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Biomedical subjects

D Lebrec

Publications and source records attributed to D Lebrec.

At least 127 records · Page 7Linked to original sources
PubMed1994

Vascular hyporesponsiveness to endothelin 1 in rats with cirrhosis.

BACKGROUND/AIMS: Because the vasodilator nitric oxide is overproduced in cirrhosis, this substance may decrease pressor responses to the vasoconstrictor endothelin 1. This study aimed to examine the effects of a NO synthesis inhibitor (NG-nitro-L-arginine methyl ester; L-NAME) on vascular responsiveness to endothelin 1 in normal and cirrhotic rats. METHODS: Pressor dose-response curves to endothelin 1 (0.5, 1, 3, 6, and 10 micrograms/kg intravenously) were obtained in animals with or without pretreatment with L-NAME. RESULTS: Pressor responses to endothelin 1 alone were significantly lower in cirrhotic than in normal rats. In cirrhotic animals, pressor responses to 3, 6, and 10 micrograms/kg of endothelin 1 were significantly higher in the presence than in the absence of L-NAME. The responses to the other doses of endothelin 1 were not affected by L-NAME. In normal rats, pressor responses to all doses of endothelin 1 were significantly higher in the presence than in the absence of L-NAME. In animals pretreated with L-NAME, pressor responses to 6 and 10 micrograms/kg of endothelin 1 did not differ between cirrhotic and normal rats, whereas responses to other doses remained lower in cirrhotic than in normal rats. CONCLUSIONS: In rats with cirrhosis, NO seems to contribute to vascular hyporeactivity to high doses but not to low doses of endothelin 1.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Altered control of vascular tone by adenosine triphosphate-sensitive potassium channels in rats with cirrhosis.

BACKGROUND/AIMS: Because the activation of arterial adenosine triphosphate (ATP)-sensitive potassium (KATP) channels is known to induce vasodilation, these channels may contribute to baseline vasodilator tone in cirrhosis. This study aimed to examine hemodynamic responses to glibenclamide, a KATP channel blocker, and to aprikalim, a vasodilator activating KATP channels, in normal and cirrhotic rats. METHODS: Splanchnic and systemic hemodynamic responses to glibenclamide (2.5, 5, 20, 30 mg/kg, intravenously) were studied. The arterial pressure response to aprikalim (200 mu/kg, intravenously) was studied with and without glibenclamide pretreatment (20 mg/kg). RESULTS: In cirrhotic rats, glibenclamide (5, 20, 30 mg/kg but not 2.5 mg/kg) significantly increased vascular resistance in portal and systemic territories. In normal rats, the latter effects occurred with 20 and 30 mg/kg of glibenclamide only. Aprikalim-induced arterial hypotension was significantly less marked in cirrhotic than in normal rats. Following glibenclamide, aprikalim-induced arterial hypotension was significantly less marked in cirrhotic than in normal animals. CONCLUSIONS: In rats with cirrhosis, the glibenclamide-induced vasoconstriction indicates that a vasodilator tone due to KATP channel opening existed under baseline conditions. Moreover, this study suggests that the control of vascular tone by KATP channels is altered in cirrhosis.

Adenosine Triphosphate↗
PubMed1994

Pharmacological treatment of portal hypertension: hemodynamic effects and prevention of bleeding.

In the past 10 years, it has been clearly shown that vasoactive substances reduce portal pressure in patients or animals with portal hypertension. Some of these substances act by inducing splanchnic vasoconstriction, while others reduce hepatic and porto-systemic collateral vascular resistance and, thus, induce a portal hypotensive effect. Still others induce arterial hypotension, which causes a vasoconstrictive effect in the splanchnic territory. Since these drugs act on different vascular receptors, their combination should have a more marked effect on portal hypertension. Up to now, only nonselective beta-blockers have been used in the prevention of first gastrointestinal bleeding in patients with portal hypertension and esophageal varices and in the prevention of recurrent gastrointestinal bleeding. These trials have shown that propranolol or nadolol significantly reduce either a first episode of bleeding or recurrent bleeding. This pharmacological treatment also improves the survival rate in these patients. All of these studies have helped us to understand, in part, why gastrointestinal hemorrhage occurs in certain patients. Additional studies of beta-blockers or other substances are, nevertheless, necessary to select patients who will respond to this type of treatment. Finally, it is possible that the pharmacological treatment of portal hypertension may also be used before esophageal varices occur.

