Effects of the endothelin receptor antagonist, SB 209670, on circulatory failure and organ injury in endotoxic shock in the anaesthetized rat.
1. This study investigates the effects of the non-selective ETA/ETB receptor antagonist, SB 209670, on systemic haemodynamics, renal function, liver function, acid-base balance and survival in a rat model of endotoxic shock. 2. Injection of E. coli lipopolysaccharide (LPS, 10 mg kg-1, i.v.) resulted in increases in the serum levels of tumour necrosis factor-alpha (TNF-alpha, maximum 60 min after LPS), endothelin-1, (ET-1; maximum 120 min after LPS), and interferon-gamma (IFN-gamma, maximum 180 min after LPS). 3. Injection of LPS also resulted in a fall in blood pressure from 113 +/- 3 mmHg (time = 0) to 84 +/- 4 mmHg at 360 min (n = 15) as well as a hyporeactivity to the vasoconstrictor responses elicited by noradrenaline (NA, 1 microgram kg-1, i.v.). Pretreatment of rats with a continuous infusion of SB 209670 (3 mg kg-1, i.v. bolus + 100 micrograms kg-1, i.v. infusion commencing 15 min prior to LPS) significantly augmented the hypotension as well as the vascular hyporeactivity to NA caused by endotoxaemia. 4. Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus given 15 min prior to LPS) or infusion of SB 209670 (bolus dose and infusion as above) resulted in a reduction in 6 h-survival from 71% (control) to 30% and 13%, respectively. 5. Endotoxaemia for 4 h resulted in rises in the serum levels of urea and creatinine (indicators of renal failure), but not in the serum levels of bilirubin, GPT and GOT (indicators of liver dysfunction and/or hepatocellular injury). Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus 15 min prior to LPS) significantly augmented the serum levels of creatinine, bilirubin, GPT and GOT caused by endotoxin. In addition, endotoxaemia caused, within 15 min, an acute metabolic acidosis (falls in pH, HCO3- and base excess) which was compensated by hyperventilation (fall in PaCO2). Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus) significantly augmented the metabolic acidosis caused by LPS. 6. Thus, the non-selective ETA/ETB receptor antagonist, SB 209670, augments the degree of (i) hypotension, (ii) vascular hyporeactivity to noradrenaline, (iii) renal dysfunction and (iv) metabolic acidosis caused by endotoxin in the anaesthetized rat. In contrast to rats treated with LPS alone, LPS-rats treated with SB 209670 exhibited liver dysfunction and hepatocellular injury. We propose that the release of endogenous ET-1 serves to maintain blood pressure and subsequently organ perfusion in septic shock.
Ruetten
H
H
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London.
Thiemermann
C
C
Vane
J R
JR
D000136:Acid-Base Equilibrium; D000758:Anesthesia; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000097:blood / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007189:Indans / Q000494:pharmacology*; D007371:Interferon-gamma / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012772:Shock, Septic / Q000097:blood* / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007189:Indans; D008070:Lipopolysaccharides; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014409:Tumor Necrosis Factor-alpha; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-; D007371:Interferon-gamma; D009638:Norepinephrine