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Biomedical subjects

D Lebrec

Publications and source records attributed to D Lebrec.

At least 55 records · Page 3Linked to original sources
PubMed1999

Relation between severity of liver disease and renal oxygen consumption in patients with cirrhosis.

BACKGROUND: Worsening cirrhosis may lead to increased renal O2 metabolism caused by activation of neurohumoral antinatriuretic substances. AIMS: To evaluate the relation between the severity of liver disease, sodium excretion, and neurohumoral antinatriuretic substances on the one hand and renal O2 metabolism on the other in patients with cirrhosis. METHODS: Renal O2 consumption and haemodynamics as well as plasma concentrations of noradrenaline, renin, and aldosterone were measured. Investigations were performed in 14 patients with Pugh's grade A, 43 with grade B, and 29 with grade C liver disease. RESULTS: Renal O2 consumption significantly increased with the severity of cirrhosis (grade A, 8.9 (1.6); grade B, 15.5 (1.3); grade C, 18.0 (1.5) ml/min/m2). Plasma concentrations of noradrenaline, renin, and aldosterone significantly increased while mean arterial presssure and systemic vascular resistance significantly decreased with the severity of the disease. A significant inverse correlation was found between renal O2 consumption and sodium excretion. A significant direct correlation was found between plasma levels of noradrenaline and aldosterone on the one hand and renal O2 consumption on the other. Renal blood flow and the glomerular filtration rate did not differ significantly between patients with grade C and grade A or B disease. CONCLUSIONS: This study shows for the first time that, in patients with cirrhosis, worsening of the disease is associated with an increase in renal O2 consumption. The results suggest that increased renal O2 consumption is due to renal tubular sodium retention caused by increased levels of neurohumoral antinatriuretic substances. This neurohumoral activation is related to cirrhosis induced vasodilation.

Adult↗
PubMed1999

Relationship between vascular reactivity in vitro and blood flows in rats with cirrhosis.

In cirrhosis there is a hyperdynamic circulation, which occurs mainly in the systemic and splanchnic regions. Using isolated-vessel models, previous studies have shown reduced aortic reactivity to vasoconstrictors in rats with cirrhosis. The aim of the present study was to evaluate and compare the vascular responsiveness to phenylephrine in arterial rings and the blood flows from different regions in rats with cirrhosis and controls. Reactivity was studied in isolated thoracic aortic, superior mesenteric arterial and carotid arterial rings from sham-operated and bile-duct-ligated rats by measuring the cumulative concentration-dependent tension induced by phenylephrine (10(-9)-10(-4) M). Blood flows were measured by the radioactive microsphere method. In rats with cirrhosis, a significant hyporeactivity to phenylephrine was observed in both the aorta and the superior mesenteric artery compared with the corresponding arteries of normal rats. This hyporesponsiveness was corrected by N(omega)-nitro-L-arginine (0.1 mM). In contrast, carotid artery reactivity and the responses to N(omega)-nitro-L-arginine were similar in the cirrhotic and control groups. In each case, cardiac output and mesenteric arterial blood flow were significantly higher in cirrhotic than in normal rats. Cerebral blood flows were not significantly different between the two groups. In cirrhotic rats, arterial hyporeactivity may be a consequence of increased regional blood flow and increased production of nitric oxide.

Animals↗
PubMed1998

Acute and chronic haemodynamic effects of naftazone in portal hypertensive rats.

