piperidines and Hypertension--Portal

The endocannabinoid system comprises receptors, CB1 and CB2, their endogenous lipidic ligands and machinery dedicated to endocannabinoid synthesis and degradation. An overactive endocannabinoid system appears to contribute to the pathogenesis of several diseases, including liver diseases. With the increasing incidence of non-alcoholic fatty liver disease (NAFLD) in parallel with the obesity epidemic, the development of effective therapies is gaining considerable interest. Several recent experimental lines of evidence identify CB receptors as potential novel therapeutic targets in the management of NAFLD. Endogenous activation of peripheral CB1 receptors is a key mediator of insulin resistance and enhances liver lipogenesis in experimental models of NAFLD. Moreover, we have shown that adipose tissue CB2 receptors are markedly upregulated and promote fat inflammation, thereby contributing to insulin resistance and liver steatosis. Data from our group also indicate that tonic activation of CB1 receptors is responsible for progression of liver fibrosis, whereas CB2 receptors display anti-fibrogenic properties. The clinical relevance of these findings is supported by studies in patients with chronic hepatitis C indicating that daily cannabis use is an independent predictor of both fibrosis and steatosis severity. Moreover, preliminary data derived from clinical trials strongly suggest that selective CB1 antagonism improves insulin resistance and reduces liver fat. Tempering these promises, the first generation of CB1 antagonists raised concern due to an alarming rate of mood disorders and the development program of these molecules was suspended. Current research efforts are therefore focused on developing formulations of CB1 antagonists that do not enter the central nervous system, and preliminary experimental data obtained with such molecules are encouraging.

Topics: Animals; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Endocannabinoids; Fatty Liver; Humans; Hypertension, Portal; Inflammation; Insulin Resistance; Liver Cirrhosis; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant

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

Measurement of the hepatic venous pressure gradient (HVPG) offers valuable prognostic information in patients with cirrhosis. In specific circumstances, (children, agitated patients, TIPS placement) deep sedation is required. This study aims to assess the impact of deep sedation on the accuracy of hepatic/portal pressure measurements.. Forty-four patients were included. Measurements of baseline HVPG (n = 30), HVPG response to i.v. propranolol (n = 11), portal pressure gradient (PPG) after TIPS (n = 27) and of cardio-pulmonary pressures (n = 25) were obtained in awake conditions and under deep sedation with propofol and remifentanil.. During deep sedation, a marked oscillation within respiratory cycle was observed in abdominal pressures. End-expiratory sedated HVPG showed a better agreement with awake HVPG (intra-class correlation coefficient - ICC 0.864) than end-inspiratory HVPG (ICC 0.796). However, in almost half of the patients both values differed by more than 10%. Accuracy was not improved by using mean HVPG along the respiratory cycle. Similarly, changes in HVPG caused by propranolol while under sedation had a poor agreement to those obtained in awake conditions. Indeed, about a half of patients were misclassified according to the 10% HVPG reduction target. After TIPS, PPG values obtained under sedation were significantly different to awake PPG, usually underestimating the awake value. The systemic hemodynamic changes induced by sedation were not associated to a greater variability of PPG/HVPG measurements.. Deep sedation with propofol and remifentanil adds substantial variability and uncertainty to HVPG/PPG measurements. This must be considered when using these values to estimate prognosis, or targeting HVPG/PPG reductions.

Topics: Adult; Aged; Anesthetics, Intravenous; Blood Pressure Determination; Deep Sedation; Female; Hepatic Veins; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Piperidines; Portal Pressure; Portal Vein; Portasystemic Shunt, Transjugular Intrahepatic; Predictive Value of Tests; Propofol; Prospective Studies; Remifentanil; Reproducibility of Results; Respiratory Mechanics; Time Factors

Topics: Anesthetics, Intravenous; Blood Pressure Determination; Deep Sedation; Female; Hepatic Veins; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Piperidines; Portal Pressure; Portal Vein; Propofol; Remifentanil

