Role of Endogenous Endothelin in Gastric Mucosal Injury Induced by Hemorrhagic Shock in Rats

1 The non-selective endothelin (ET) receptor antagonist bosentan has been shown to restore systemic and gut oxygen delivery and reverse intestinal mucosal acidosis in porcine endotoxin shock. 2 To further elucidate the speci®c role of the ET A as opposed to the ET B receptor and their e ects in the splanchnic region a non-selective (ET MIX ra) A-182086 and selective ET A (ET A ra) PD155080 and ET B (ET B ra) A-192621 receptor antagonists were administered, separately or simultaneously (ET A+B ra) 2 h after onset of endotoxin shock. These four groups were compared to a control group receiving only endotoxin and vehicle. 3 Thirty-nine pigs were anaesthetized and catheterized for measurement of central and regional haemodynamics. A tonometer in the distal ileum was used for measurement of mucosal PCO 2 . Blood gases and plasma ET-1-LI levels as well as histological samples from the gut were assessed. Intervention was started 2 h after onset of endotoxemia and the experiments were terminated after 5 h. 4 Endotoxin-induced changes in systemic, gut oxygen delivery and portal hepatic vascular resistance and systemic acidosis were e ectively counteracted by both ET A+B ra and ET MIX ra. ET A ra administration was not e ective while ET B ra proved to be fatal as all animals in this group died prior to full time of the experiment. While both ET A+B ra and ET MIX ra improved gut oxygen delivery only the latter attenuated the profound endotoxin-induced ileal mucosal acidosis. 5 The lethal e ect seen from selective ET B receptor antagonism in the current study may be due to increased ET A receptor activity as plasma levels of ET-1 is increased several fold by blocking the ET B receptor and thereby the plasma-ET-1-clearing function. Furthermore, a loss of endothelial ET B receptor vasodilating properties may also have contributed to the lethal course in the ET B ra group 6 The ®ndings in this study suggest that ET is involved in the profound endotoxin-induced disturbances in splanchnic homeostasis in porcine endotoxaemia. Furthermore, antagonism of both ET A and ET B receptors is necessary to e ectively counteract these changes.

Section: Discussionmentioning

confidence: 99%

Differentiated effects on splanchnic homeostasis by selective and non‐selective endothelin receptor antagonism in porcine endotoxaemia

Oldner

Wanecek

Weitzberg

et al. 1999

“…For instance, the decrease in microvascular blood flow caused by injection of live E. coli bacteria into anaesthetized rats is attenuated by pretreatment of animals with a monoclonal antibody to ET-1 (Wilson et al, 1993). Similarly, the ETA receptor antagonist, BQ-485, attenuates the decrease in gastric mucosa blood flow and subsequently the injury to the gastric mucosa caused by endotoxic shock in the rat (Kitajima et al, 1994). The delayed and sustained increase in pulmonary arterial pressure associated with endotoxaemia in the pig is also attenuated by bosentan, a non-selective ETA/ETB receptor antagonist (Weitzberg and Lundberg, personal communication).…”

Section: Measurement Of Serum Nitritementioning

confidence: 99%

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

Ruetten

Thiemermann

Vane

1996

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.

“…The complex haemodynamic response following haemorrhage involves the activation of different overlapping vasopressor systems that preserve circulatory homeostasis (Schadt & Ludbrook, 1991), e.g., the sympathetic (Chien, 1967; Darlington et al ., 1986; Korner et al ., 1990; Leskinen et al ., 1994), the renin‐angiotensin (Freeman et al ., 1975; Pang, 1983; Korner et al ., 1990; Schadt & Gaddis, 1990) and vasopressin (Zerbe et al ., 1982; Hock et al ., 1984; Pang, 1983; Johnson et al ., 1988; Korner et al ., 1990; Imai et al ., 1996) systems. ET likely also plays a vital role in haemodynamic compensation following haemorrhage, since plasma concentration of ET‐1 is very high following haemorrhage in rats (Michida et al ., 1994; Vemulapalli et al ., 1994; Zimmerman et al ., 1994; Kitajima et al ., 1995) and dogs (Chang et al ., 1993; Notarius et al ., 1995). Furthermore, unlike catecholamines, angiotensin II and vasopressin, ET‐1 has a very long duration of vasoconstrictor action that lasts more than 1 h.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma concentrations of ET‐1 are normally low. However, in certain pathophysiological conditions, such as hypovolaemic hypotension, increased circulating levels of ET‐1 have been described (Chang et al ., 1993; Michida et al ., 1994; Vemulapalli et al ., 1994; Zimmerman et al ., 1994; Kitajima et al ., 1995), which raises the possibility that endogenous ET may modulate cardiovascular function in hypovolaemia. Therefore, it is possible that ET may participate in the control of arterial resistance, venous resistance, MAP and MCFP in haemorrhage, and this may be mediated through the activation of ET A and ET B receptors.…”

Section: Introductionmentioning

confidence: 99%

Role of endothelin ET_A‐ and ET_B‐receptors in haemodynamic compensation following haemorrhage in anaesthetized rats

Palacios

Lim

Pang

2002

1 This study examined the role of endothelin ET A and ET B receptors on haemodynamic compensation following haemorrhage (717.5 ml kg 71 ) in thiobutabarbitone-anaesthetized rats. Rats were divided into four groups (n=6 each): time-control, haemorrhage-control, haemorrhage after treatment with FR 139317 (ET A -receptor antagonist), and haemorrhage after treatment with BQ-788 (ET B -receptor antagonist). 2 In the time-control rats, there were no signi®cant changes in any haemodynamics for the duration of the experiments. Relative to the time-control rats, rats given haemorrhage had reduced mean arterial pressure (MAP), cardiac output (CO) and mean circulatory ®lling pressure (MCFP), but increased systemic vascular resistance (R SV ). Venous resistance (R V ) was slightly (but insigni®cantly) reduced by haemorrhage. MAP, however, gradually returned towards baseline (717+4 and 73+2 mmHg at 10 and 60 min after haemorrhage, respectively) as a result of a further increase in R SV . 3 Pre-treatment with FR 139317 (i.v. 1 mg kg 71 , followed by 1 mg kg 71 h 71 ) accentuated haemorrhage-induced hypotension through abolition of the increase in R SV . FR 139317 did not modify haemorrhage-induced changes in CO, MCFP and R V . 4 Pre-treatment of BQ-788 (3 mg kg 71 ) did not a ect MAP or MCFP following haemorrhage; however, CO was lower, and R SV as well as R V were higher relative to the readings in the haemorrhaged-control rats. 5 These results show that following compensated haemorrhage, ET maintains arterial resistance and blood pressure via the activation of ET A but not ET B receptors.