It has been demonstrated that hyperproduction of nitric oxide (NO) plays a major role in the vasodilatation of cirrhosis; thus, the vasodilatation might be reversed by an inhibition of NO production. Experimental studies in isolated aortic rings showed that naftazone inhibits the effects of NO production. The aim of this study was to evaluate the haemodynamic effects of acute and chronic administration of naftazone in rats with portal hypertension. Haemodynamic values were measured either before and 10 min after intravenous administration of 432 microg/kg of naftazone or after 4 days of oral administration of 10 mg/kg per day. Acute administration of naftazone significantly reduced portal pressure in portal vein-stenosed and cirrhotic rats. This reduction was related to a decrease in the resistance of the liver and collateral circulation and it was associated with an increased cardiac output. Oral administration of naftazone significantly decreased portal pressure in rats with portal vein stenosis; this decrease depended on a significant reduction of portal blood flow. In both groups, arterial pressure did not change significantly. These haemodynamic effects differed from those observed following prazosin or propranolol administration. However, these effects were similar but less marked than those observed following N-nitro-L-arginine administration in systemic and splanchnic arterial territories. In conclusion, acute and oral administration of naftazone significantly reduces portal pressure by two different mechanisms in portal hypertensive rats. The exact mechanism has, however, to be elucidated.

Animals↗
PubMed1998

Beneficial hemodynamic effects of bosentan, a mixed ET(A) and ET(B) receptor antagonist, in portal hypertensive rats.

In patients with cirrhosis, the plasma level of endothelin, a potent vasoconstrictor peptide, is elevated, and endothelin plays a role in increased intrahepatic vascular resistance. Thus, the aim of this study was to evaluate the hemodynamic effects of bosentan, a mixed ET(A) and ET(B) endothelin receptor antagonist in three models of portal hypertension. In all groups of rats, endothelin (2 microg/kg intravenously) administration significantly increased intrahepatic vascular resistance. In rats with secondary biliary cirrhosis, bosentan (30 mg/kg) significantly reduced portal pressure from 14.6 +/- 1.2 to 12.1 +/- 0.6 mm Hg, while portal blood flow and cardiac output increased by 45% and 57%, respectively. Thus, hepatocollateral vascular resistance decreased significantly from 177 +/- 19 to 101 +/- 9 dyn x s x cm(-5) x 10(-3). Similar results were observed in rats with CCl4-induced cirrhosis. In isolated perfused cirrhotic rat livers, bosentan (1 to 100 micromol/L) had no significant effect on hepatic vascular resistance. In portal vein-stenosed rats, bosentan administration significantly decreased portal pressure from 13.1 +/- 0.6 to 11.4 +/- 0.5 mm Hg by reducing portosystemic vascular resistance, because bosentan had no effect on vascular resistance of normal rat liver. In conclusion, bosentan administration decreased portal pressure in vivo by reducing hepatocollateral vascular resistance in rats with cirrhosis. Thus, mixed endothelin receptor antagonists might be a new approach in the pharmacological treatment of portal hypertension.

Animals↗
PubMed1998

Effects of protein kinase C modulators on Na+/K+ adenosine triphosphatase activity and phosphorylation in aortae from rats with cirrhosis.

Protein kinase C (PKC) modulates the activity and phosphorylation of the catalytic alpha-subunit of sodium-potassium-adenosine triphosphatase (Na+/K+ ATPase) in normal arteries. Because PKC is altered in cirrhotic aortae, Na+/K+ ATPase may also be altered in these arteries. The aim of the present study was to investigate alpha-subunit activity and phosphorylation in aortae from normal and cirrhotic rats, under baseline conditions and during exposure to PKC modulators. Alpha-subunit activity was assessed by measuring the amount of 32P released by hydrolysis of [gamma-32P]ATP in freshly isolated cell membranes (in the absence of PKC modulators only) and membrane depolarization caused by ouabain-induced alpha-subunit inhibition in isolated aortae (in the absence and presence of PKC modulators). Alpha-subunit phosphorylation was assessed by incorporation of 32P into alpha-subunits. Staurosporine, a PKC inhibitor, and phorbol 12,13-dibutyrate (PDBU), a PKC activator, were used. In addition, alpha-subunit expression was studied by Western blot analysis. In the absence of PKC modulators, the amount of 32P released by hydrolysis of [gamma-32P]ATP and ouabain-induced membrane depolarization were significantly lower in cirrhotic than in normal aortae. Staurosporine suppressed ouabain-induced membrane depolarization in cirrhotic and normal arteries. Ouabain-induced membrane depolarization was similar in cirrhotic aortae exposed to PDBU and in normal arteries studied under baseline conditions. Alpha-subunit phosphorylation was significantly lower in cirrhotic than in normal aortae, in aortae under baseline conditions, and in arteries exposed to staurosporine. Phosphorylation of the alpha-subunit was similar in cirrhotic aortae exposed to PDBU and in normal arteries under baseline conditions. Western blot analysis showed that the amount of alpha-subunit did not significantly differ between cirrhotic and normal aortae. In conclusion, a decrease in baseline Na+/K+ ATPase alpha-subunit activity occurs in aortae from cirrhotic rats as a result of reduced basal PKC activity. This PKC-dependent decreased alpha-subunit activity may be caused by a reduction in PKC-induced alpha-subunit phosphorylation.

