Evidence for altered vascular responses to exogenous endothelin-1 in patients with advanced cirrhosis with restoration of the normal vasoconstrictor response following successful liver transplantation

• Published in: Gut Vol. 52; no. 10; pp. 1505 - 1510
• Main Authors: Vaughan, R B, Angus, P W, Chin-Dusting, J P F
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.10.2003; BMJ; BMJ Publishing Group Ltd; BMJ Publishing Group LTD; Copyright 2003 by Gut
• Subjects: Analysis of Variance; area under the curve; AUC; Biological and medical sciences; cardiac index; cardiac output; Case-Control Studies; central venous pressure; Chronic Disease; cirrhosis; CVP; EDRFs; endothelial nitric oxide synthase; Endothelin; endothelin A receptor; Endothelin A Receptor Antagonists; endothelin B receptor; endothelin-1; Endothelin-1 - pharmacology; endothelium derived relaxing factors; Endothelium, Vascular - drug effects; eNOS; ET-1; ETA; ETB; Female; Forearm - blood supply; forearm plethysmography; Gastroenterology. Liver. Pancreas. Abdomen; heart rate; Humans; Influence; Infusions, Intravenous; Liver; Liver cirrhosis; Liver Cirrhosis - metabolism; Liver Cirrhosis - surgery; liver transplantation; Liver Transplantation - physiology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; mean arterial pressure; Medical research; Medical sciences; Middle Aged; nitric oxide; Other diseases. Semiology; Peptides, Cyclic - pharmacology; Physiological aspects; Plethysmography; Postoperative Period; RAP; right atrial pressure; Smooth muscle; Statistics; SVRI; systemic vascular resistance index; Transplantation; Transplants & implants; Vasoconstrictors; Vasodilation; Vasodilator Agents - pharmacology; Australia; Human; Exogenous; Treatment efficiency; Hepatic disease; Endothelin 1; Transplantation; Blood flow; Cirrhosis; Surgery; Clinical biology; Digestive diseases; Advanced stage; Vasoconstrictor agent
• ISSN: 0017-5749; 1468-3288; 1468-3288; 1458-3288
• DOI: 10.1136/gut.52.10.1505

Background and aims: There is evidence that dampened responses to endogenous vasoconstrictors contribute to the hyperdynamic circulation that is characteristic of advanced cirrhosis. The aim of this study was to determine whether there is an altered vascular responsiveness to the endothelium derived constricting factor endothelin-1 (ET-1) in patients with decompensated chronic liver disease which might contribute to this abnormal circulatory state, and whether normal endothelin responses are restored following liver transplantation. Methods: Using forearm plethysmography, we studied the vascular response to an intra-arterial ET-1 infusion in six patients with end stage cirrhosis, before and after liver transplantation, compared with six normal control subjects. Responses to the selective endothelin A (ETA) receptor subtype antagonist, BQ123, were also examined. Results: The forearm vessels of patients with cirrhosis vasodilated in response to ET-1 infusion while in healthy controls a marked vasoconstriction response was observed (p<0.0001, area under the curve time-blood flow was normal compared with the cirrhosis groups, ANOVA). Prior to commencement of liver transplant surgery, cirrhotic patients were confirmed to have a hyperdynamic circulation with a high cardiac index (4.07 (0.23) l/min/m2 (normal range 2.8–3.6 l/min/m2)) and low systemic vascular resistance index (1284 (115) dyn×s/cm5/m2 (normal range 1760–2600 dyn×s/cm5/m2)). Following transplantation, normal vasoconstrictor responses to ET-1 were restored. Responses to BQ123 were not different in patients with advanced cirrhosis compared with controls. Conclusion: In patients with end stage cirrhosis, ET-1 produces vasodilatation at a dose that causes marked vasoconstriction in normal control subjects. This effect is not attributable to impairment of ETA receptor responses. Our findings suggest that altered endothelin responses may contribute to the generalised dilatation of the circulation that occurs in patients with advanced liver disease.