Animals↗
PubMed1994

Effect of clonidine on liver oxygen extraction during alcohol withdrawal in man.

Since catecholamines can alter splanchnic oxygen transport and extraction, the suppression of sympathetic overactivity during alcohol withdrawal might improve hepatic oxygen extraction. Therefore, this study investigated the effects of clonidine, a centrally-acting alpha 2-agonist which reduces sympathetic nervous outflow, on splanchnic oxygen transport and extraction in 13 patients with chronic alcoholism during alcohol withdrawal. All patients had elevated transaminases and steatosis at liver biopsy and were withdrawn from alcohol 51 +/- 15 h (mean +/- SD) before the study. Hepatic blood flow, cardiac output and the oxygen contents were measured in the radial and pulmonary arteries and in the hepatic veins before and 45 min after intravenous administration of clonidine, 150 micrograms. Basal hepatic blood flow was inversely correlated with norepinephrine plasma concentrations (r = -0.63, p < 0.025). After clonidine administration, the decrease in plasma norepinephrine correlated with the norepinephrine basal value (r = 0.889, p < 0.001), and splanchnic oxygen extraction increased (from 40 +/- 15 to 49 +/- 17%, p < 0.025). After clonidine administration, splanchnic oxygen extraction was correlated with the decrease in plasma norepinephrine (r = 0.72, p < 0.01). Arterial lactate concentration decreased (from 0.74 +/- 0.20 to 0.64 +/- 0.23 mmol/l, p < 0.01). These results suggest that defective liver oxygen extraction might occur during alcohol withdrawal as a result of sympathetic nervous hyperactivity. Alterations in the hepatic microcirculation during withdrawal might be related to catecholamine secretion and be controlled by pharmacological manipulation.

Adult↗
PubMed1994

Blunted systemic, splanchnic, and renal hemodynamic responses to atrial natriuretic peptide in rats with cirrhosis.

Systemic, splanchnic and renal hemodynamic responses to saline, physiological (25 ng.kg-1.min-1) and pharmacological (100, 300 and 600 ng.kg-1.min-1) doses of alpha human atrial natriuretic peptide were measured in normal (n = 7 for saline and 7-8 for each dose of atrial natriuretic peptide) and cirrhotic (n = 7 for saline and 7-8 for each dose of atrial natriuretic peptide), conscious, unrestrained rats. In addition, plasma norepinephrine concentrations were measured in normal and cirrhotic rats, before and following a 300-ng.kg-1.min-1 dose of atrial natriuretic peptide. In cirrhotic rats, splanchnic, renal and systemic hemodynamics were not significantly affected by either physiological or pharmacological doses of atrial natriuretic peptide. In normal rats, a 300 ng.kg-1.min-1 dose of atrial natriuretic peptide significantly decreased cardiac index, portal tributary blood flow and renal blood flow, and significantly increased vascular resistance in the systemic, portal, and renal territories. The other doses of atrial natriuretic peptide did not significantly change regional and systemic hemodynamics. Atrial natriuretic peptide-induced changes in plasma norepinephrine concentrations were significantly higher in normal than in cirrhotic rats (1827 +/- 834 vs. 59 +/- 46 pg/ml, mean +/- S.E., respectively). In conclusion, this study shows that the normal cardiovascular response to a 300 ng.kg-1.min-1 atrial natriuretic peptide infusion is blunted in cirrhotic rats. Moreover, in cirrhotic rats, blunting of vasoconstriction following atrial natriuretic peptide administration seems to be due to a lack of increased sympathetic vascular tone.

Animals↗
PubMed1994

Hemodynamic effects of acute administration of furosemide in patients with cirrhosis receiving beta-adrenergic antagonists.