Animals↗
PubMed1998

Beneficial effects of the 2-day administration of terlipressin in patients with cirrhosis and hepatorenal syndrome.

BACKGROUND/AIMS: A treatment to induce a sustained increase in glomerular filtration rate in patients with hepatorenal syndrome has not yet been identified. Thus, the aim of the present study was to investigate the effects of terlipressin for 2 days on the glomerular filtration rate in patients with cirrhosis and hepatorenal syndrome. METHODS: A double-blind, cross-over randomized study was performed in nine patients. Patients received terlipressin (2 mg/day for 2 days) and a placebo for 2 days in a randomized order. RESULTS: Terlipressin administration significantly increased creatinine clearance (from 15+/-2 ml/min to 27+/-4 ml/min) and urine output (from 628+/-67 ml/day to 811+/-76 ml/day), but did not significantly change urinary sodium concentrations. Urinary sodium excretion was not significantly different after placebo administration (0.6+/-0.1 mmol/24 h) and terlipressin administration (9.3+/-7.2 mmol/24 h). Terlipressin administration significantly decreased plasma concentrations of renin and aldosterone but not atrial natriuretic peptide levels. Placebo elicited no significant effects. CONCLUSIONS: This study shows that 2-day terlipressin administration increases the glomerular filtration rate in patients with cirrhosis and hepatorenal syndrome.

Atrial Natriuretic Factor↗
PubMed1998

Protein kinase C alterations in aortic vascular smooth muscle cells from rats with cirrhosis.

BACKGROUND/AIMS: Alterations in signal transduction in vascular smooth muscle cells may contribute to vascular hyporeactivity in cirrhosis. Protein kinase C plays a role in vascular cell contraction by modifying contractile proteins and intracellular [Ca2+] homeostasis. The aim of this study was to examine the vascular reactivity and expression of protein kinase Calpha in aortae from rats with cirrhosis. METHODS: The contractile response to phorbol ester, a protein kinase C activator, was evaluated in endothelium-denuded aortic rings from normal and cirrhotic rats. Protein kinase Calpha expression was determined by Western blot analysis. RESULTS: Maximal contraction was significantly less marked in cirrhotic (1.24+/-0.24 g) than in control (3.43+/-0.27 g) aortae. Phorbol myristate-acetate-induced contraction was dependent on extracellular [Ca2+] concentrations, as shown by a reduction in maximal contraction when control and cirrhotic aortic rings were exposed to a Ca2+-free medium. Increasing the intracellular [Ca2+], by incubation with a Ca2+ ionophore, significantly increased the maximal contraction induced by phorbol myristate-acetate in cirrhotic but not in control rat aortae. Protein kinase Calpha expression was significantly lower in aortae in cirrhotic than in control rats. CONCLUSION: These results confirm alterations in protein kinase C in aortae from cirrhotic rats.

Animals↗
PubMed1998

Development of analogues: successes and failures.

