Endothelin-1 contributes to maintenance of systemic but not portal haemodynamics in patients with early cirrhosis: a randomised controlled trial.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Tripathi
D
D
Department of Hepatology, Royal Infirmary, 51 Little France Crescent, Edinburgh EH16 4SU, UK. tdrdhir@aol.com
Therapondos
G
G
Ferguson
J W
JW
Newby
D E
DE
Webb
D J
DJ
Hayes
P C
PC
D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000502:physiology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006975:Hypertension, Portal / Q000188:drug therapy / Q000503:physiopathology*; D008102:Liver Circulation / Q000187:drug effects; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000009:adverse effects / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000009:adverse effects / Q000494:pharmacology; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)