In patients with cirrhosis, both beta-blockers and diuretics decrease the degree of portal hypertension. Since their mechanisms of action differ, the combination of these two substances should induce a more pronounced effect on portal pressure than one of these substances alone. Thus, the hemodynamic effects of furosemide were evaluated in ten patients with cirrhosis receiving beta-blockers. One hour after furosemide (0.75 mg/kg intravenously) administration, cardiac output decreased significantly from 6.2 +/- 0.6 to 5.2 +/- 0.3 l/min and blood volume from 8.0 +/- 1.6 to 5.3 +/- 0.5 l. Mean arterial pressure was not affected. Wedged and free hepatic venous pressures did not change significantly; nor did the hepatic venous pressure gradient (19.6 +/- 1.7 to 18.6 +/- 1.5 mmHg). Azygos blood flow was not affected (0.46 +/- 0.05 to 0.50 +/- 0.07 l/min). In conclusion, this study did not demonstrate that the addition of furosemide to propranolol further decreased portal pressure in patients with cirrhosis. The long-term effects of this combination are unknown and should be tested.

Adrenergic beta-Antagonists↗
PubMed1994

Hemodynamic responses to selective blockade of beta 2- and beta 1-adrenoceptors in conscious rats with cirrhosis.

This study examined the hemodynamic effects of selective beta 2-adrenergic blockade (ICI 118,551, 100 micrograms/kg intravenous (i.v.)), selective beta 1-blockade (atenolol, 2 mg i.v.) and nonselective beta-blockade (propranolol, 2 mg i.v.) in conscious rats with cirrhosis. Pressure and blood flow measurements (radioactive microsphere method) were performed before and following drug administration. ICI 118,551 significantly decreased portal tributary blood flow (21%), portal pressure (4%) and cardiac index (12%). Portal tributary blood flow decreases were significantly more marked than changes in cardiac index. Atenolol significantly decreased portal tributary blood flow (27%), portal pressure (15%), cardiac index (17%) and arterial pressure (7%). Propranolol significantly decreased portal tributary blood flow (37%), portal pressure (17%), cardiac index (30%), and arterial pressure (9%). Portal tributary blood flow decreases due to ICI 118,551, but not those due to atenolol, were significantly less marked than the decreases caused by propranolol. ICI 118,551- and atenolol-induced cardiac index decreases were significantly less marked than propranolol-induced decreases. In conclusion, in rats with cirrhosis, selective beta 2-blockade reduces portal pressure and portal tributary blood flow mainly by a direct effect on splanchnic vessels. This portal hypotensive action, however, was slight. Propranolol decreases portal tributary blood flow by the combination, but not the summation, of its beta 1- and beta 2-blocking effects.

Adrenergic beta-Antagonists↗
PubMed1994

Effects of glibenclamide on systemic and splanchnic haemodynamics in conscious rats.

1. The effects of the sulphonylurea, glibenclamide (20 mg kg-1, i.v.), at a dose that blocks vascular potassium channels, on systemic and splanchnic haemodynamics (radioactive microspheres) were studied in conscious rats. 2. Glibenclamide significantly decreased cardiac index and hepatic artery blood flow while it significantly increased vascular resistance in systemic, portal and hepatic arterial territories. 3. In rats with suppressed cardiovascular reflexes, glibenclamide induced vasoconstriction in systemic, portal and hepatic arterial territories. 4. Intracerebroventricular administration of glibenclamide did not alter systemic or regional vascular tone. 5. Glibenclamide blunted the vasodilator effect of the potassium channel opener, diazoxide but not that of the L-type calcium channel blocker, nicardipine. 6. Another sulphonylurea, glipizide (20 mg kg-1, i.v.), induced significant systemic and splanchnic vasoconstriction. 7. Thus, the glibenclamide-induced blockade of vascular potassium channels caused a vasoconstriction in the systemic and splanchnic vascular beds. In these territories, therefore, the opening of glibenclamide-sensitive potassium channels might be responsible for a basal vasodilator tone.

Animals↗
PubMed1994

Effects of vasopressin on haemodynamics in portal hypertensive rats receiving clonidine.

