood flow markedly decreased. Plasma ET-1 levels in cirrhotic rats were higher than those in normal rats. When BQ-123 was infused, the portal pressure was significantly reduced by more than 2 cm H2O, compared with the control group (p < 0.05). Hepatic tissue blood flow was maintained at the level before infusion. In liver cirrhosis, the sinusoids were covered with continuous endothelial cells, and the number of sinusoidal endothelial fenestrae extremely decreased. ET-1 was remarkably enhanced in sinusoidal endothelial cells within the regenerating nodules, and the reaction products of ETA receptors were mainly recognized in hepatic stellate cells.. The augmented action of ET-1 via the ETA receptor may be involved in the mechanism of portal hypertension in liver cirrhosis.

Topics: Animals; Endothelial Cells; Endothelin A Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Hypertension, Portal; Immunohistochemistry; Liver; Liver Circulation; Liver Cirrhosis, Experimental; Male; Microcirculation; Microscopy, Electron, Scanning; Peptides, Cyclic; Rats; Rats, Wistar

Hepatic and circulating endothelin-1 (ET-1) are increased in patients with cirrhosis and in cirrhotic animals. However, the distinct roles of ET receptor subtypes ETA and ETB in cirrhosis and portal hypertension (PHT) have not been clearly elucidated. Thus, we studied the effects of selective ET-1 antagonists (ETA-ant or ETB-ant) and nonselective ET-1 antagonist (ETA/B-ant) on hepatic hemodynamics in cirrhotic rats. Liver fibrosis and PHT were induced by complete bile duct ligation (BDL) in rats. Two weeks after BDL or sham surgery, hemodynamic responses were measured during intraportal infusion of incremental doses of the following ET-ants: (i) BQ-123, (ii) BQ-788, and (iii) bosentan. After equilibration with vehicle, doses of ET-ants were infused for 30 min periods, and steady-state systemic and hepatic hemodynamics, portal venous pressure (PVP), and hepatic blood flow (HBF) were measured. BDL induced significant PHT and elevated concentrations of plasma ET-1 compared with sham. ETA-ant decreased PVP of cirrhotic rats but had no effect on sham, whereas ETB-ant increased PVP in sham but had no effect in BDL. Nonselective ETA/B-ant decreased PVP of BDL similarly to ETA-ant. Both ETA-ant and ETB-ant decreased local HBF, whereas a nonselective antagonist did not change HBF in sham; however no significant changes were observed in HBF of BDL rats with any of the antagonists. These findings suggest ETA activation contributes to PHT in cirrhotic rats, whereas ETB-mediated portal depressor effects are attenuated in cirrhotic rats compared with noncirrhotic rats.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression; Hemodynamics; Hepatic Stellate Cells; Hypertension, Portal; Liver; Liver Cirrhosis; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Portal Pressure; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Regional Blood Flow; Sulfonamides

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

Sinusoidal endothelial fenestrae (SEF) regulate the sinusoidal circulation by altering their diameter and number. This study documented the effects of endothelin (ET) receptor antagonists on SEF and hepatic microcirculation.. The portal pressure and hepatic tissue blood flow were measured with a hydromanometer and a laser Doppler blood flow meter, respectively. BQ-123 (ET(A) receptor antagonist) or BQ-788 (ET(B) receptor antagonist) was continuously infused into normal rats at the rate of 10 nmol/min for 10 min. The sinusoids were observed at 60 min after the infusion by scanning electron microscopy. The localization of ET-1 and ET(A) and ET(B) receptors was examined by the indirect immunoperoxidase method.. When BQ-123 was infused, the portal pressure gradually decreased with time, and it showed a significant reduction compared with the control groups. On the other hand, a decrease in portal pressure was not evident in the BQ-788-infused groups. Hepatic tissue blood flow was maintained at the value prior to the infusion in both groups. BQ-123 also caused a marked dilatation of the SEF. The diameters of the SEF after BQ-123 infusion were almost three times those of normal SEF. ET-1 was evenly present along the sinusoidal walls, and the reaction products of the ET(A) receptors were recognized along the portal vein and in the sinusoidal cells, that is, the hepatic stellate cells and endothelial cells.. Action of ET-1 via the ET(A) receptors may regulate the size of SEF in addition to hepatic microcirculation.

