Effects of the endothelin receptor antagonist, SB 209670, on circulatory failure and organ injury in endotoxic shock in the anaesthetized rat

Abstract

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. 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-', 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-', 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, LPSrats 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.

Effect of selective blockade of endothelin ETB receptors on the liver dysfunction and injury caused by endotoxaemia in the rat

“…Interestingly, ETB receptors are responsible for the clearance of ET-1 from the circulation and BQ-788 enhances the vasoconstrictor responses elicited by exogenous ET-1 . The release of endogenous ET-1 serves to maintain blood pressure and organ perfusion in conscious (Gardiner et al, 1995) and anaesthetized rats with endotoxaemia (Ruetten et al, 1996). Prevention by BQ-788 of ET-1 clearance and, hence, an an increase in the plasma levels of ET-1 may well explain the improvement in blood pressure caused by Attenuation by of the vascular hyporeactivity to noradrenaline may also contribute to the beneficial haemodynamic effects of the ETB-receptor antagonist in rats with endotoxic shock.…”

“…in portal venules, results in vasoconstriction and, hence, may also contribute to a reduction in hepatic blood flow (Kurihara et al, 1992;Bauer et al, 1994;Zhang et al, 1995). As endotoxaemia (this model) results in a rapid and substantial increase in the plasma levels of ET-1 (Ruetten et al, 1996), any reduction in sinusoidal blood flow is likely to be due to extra-sinusoidal as well as sinusoidal constriction. Szabo et al, 1993;Thiemermann et al, 1995).…”

“…The non-selective ETA/ETB receptor antagonist SB 209670 British Journal of Phamacology (1996) 119, 479-486 (Ohlstein et al, 1994;Douglas et al, 1995) aggravates the circulatory failure (Gardiner et al, 1995;Ruetten et al, 1996) as well as the renal and liver dysfunction caused by endotoxin in the rat (Ruetten et al, 1996). Although the rapid release of endogenous ET-1 in endotoxaemia serves to maintain blood pressure and organ perfusion (beneficial effect of ET-1), excessive rises in the serum levels of ET-1 for longer periods are also associated with excessive vasoconstriction in some vascular beds (harmful effects of ET-1) (Ruetten et al, 1996).…”

“…The non-selective ETA/ETB receptor antagonist SB 209670 British Journal of Phamacology (1996) 119, 479-486 (Ohlstein et al, 1994;Douglas et al, 1995) aggravates the circulatory failure (Gardiner et al, 1995;Ruetten et al, 1996) as well as the renal and liver dysfunction caused by endotoxin in the rat (Ruetten et al, 1996). Although the rapid release of endogenous ET-1 in endotoxaemia serves to maintain blood pressure and organ perfusion (beneficial effect of ET-1), excessive rises in the serum levels of ET-1 for longer periods are also associated with excessive vasoconstriction in some vascular beds (harmful effects of ET-1) (Ruetten et al, 1996). In order to gain a better understanding of the receptors which mediate the above effects of endogenous ET-1 in endotoxaemia, we have now investigated the effects of the selective ETA receptor antagonist, BQ-485 (Nakahashi et al, 1995), and the selective ETB receptor antagonist, BQ-788 , on (i) systemic haemodynamics, (ii) vascular hyporeactivity, (iii) renal function, (iv) liver function and integrity, and (v) acid-base balance in a rat model of endotoxic shock.…”

Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2

“…Endotoxemia was induced by administration of E. coli LPS (10 mg/kg iv infusion for 30 min; LPS W E. coli 0111:B4, Sigma, St. Louis, MO) using the left femoral vein catheter as described previously (37). The animals were then randomized into two groups; sham-treated and LPS-treated animals at the time of surgery.…”