The effects of clonidine, vasopressin or a combination of both substances on splanchnic and systemic haemodynamics were measured in conscious rats with portal vein stenosis. Clonidine alone significantly decreased portal pressure, portal tributary blood flow and cardiac index, but did not change arterial pressure. Vasopressin alone significantly increased arterial pressure and significantly decreased portal pressure, portal tributary blood flow and cardiac index. Changes in portal tributary blood flow, arterial pressure and cardiac index were significantly higher with vasopressin than with clonidine alone. Vasopressin infusion in rats pretreated with clonidine significantly increased arterial pressure and significantly decreased portal pressure, portal tributary blood flow and cardiac index. Changes in arterial and portal pressures and portal tributary blood flow were significantly higher with combined therapy than with clonidine alone. Changes in arterial and portal pressures and portal tributary blood flow did not differ between combined therapy and vasopressin alone. Changes in cardiac index were significantly higher with combined therapy than with clonidine or vasopressin alone. Hepatic artery blood flow was not affected by either clonidine or vasopressin but significantly declined with combined therapy. In conclusion, this study suggests that a combination of vasopressin and clonidine accentuates the portal hypotensive action of clonidine but not the action of vasopressin. Moreover, this study suggests that a combination of vasopressin and clonidine may have deleterious effects on systemic and hepatic artery vascular beds.

Animals↗
PubMed1994

[Relationships between plasma concentrations of endothelin and the severity of liver cirrhosis].

OBJECTIVES: Results of studies on plasma endothelin concentrations in patients with cirrhosis are conflicting. Moreover, the relationships between plasma endothelin concentrations and the severity of cirrhosis have not yet been studied. The aim of this study was to measure plasma endothelin concentrations in controls and in patients with cirrhosis. In addition, this study examined the relationships between plasma endothelin concentrations, and the severity of liver disease, splanchnic and systemic hemodynamics. METHODS: Plasma endothelin concentrations (in the hepatic vein and the right atria), hepatic venous pressures, arterial pressure, cardiac output, pulmonary pressures and plasma concentrations of sodium and creatinine were measured in 7 controls and 28 patients with cirrhosis. RESULTS: Plasma endothelin concentrations in the hepatic vein and the right atria were significantly higher in patients with cirrhosis (18.9 +/- 2.9 and 20.2 +/- 3.1 pg/mL, respectively) than in controls (6.1 +/- 1.1 and 7.2 +/- 1.1 pg/mL, respectively). In these patients, hepatic venous plasma endothelin concentrations were significantly correlated with Pugh's score (r = 0.49), hepatic venous pressure gradient (r = -0.44), and plasma sodium concentrations (r = -0.46). No significant correlation was found between plasma endothelin concentrations and systemic hemodynamics. CONCLUSION: Plasma endothelin concentrations are increased in patients with cirrhosis. Moreover, this increase is more marked in patients with severe liver disease than in patients with no or moderate impairment of liver function.

Blood Chemical Analysis↗
PubMed1993

Hemodynamic effects of nipradilol, a new beta-adrenergic antagonist combined with a nitroxy base, in rats with intra- or extra-hepatic portal hypertension.

It has been demonstrated that beta-adrenergic antagonists and nitrovasodilators reduce portal pressure in patients with portal hypertension. Thus, the hemodynamic effects of nipradilol, a new beta-adrenergic antagonist combined with a nitroxy base, was studied in conscious and unrestrained rats in two models of portal hypertension. The hemodynamic effects were compared to those obtained after propranolol administration. Both nipradilol (20 mg/kg) and propranolol (20 mg/kg) significantly decreased portal pressure in both groups of portal hypertensive rats. In cirrhotic rats, nipradilol decreased portal pressure (-24 +/- 2%) more than propranolol (-9 +/- 2%). Both nipradilol and propranolol significantly decreased portal tributary blood flow and cardiac index in both groups. Changes in portal tributary blood flow and cardiac index were not significantly different between nipradilol and propranolol. Propranolol, but not nipradilol significantly increased hepatocollateral resistance in cirrhotic rats but not in portal vein stenosed rats. Thus, the marked reduction of portal pressure after nipradilol administration depends in part on a limited increase in hepatocollateral resistance. Nipradilol significantly decreased mean arterial pressure, while propranolol did not change this value in either groups. In conclusion, nipradilol markedly decreased portal pressure in rats with portal hypertension. This beneficial effect suggests that nipradilol should be tested in the patients with portal hypertension.

