1. We investigated the effects of the selective
endothelin (ET)A receptor antagonist
BQ-485 and the selective ETB receptor antagonist
BQ-788 on
circulatory failure,
multiple organ dysfunction syndrome (
MODS) and the alterations in acid base balance caused by endotoxaemia in the anaesthetized rat. 2. Male Wistar rats were anaesthetized (
thiopentone sodium; 120 mg kg-1, i.p.) and received a continuous infusion of vehicle (saline, 0.6 ml kg-1h-1, i.v.),
BQ-485 (10 nmol kg-1 min-1, i.v.) or
BQ-788 (10 nmol kg-1 min-1, i.v.). Fifteen min later, animals received a bolus injection of either
saline (0.9% NaCl, 1 ml kg-1, i.v.) or E. coli
lipopolysaccharide (LPS, 10 mg kg-1, i.v.). 3. Injection of LPS resulted in a fall in blood pressure from 115 +/- 4 mmHg (time 0) to 82 +/- 4 mmHg at 360 min (n = 15) as well as a hyporeactivity to the pressor responses to
noradrenaline (NA, 1 microgram kg-1, i.v.). Infusion of
BQ-788 attenuated the delayed
hypotension (at 360 min: 100 +/- 4 mmHg, n = 7; P < 0.05) and significantly enhanced the pressor responses elicited by NA (at 60 to 240 min). In contrast, treatment of LPS-rats with
BQ-485 augmented the
hypotension (at 360 min), but did not affect the vascular hyporeactivity elicited by endotoxaemia. 4. Endotoxaemia for 360 min resulted in rises in the serum levels of
urea and
creatinine (indicators of
renal failure),
glutamate-
oxalate-
transferase (GOT) and
glutamate-
pyruvate-
transferase (GPT) (indicators of hepatocellular injury), and
bilirubin and gamma-glutamyl
transferase (gamma GT) (indicators of
liver failure) as well as
nitrite (
indicator of the induction of
nitric oxide synthase; iNOS). Treatment of LPS-rats with
BQ-788, but not with
BQ-485, attenuated the degree of liver injury and failure, while neither
BQ-788 nor
BQ-485 affected the
acute renal failure or the induction of iNOS caused by
endotoxin. 5. Endotoxaemia also caused (within 15 min) an acute
metabolic acidosis (falls in pH, HCO3-and base excess) which was compensated by
hyperventilation (fall in PaCO2). Treatment of LPS-rats with
BQ-788 or
BQ-485 did not affect the
metabolic acidosis caused by LPS. 6. Thus, the selective ETB receptor antagonist
BQ-788 attenuated (i) the delayed
hypotension, (ii) the vascular hyporeactivity to NA as well as (iii) the degree of hepatocellular injury and dysfunction caused by
endotoxin in the anaesthetized rat. In contrast, the selective ETA receptor antagonist did neither attenuate the
circulatory failure nor the liver or renal dysfunction associated with endotoxaemia. We propose that the prevention of the hepatocellular dysfunction and injury caused
BQ-788 in endotoxaemia is due to an improvement in
oxygen delivery to the liver secondary to (i) inhibition of pre-sinusoidal constriction, (ii) inhibition of sinusoidal constriction, and (iii) improvement in perfusion pressure.