endothelin-1 and Liver-Cirrhosis--Alcoholic

To assess the effect of tezosentan, a parenteral dual ET receptor antagonist, on splanchnic and systemic hemodynamics in patients with cirrhosis. In addition, the safety, pharmacokinetics, and pharmacodynamics of tezosentan were evaluated.. The population consisted of patients with cirrhosis with clinically significant portal hypertension. This was a randomized, double-blind, multicenter study. The patients were randomized 3:1 to tezosentan (3 mg/h for 2-3 h) or placebo. HVPG, hepatic blood flow (HBF, ICG method), and systemic arterial pressures were measured before and after tezosentan administration. Plasma concentrations of tezosentan and ET-1 were determined peripherally and in the hepatic vein.. Eighteen patients received tezosentan and six placebo. Baseline clinical, biochemical, and hemodynamic characteristics were balanced between the two groups. There was no significant treatment effect on HVPG. The extraction ratio (0.31), the plasma clearance of ICG (280 ml/min), and the HBF (1,430 ml/min) did not show any relevant changes during the infusion of tezosentan, and there were no differences between placebo- and tezosentan-treated patients. A linear relationship was observed between the maximum-fold increase in ET-1 concentration and the steady-state tezosentan plasma concentration (r = 0.82). There was a strong correlation (r = 0.88) between plasma clearance of ICG and that of tezosentan (10.2 l/h). Arterial pressure and heart rate did not significantly change in either group.. In patients with cirrhosis, a 2- to 3-h tezosentan infusion was safe and well tolerated but did not change the HVPG. Tezosentan infusion had no influence on the extraction ratio and plasma clearance of ICG and did not change HBF.

Topics: Antihypertensive Agents; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Female; Heart Rate; Hemodynamics; Humans; Hypertension, Portal; Infusions, Parenteral; Liver; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Metabolic Clearance Rate; Middle Aged; Pyridines; Severity of Illness Index; Splanchnic Circulation; Tetrazoles; Vasodilator Agents

Patients with cirrhosis exhibit impaired regulation of the arterial blood pressure, reduced baroreflex sensitivity (BRS), and prolonged QT interval. In addition, a considerable number of patients have a pulmonary dysfunction with hypoxemia, impaired lung diffusing capacity (Dl(CO)), and presence of hepatopulmonary syndrome (HPS). BRS is reduced at exposure to chronic hypoxia such as during sojourn in high altitudes. In this study, we assessed the relation of BRS to pulmonary dysfunction and cardiovascular characteristics and the effects of hyperoxia. Forty-three patients with cirrhosis and 12 healthy matched controls underwent hemodynamic and pulmonary investigations. BRS was assessed by cross-spectral analysis of variabilities between blood pressure and heart rate time series. A 100% oxygen test was performed with the assessment of arterial oxygen tensions (Pa(O(2))) and alveolar-arterial oxygen gradient. Baseline BRS was significantly reduced in the cirrhotic patients compared with the controls (4.7 +/- 0.8 vs. 10.3 +/- 2.0 ms/mmHg; P < 0.001). The frequency-corrected QT interval was significantly prolonged in the cirrhotic patients (P < 0.05). There was no significant difference in BRS according to presence of HPS, Pa(O(2)), Dl(CO), or Child-Turcotte score, but BRS correlated with metabolic and hemodynamic characteristics. After 100% oxygen inhalation, BRS and the QT interval remained unchanged in the cirrhotic patients. In conclusion, BRS is significantly reduced in patients with cirrhosis compared with controls, but it is unrelated to the degree of pulmonary dysfunction and portal hypertension. Acute hyperoxia does not significantly revert the low BRS or the prolonged QT interval in cirrhosis.

Topics: Aged; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Baroreflex; Case-Control Studies; Endothelin-1; Female; Humans; Hyperoxia; Liver Cirrhosis, Alcoholic; Lung Diseases; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Oxygen; Renin

Static and dynamic functions of the wall of large arteries are largely unknown in cirrhosis in vivo. The present study was undertaken to determine arterial compliance (COMP(art)) in relation to vasodilator and vasoconstrictor systems in patients with cirrhosis. In addition, vasoactivity was manipulated by inhalation of oxygen.. In 20 patients with alcoholic cirrhosis and 12 controls we determined COMP(art) (stroke volume relative to pulse pressure), cardiac output, plasma volume, systemic vascular resistance, central circulation time, plasma catecholamines, renin activity, endothelin-1, and calcitonin gene related peptide (CGRP) at baseline and during oxygen inhalation.. COMP(art) was significantly increased in cirrhotic patients compared with controls (1.32 v 1.06 ml/mm Hg; p< 0.05) and inversely related to plasma adrenaline levels (r=-0.53; p<0.02) but positively related to circulating levels of CGRP (r=0.58; p<0.01). No significant relation was found for plasma noradrenaline, renin activity, or endothelin-1. COMP(art) was positively related to plasma volume (r=0.50; p<0.02) and inversely to systemic vascular resistance (r=-0.69; p<0.001) and central circulation time (r=-0.49; p<0.02). During oxygen inhalation, COMP(art) decreased (-13%; p<0.005) and systemic vascular resistance increased (+10%; p<0.001) towards normal values without significant changes in mean arterial pressure. Plasma adrenaline (-16%; p<0.01) decreased and the relation to COMP(art) disappeared. The relation of COMP(art) to CGRP and circulatory variables remained unchanged.. Elevated arterial compliance in cirrhosis is related to low adrenaline, high CGRP, and systemic hyperdynamics but not to indicators of the activated vasoconstrictor systems (noradrenaline, renin, endothelin-1). Thus the altered static and dynamic characteristics of the wall of large arteries are intimately associated with circulatory and vasodilatory derangement in cirrhosis but biomanipulation indicates that the changes are, at least in part, reversible during isobaric conditions.

Topics: Adult; Aged; Calcitonin Gene-Related Peptide; Case-Control Studies; Chromatography, High Pressure Liquid; Compliance; Endothelin-1; Epinephrine; Female; Hemodynamics; Humans; Least-Squares Analysis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Norepinephrine; Oxygen Inhalation Therapy; Radioimmunoassay; Renin; Statistics, Nonparametric; Vasoconstriction