Adrenergic beta-Antagonists↗
PubMed1993

Early colchicine administration reduces hepatic fibrosis and portal hypertension in rats with bile duct ligation.

Chronic administration of colchicine has been suggested as a potential treatment for hepatic fibrosis. The purpose of this study was to examine the effects of chronic oral administration of colchicine on the histological and hemodynamic abnormalities of bile duct ligation in the rat. Forty-eight rats with ligation-section of the common bile duct were randomly and blindly assigned to receive either colchicine (50 mu/kg day) or placebo by gavage for 4 weeks. At the end of the treatment period, morphometric analysis showed that hepatocyte and sinusoidal volume fractions were significantly higher in rats treated with colchicine than in rats receiving placebo (42.4 +/- 1.3 vs. 32.1 +/- 2.6% (mean +/- S.E.) and 8.3 +/- 0.6 vs 4.7 +/- 0.4%, respectively), while bile duct volume fractions (reflecting bile ductular proliferation) and connective tissue fractions were significantly lower in rats treated with colchicine than in rats receiving placebo (12.1 +/- 0.9 vs. 17.0 +/- 0.1% and 37.2 +/- 0.9 vs. 46.1 +/- 2.0%, respectively). Portal pressure (13.4 +/- 0.7 vs. 17.8 +/- 0.5 mmHg), portal tributary blood flow (5.8 +/- 0.4 vs. 8.7 +/- 0.5 ml.min-1.100 g-1) and cardiac index (40.8 +/- 2.3 vs. 50.6 +/- 1.5 ml.min-1.100 g-1) were significantly lower in colchicine-treated rats than in placebo treated animals. In conclusion, in rats with bile duct ligation, colchicine limits the severity of liver lesions and, consequently, of portal hypertension and hyperkinetic syndrome.

Administration, Oral↗
PubMed1993

Pharmacologic prevention of variceal bleeding and rebleeding.

A review of nine placebo-controlled studies for the prevention of first bleeding and 14 for the prevention of rebleeding in patients with cirrhosis and oesophageal varices indicates that beta-adrenergic antagonists significantly reduced the incidence of both initial and recurrent gastrointestinal bleeding over study durations ranging from 1 to 2 years, provided the patients complied with the regimen. Three meta-analyses concluded that beta-blockers also significantly reduced the risk of fatal bleeding, although this remains controversial. These agents were also effective in patients with portal hypertension from causes other than alcoholic cirrhosis, although not in hepatocellular carcinoma. Side effects occurred in 3-40% of patients and required discontinuation of beta-blocker administration in 5%. In two clinical trials in which beta-blocker therapy was compared with endoscopic sclerotherapy, the drug was at least as effective as sclerotherapy in preventing first episodes of variceal bleeding. In nine studies, the two modalities were comparably effective in preventing rebleeding. Used in combination, beta-blockers and sclerotherapy were more effective in preventing rebleeding than either used alone. However, neither treatment unequivocally prolonged survival relative to placebo.

Adrenergic beta-Antagonists↗
PubMed1993

Reduced splanchnic vasoconstriction to angiotensin II in conscious rats with biliary cirrhosis.

