EFFECT OF SELECTIVE BLOCKADE OF ENDOTHELIN ET(B) RECEPTORS ON THE LIVER DYSFUNCTION AND INJURY CAUSED BY ENDOTOXEMIA IN THE RAT

1 We investigated the effects of the selective endothelin (ET)(A) rece ptor antagonist BQ-485 and the selective ET(B) receptor antagonist BQ- 788 on circulatory failure, multiple organ dysfunction syndrome (MODS) and the alterations in acid base balance caused by endotoxaemia in th e anaesthetized rat. 2 Male Wistar rats were anaesthetized (thiopenton e sodium; 120 mg kg(-1), i.p.) and received a continuous infusion of v ehicle (saline, 0.6 ml kg(-1) h(-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 hypo reactivity to the presser responses to noradrenaline (NA, 1 mu g kg(-1 ), i.v.). Infusion of BQ-788 attenuated the delayed hypotension (at 36 0 min: 100 +/- 4 mmHg, n = 7; P < 0.05) and significantly enhanced the presser responses elicited by NA (at 60 to 240 min). In contrast, tre atment of LPS-rats with BQ-485 augmented the hypotension (at 360 min), but did not affect the vascular hyporeactivity elicited by endotoxaem ia. 4 Endotoxaemia for 360 min resulted in rises in the serum levels o f urea and creatinine (indicators of renal failure), glutamate-oxalate -transferase (GOT) and glutamate-pyruvate-transferase (GPT) (indicator s of hepatocellular injury), and bilirubin and gamma-glutamyl transfer ase (gamma GT) (indicators of liver failure) as well as nitrite (indic ator of the induction of nitric oxide synthase; iNOS). Treatment of LP S-rats with BQ-788, but not with BQ-485, attenuated the degree of live r injury and failure, while neither BQ-788 nor BQ-485 affected the acu te renal failure or the induction of iNOS caused by endotoxin. 5 Endot oxaemia also caused (within 15 min) an acute metabolic acidosis (falls in pH, HCO3- and base excess) which was compensated by hyperventilati on (fall in Paco(2)). Treatment of LPS-rats with BQ-788 or BQ-485 did not affect the metabolic acidosis caused by LPS. 6 Thus, the selective ET(B) receptor antagonist BQ-788 attenuated (i) the delayed hypotensi on, (ii) the vascular hyporeactivity to NA as well as (iii) the degree df hepatocellular injury and dysfunction caused by endotoxin in the a naesthetized rat. In contrast, the selective ET(A) receptor antagonist did neither attenuate the circulatory failure nor the liver or renal dysfunction associated with endotoxaemia. We propose that the preventi on of the hepatocellular dysfunction and injury caused BQ-788 in endot oxaemia is due to an improvement in oxygen delivery to the liver secon dary to (i) inhibition of pre-sinusoidal constriction, (ii) inhibition of sinusoidal constriction, and (iii) improvement in perfusion pressu re.