Topics: Animals; Antihypertensive Agents; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Hypertension, Portal; Immunohistochemistry; Liver; Liver Circulation; Male; Microcirculation; Microscopy, Electron, Scanning Transmission; Peptides, Cyclic; Rats; Rats, Wistar; Vasodilation

Endothelin-1 (ET-1) may induce intrahepatic vasoconstriction and consequently increase portal pressure. Endothelin-1 has been shown to exert a direct vasoconstrictive effect on the collateral vessels in partially portal vein-ligated rats with a high degree of portal-systemic shunting. This study investigated the collateral vascular responses to ET-1, the receptors in mediation and the regulation of ET-1 action by nitric oxide and prostaglandin in cirrhotic rats with a relatively low degree of portal-systemic shunting.. The portal-systemic collaterals of common bile duct-ligated (BDL) cirrhotic rats were tested by in situ perfusion. The concentration-response curves of collaterals to graded concentrations of ET-1 (10(-10)-10(-7) m) with or without BQ-123 (ET(A) receptor antagonist, 2 x 10(-6) m), BQ-788 (ET(B) receptor antagonist, 10(-7) m) or both were recorded. In addition, the collateral responses to ET-1 with preincubation of N(omega)-nitro-L-arginine (NNA, 10(-4) M), indomethacin (INDO, 10(-5) M) or in combination were assessed.. Endothelin-1 significantly increased the perfusion pressures of portal-systemic collaterals. The ET-1-induced constrictive effects were inhibited by BQ-123 or BQ-123 plus BQ-788 but not by BQ-788 alone. The inhibitory effect was greater in the combination group. Pretreatment of NNA or NNA plus INDO equivalently enhanced the response of ET-1 while pretreatment of INDO alone exerted no effect.. Endothelin-1 has a direct vasoconstrictive effect on the collaterals of BDL cirrhotic rats, mainly mediated by ET(A) receptor. Endogenous nitric oxide may play an important role in modulating the effects of ET-1 in the portal-systemic collaterals of BDL cirrhotic rats.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Collateral Circulation; Common Bile Duct; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Hypertension, Portal; Indomethacin; Ligation; Liver Cirrhosis, Experimental; Male; Nitric Oxide; Nitroarginine; Oligopeptides; Peptides, Cyclic; Piperidines; Portal System; Prostaglandin Antagonists; Rats; Rats, Sprague-Dawley; Vasoconstriction; Vasoconstrictor Agents

Portal hypertension is associated with increased hepatic and collateral resistance to an increased portal blood flow. Endothelin-1 (ET-1) can induce intrahepatic vasoconstriction and consequently increase portal pressure. It is unknown if ET-1 also modulates portal pressure by a direct vasoconstrictive effect on collaterals. This study investigated the collateral vascular responses to ET-1, the receptors in mediation, and the regulation of ET-1 action by nitric oxide and prostaglandin. The portal-systemic collaterals of partially portal vein-ligated rats were tested by in situ perfusion. The concentration-response curves of collaterals to graded concentrations of ET-1 (10(-10)-10(-7) mol/L) with or without BQ-123 (ET(A) receptor antagonist, 2 x 10(-6) mol/L), BQ-788 (ET(B) receptor antagonist, 10(-7) mol/L) or both were recorded. In addition, the collateral responses to ET-1 with preincubation of n(omega)-nitro-L-arginine (NNA; 100 mol/L), indomethacin (INDO; 10 mol/L), or in combination were performed. ET-1 increased the perfusion pressure of collaterals and its effect was significantly suppressed by BQ-123 alone and BQ-123 plus BQ-788, but not BQ-788 alone (P <.05). Incubation with NNA, INDO, or both significantly enhanced the response of collaterals to ET-1 (P < .05). These results show that ET-1 produces a direct vasoconstrictive effect on the collateral vessels of portal hypertensive rats. This effect is mediated by ET(A,) but not ET(B), receptors. Both nitric oxide and prostaglandin modulate the collateral vascular response to ET-1 and may therefore participate in the development and maintenance of portal hypertension.