Decreased pressor reactivity to angiotensin II has been demonstrated in portal hypertension due to cirrhosis. The present study investigated the respective roles of portal hypertension and cirrhosis and the hemodynamic mechanisms of the depressor response in different models of portal hypertension in conscious rats. Dose-pressor curves were studied in sham-operated, portal vein stenosed (portal hypertension without cirrhosis) and biliary cirrhotic rats following angiotensin II administration. Decreased pressor response was observed in cirrhotic rats but not in portal vein stenosed rats. The hemodynamic effects of angiotensin II administration (11 ng.100 g-1 body wt.min-1, i.v.) were studied in conscious sham-operated and biliary cirrhotic rats (radioactive microsphere method). The percentage of change from basal values following angiotensin II administration were significantly more marked in sham-operated rats than in cirrhotic rats for mean arterial pressure (+34 vs. +6%), cardiac index (-36 vs. -22%), systemic vascular resistance (+117 vs. +40%). After angiotensin II, portal tributary and hepatic artery blood flows significantly decreased in sham-operated rats (-31 and -14%, respectively) but not in cirrhotic rats (+1 and +23%), whereas changes in renal blood flow were not significantly different between the two groups (-44 vs. -34%). In conclusion, in biliary cirrhotic rats, decreased pressor response to angiotensin II depends on the presence of liver disease rather than on portal hypertension or basal hemodynamic alterations. It also depends on the decreased vasoconstrictive effect which predominates in the splanchnic vascular bed.

Angiotensin II↗
PubMed1993

Effects of terlipressin on hemodynamics and oxygen content in conscious portal vein stenosed and cirrhotic rats receiving propranolol.

Terlipressin is used in patients with variceal bleeding but its effects in patients receiving beta-adrenergic antagonists are unknown. In this study, the hemodynamic effects of terlipressin were evaluated in conscious portal hypertensive rats which had previously received a single dose of propranolol. Moreover, oxygen content and acid-base status were studied. In portal vein stenosed and cirrhotic rats, the addition of terlipressin (0.05 mg/kg) to propranolol (0.4 mg/kg) produced a decrease in portal pressure of 34% and 17%, respectively, and in portal tributary blood flow of 46% and 42%, respectively. In cirrhotic rats, however, the decrease in portal pressure was not significantly different when propranolol was combined with terlipressin than when propranolol was administered alone. Cardiac index also further decreased after terlipressin administration. In both groups of rats, these values were similar to those observed after terlipressin alone. In portal vein stenosed rats but not in cirrhotic rats, arterial pH was significantly lower following the combination of propranolol plus terlipressin than following saline, propranolol or terlipressin alone. In conclusion, terlipressin further reduces both portal pressure and cardiac index in rats with portal hypertension receiving beta-blockers. In portal vein stenosed rats but not in cirrhotic rats, the addition of terlipressin to propranolol induces acidemia. This study suggests that terlipressin might further reduce portal pressure in patients with portal hypertension treated with beta-blockers.

Animals↗
PubMed1993

Renal hemodynamics in patients with cirrhosis: relationship with ascites and liver failure.

In patients with cirrhosis and ascites decreased renal blood flow might be related to the severity of liver disease but the relationship between the severity of cirrhosis and renal perfusion has not yet been established. Thus we measured renal, systemic and splanchnic hemodynamics in 63 patients with ascites and in 28 without ascites. When compared to patients without ascites, patients with ascites had lower renal blood flow (1,170 +/- 100 vs. 935 +/- 55 ml/min/1.73 m2; mean +/- SEM, p < 0.05) and renal perfusion pressure (78 +/- 2 vs. 72 +/- 1 mm Hg, p < 0.05 and higher inferior vena cava pressure (6.5 +/- 0.7 vs. 10.7 +/- 0.7 mm Hg, p < 0.05). Patients with ascites had significantly higher serum bilirubin concentrations, hepatic venous pressure gradient and lower serum albumin concentrations, indocyanine green (ICG) extraction than patients without ascites. Renal vascular resistance, glomerular filtration rate, mean arterial pressure, cardiac index and systemic vascular resistance were not significantly different between the two groups. By multiple regression analysis no significant correlation was found between liver tests (i.e., prothrombin time, serum bilirubin and albumin concentrations, ICG extraction), hepatic venous pressure gradient, cardiac index and systemic vascular resistance on the one hand and renal blood flow on the other. No significant correlation was found between glomerular filtration rate and liver tests. In conclusion, in patients with cirrhosis and ascites, renal hypoperfusion is not related to the severity of liver disease.

Ascites↗