The search for new pharmaceutical treatments has led to the isolation of products from a range of natural sources. Analogues synthesized from these products may possess an improved therapeutic effect over their natural counterparts. Two natural peptides, vasopressin and somatostatin, possess pronounced in vivo effects, so do their analogues terlipressin and octreotide. Vasopressin is a powerful vasopressor, reducing portal pressure, and has been used to treat gastrointestinal haemorrhages. However, a number of adverse cardiovascular effects resulting from an increase in peripheral vascular resistance have been associated with this drug. Terlipressin, however, is more effective, has an improved safety profile and is associated with fewer side effects than vasopressin. Somatostatin, a growth regulatory hormone, achieves haemostasis by decreasing splanchnic blood flow, and is effective in preventing early rebleeding. Somatostatin is effective in treating bleeding oesophageal varices (BOV) and is associated with fewer and more transient side effects than terlipressin. Octreotide, however, has greater stability and a longer half-life than somatostatin, but has a less favourable safety profile. Octreotide displays a number of therapeutic advantages over somatostatin, but not in the treatment of gastrointestinal indications. The development of terlipressin from vasopressin has demonstrated a number of clinical advantages, while the development of octreotide from somatostatin has not shown any significant advantage in the treatment of BOV.

Esophageal and Gastric Varices↗
PubMed1998

Vascular properties of isoflurane: comparison between normal and cirrhotic rats.

Isoflurane is known to dilate blood vessels and to modulate nitric oxide production. Because cirrhosis is characterized by over production of endothelial nitric oxide, isoflurane-induced vasodilatation may be altered in this situation. We have compared the vasodilator effects of isoflurane in normal rats and rats with secondary biliary cirrhosis. Aortic rings (intact or endothelium denuded) from normal and cirrhotic rats were suspended in HEPES solution and preconstricted with KCl 40 mmol litre-1. Isoflurane dose-dependently relaxed vessels in both groups. Maximal relaxation was comparable between normal and cirrhotic rats in intact (mean 80 (SEM 4) vs 81 (6)%; ns) and in denuded (100 (4) vs 95 (5)%; ns) vessels. Intact vessels relaxed more than denuded vessels in both groups (100 (4) vs 80 (4)% (P = 0.0008) in normal rats and 95 (5) vs 80 (6)% (P = 0.0008) in cirrhotic rats). We conclude that cirrhosis did not modify isoflurane-induced vasodilatation and that the modulator effect of endothelium was conserved.

Anesthetics, Inhalation↗
PubMed1998

A discussion of how terlipressin limits mortality in cases of bleeding oesophageal varices.

Bleeding oesophageal varices (BOV) are a potentially life-threatening complication of portal hypertension. While endoscopic sclerotherapy and banding ligation are often employed in an attempt to arrest bleeding, the use of vasoactive pharmacological agents to control haemorrhage has a number of advantages. While many of the available vasoactive agents control acute bleeding and may exert a beneficial influence over hepatic haemodynamics, terlipressin (triglycyl lysine-vasopressin) is the only agent that has been shown actually to decrease mortality in cases of BOV. It is hypothesized that this increase in survival rate is due to the apparently unique multifactorial influence of terlipressin over variceal haemostasis and blood flow, hepatic and gastric haemodynamics and renal function, combined with the likelihood of only minimal adverse events.

Antihypertensive Agents↗
PubMed1998

Influence of transjugular intrahepatic portosystemic shunts (TIPS) on tissue oxygenation in patients with cirrhosis.

UNLABELLED: AIMS/BACKGROUNDS: The aim of this prospective study was to evaluate the influence of transjugular portosystemic intrahepatic shunts (TIPS) on tissue oxygenation in patients with cirrhosis and refractory ascites. METHODS: Five shunted patients were included in the study. The blood and tissue oxygenation values were analyzed 12 days and 4 months after TIPS procedure. The results were compared with those observed in patients treated by paracentesis. RESULTS: Unlike patients treated by paracentesis, PaO2 values remained unchanged throughout follow-up in shunted patients. After the TIPS procedure, there was a transient increase in systemic O2 transport and O2 uptake and a transient decrease in O2 saturation of hepatic oxyhemoglobin. After 4 months, TIPS resulted in an increase in PCO2 values and bicarbonate concentrations. CONCLUSIONS: The TIPS procedure seems to prevent the decrease in PaO2 observed in patients treated by paracentesis and may improve the respiratory alkalosis of cirrhosis.

Adult↗