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

Topics: Animals; Appetite Depressants; Cannabinoid Receptor Modulators; Cannabinoids; Chronic Disease; Disease Models, Animal; Disease Progression; Endocannabinoids; Fatty Liver; Glycolysis; Hepatitis C, Chronic; Hepatocytes; Humans; Hypertension, Portal; Lipogenesis; Liver; Liver Cirrhosis; Liver Diseases; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

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

The endogenous cannabinoid anandamide causes hypotension and mesenteric arteriolar dilation. A detailed analysis of its effects on systemic and portal venous hemodynamics had not yet been performed. We assessed the effects of anandamide (0.4-10 mg/kg) on systemic and portal hemodynamics with and without prior treatment with various antagonists. The specific antagonists used included SR-141716A, N(omega)-nitro-L-arginine methyl ester, indomethacin, and nordihydroguaiaretic acid. Anandamide produced a dose-dependent decrease in mean arterial pressure due to a drop in systemic vascular resistance (SVR) that was accompanied by a compensatory rise in cardiac output. Anandamide also elicited an increase in both portal venous flow and pressure, along with a decline in mesenteric vascular resistance (MVR). Pretreatment with 3 mg/kg SR-141716A, a CB(1) antagonist, prevented the decline of SVR and MVR from the lower dose of anandamide. Antagonism of nitric oxide synthetase, cyclooxygenase, or 5-lipoxygenase did not prevent the systemic nor the portal hemodynamic effects of anandamide. Furthermore, the use of R-methanandamide, a stable analog of anandamide, produced similar hemodynamic effects on the mesenteric vasculature, thereby implying that the effects of anandamide are not related to its breakdown products. Anandamide produced profound, dose-dependent alterations in both the systemic and portal circulations that could be at least partially blocked by pretreatment with SR-141716A.

Topics: Animals; Arachidonic Acids; Blood Pressure; Calcium Channel Blockers; Cannabinoids; Cardiac Output; Cyclooxygenase Inhibitors; Endocannabinoids; Enzyme Inhibitors; Heart Rate; Hypertension, Portal; Indomethacin; Liver Circulation; Male; Masoprocol; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Piperidines; Polyunsaturated Alkamides; Portal Vein; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Splanchnic Circulation

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

Endothelin-1 has been suggested to play a key role in cirrhotic portal hypertension, but a role of its receptors in vivo is not fully elucidated.. Biliary cirrhosis was induced by bile duct ligation. Expressions of endothelin-1 and its receptors were evaluated by radioimmunoassay and/or reverse-transcription polymerase chain reaction. Hemodynamics were studied using endothelin receptor agonist or antagonist.. Portal pressure and hepatic endothelin-1 concentrations progressively increased in parallel after bile duct ligation. Gene expression of hepatic prepro-endothelin-1 and endothelin B receptor enhanced after bile duct ligation, while that of endothelin A receptor was unchanged. Intraportal administration of endothelin-1 or endothelin B receptor agonist sarafotoxin 6c (0.5 nmol/kg, respectively) progressively raised portal pressure in both sham and cirrhotic rats. Portal hypertensive effect of sarafotoxin 6c was more intense in cirrhotic rats than sham animals. Neither endothelin A receptor antagonist FR139317 (1 mg/kg) nor endothelin B receptor antagonist BQ788 (1 mg/kg) alone ameliorated cirrhotic portal hypertension. Only the combined endothelin A and B blockade was associated with a decrease in portal pressure in cirrhotic rats.. These results indicate that endothelin-1 plays a major role in cirrhotic portal hypertension through endothelin receptor subtype B together with subtype A in vivo.