Topics: Animals; Collateral Circulation; Cyclooxygenase Inhibitors; Drug Combinations; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Portal; Indomethacin; Male; Nitric Oxide; Nitroarginine; Oligopeptides; Peptides, Cyclic; Piperidines; Portal System; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Vasoconstriction

Elucidation of the hepatic hemodynamics in acute ethanol administration is an issue of clinical importance for better understanding of alcoholic liver diseases. The purpose of this study is to clarify the mechanism of hepatic microcirculatory disturbances after acute ethanol administration, especially regarding the effects of ethanol on alterations of sinusoidal endothelial fenestrae (SEF) and the involvement of endothelin-1 (ET-1) in the mechanism of portal hypertension induced by ethanol. Ethanol was administrated into the portal vein via the mesenteric vein branch of rats as a continuous infusion (4 and 8 mg/min of ethanol) for 60 min. Hepatic tissue blood flow measured with a laser Doppler blood flowmeter was found to be remarkably decreased with time, whereas portal pressure began to increase at 10 min and showed a significant increase by approximately 1.5 cm H2O at 60 min. Ethanol concentrations in blood at 60 min after 4 and 8 mg/min of ethanol infusion were 0.75 mg/ml and 1.77 mg/ml, respectively. At this point, scanning electron microscopy revealed significant decreases in number and diameter of SEF both in zone 1 and zone 3, with the increase in ethanol level. These findings suggested that decreases in number and diameter of SEF, whether primary or secondary, may lead to the impairment of the transport of plasma substances from sinusoids to hepatocytes in acute ethanol administration. Furthermore, the pretreatment of BQ-123 inhibited a decrease in hepatic tissue blood flow and an increase in portal pressure caused by ethanol, indicating that ET-1 may be involved in the mechanism of hepatic circulatory disturbances in acute ethanol administration.

Topics: Animals; Antihypertensive Agents; Blood Flow Velocity; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Ethanol; Hypertension, Portal; Infusions, Intravenous; Liver; Male; Mesenteric Veins; Microscopy, Electron; Microscopy, Electron, Scanning; Peptides, Cyclic; Portal Vein; Rats; Rats, Wistar; Receptor, Endothelin A; Venous Pressure

Factors that increase resistance to blood flow through the hepatic sinusoids when portal hypertension occurs in the absence of significant hepatic fibrosis are not completely understood. Experiments were designed to test the hypothesis that endothelin-1 (ET-1) is one of the humoral factors that increases sinusoidal vascular resistance in a bile duct- ligated noncirrhotic portal hypertensive (BDL) rat. The effect of ET-1 and nitric oxide (NO) on contractility of rings of portal vein taken from BDL rats was tested. The effect of ET-1 and NO on intrahepatic resistance in an isolated perfused liver was studied, and localization of ET-1 in the liver was identified by immunohistochemistry. Portal vein rings in BDL rats showed increased maximal tension in response to ET-1, as well as a shift of the dose-response curve to the left as compared with sham-operated animals. Removal of the endothelium further increased contractility. In isolated perfused liver studies, ET-1 increased portal resistance in both sham operated and BDL rats. The endothelin Type A receptor antagonist BQ 123 lowered the high portal resistance in BDL rats to levels comparable with sham operated animals. Infusion of L-arginine lowered resistance to a much smaller extent. In livers from BDL rats, ET-1 was localized in periportal and pericentral hepatocytes and hepatic sinusoidal cells. We conclude that in a BDL model of portal hypertension where distortion of hepatic architecture by fibrosis is minimal, increased resistance to portal blood flow may be mediated by ET-1.

Topics: Animals; Arginine; Endothelin-1; Hypertension, Portal; In Vitro Techniques; Male; Nitric Oxide; omega-N-Methylarginine; Peptides, Cyclic; Perfusion; Rats; Rats, Inbred F344; Vascular Resistance; Vasoconstriction