Topics: Animals; Azepines; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Gene Expression; Hemodynamics; Hypertension, Portal; Indoles; Liver; Liver Cirrhosis, Biliary; Oligopeptides; Piperidines; Protein Precursors; Radioimmunoassay; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA

We have recently demonstrated that ritanserin, a serotonin 5-hydroxytryptamine receptor antagonist void of systemic effects, caused a significant reduction of portal pressure in conscious cirrhotic dogs. The mechanism by which ritanserin lowers portal pressure is poorly defined. We investigated the splanchnic and systemic hemodynamic effects of ritanserin (0.63 mg/kg body wt i.v., a dose known to completely inhibit binding of 5-hydroxytryptamine to its receptors), in conscious and unrestrained cirrhotic rats (n = 13). Heparinized catheters were placed into the portal vein, inferior vena cava, aorta, and left ventricle with exit from the neck. Hemodynamic studies were performed 4 h after consciousness was regained. Cardiac output and regional blood flows were measured using radiolabeled microspheres and the reference sample method. Sixty minutes after administration, ritanserin caused a significant reduction of portal pressure (-17%) with minimal changes in portal venous inflow (+3%). Portal vascular resistance decreased significantly (-23%), whereas splanchnic arteriolar resistance was similar before and after ritanserin. A significant increase in mean arterial pressure (+5%) and cardiac output (+22%) was observed. Our results suggest that ritanserin lowers portal pressure through a mechanism separate from portal venous inflow. This effect could be due to changes in intrahepatic or on portocollateral resistances, or both. These findings support the potential use of this new agent in the treatment of portal hypertension.

Topics: Animals; Consciousness; Depression, Chemical; Hemodynamics; Hypertension, Portal; Liver Cirrhosis, Experimental; Male; Piperidines; Rats; Rats, Inbred Strains; Ritanserin; Serotonin Antagonists; Splanchnic Circulation

It has recently been reported that the administration of ketanserin, a serotonin antagonist, was associated with a significant reduction in portal pressure both in portal hypertensive rats and cirrhotic patients. However, this beneficial effect on splanchnic hemodynamics was accompanied by a significant reduction in arterial pressure. Using conscious dogs, we investigated the effect of the chronic oral administration of a new specific antiserotonergic drug, ritanserin (10 mg per day for 5 days), on portal pressure and systemic hemodynamics. Eleven dogs with secondary biliary cirrhosis and portal hypertension due to chronic bile duct ligation were evaluated. One week prior to study, heparinized catheters were placed in the portal vein and brought subcutaneously to the dorsal cervical area. Measurements were made under baseline conditions, following ritanserin administration and 72 hr after the last dose. Ritanserin administration caused a significant reduction in portal pressure (from 17.3 +/- 3.1 mmHg to 13.6 +/- 4.5 mmHg; mean decrease: 23.1%; p less than 0.001). Maximal effects on portal pressure were reached on the fourth day. During the recovery period, hemodynamic parameters returned to baseline values. In six of the 11 cirrhotic dogs with successful chronic catheterization of the inferior vena cava and aorta, ritanserin administration did not cause significant changes in the mean arterial pressure, heart rate, cardiac output and peripheral vascular resistance. These data indicate that chronic implantation of venous and arterial catheters in dogs with secondary biliary cirrhosis is a useful experimental model for pharmacological studies of portal hypertension in conscious animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Cardiac Output; Common Bile Duct; Dogs; Female; Heart Rate; Hypertension, Portal; Ligation; Liver Cirrhosis, Biliary; Piperidines; Portal Vein; Ritanserin; Serotonin Antagonists; Vascular Resistance

Topics: Animals; Atropine; Blood Circulation; Blood Pressure; Blood Pressure Determination; Chloralose; Cyproheptadine; Diphenhydramine; Dogs; Endotoxins; Hemorrhage; Histamine H1 Antagonists; Histamine Release; Humans; Hypertension; Hypertension, Portal; Isoproterenol; Morphine; p-Methoxy-N-methylphenethylamine; Pharmacology; Phenothiazines; Phenoxybenzamine; Piperidines; Research; Reserpine; Shigella; Shock, Septic; Splenic Artery; Sympatholytics; Vasodilator Agents