Splanchnic organ homeostasis in experimental endotoxin shock : with special reference to the endothelin and renin-angiotensin systems

Sammanfattning: Splanchnic organ homeostasis may become severely deteriorated in states of sepsis and endotoxaemia. Gut tissue hypoxia with subsequent increases in intestinal mucosal permeability has been proposed to contribute to the development of multiple organ failure. The main aims of the present study were: to assess local metabolic endotoxin-induced deterioration in the ileum and liver as well as changes in splanchnic haemodynamic parameters in relation to other tissues and systemic variables; to evaluate the role of the endothelin (ET) and renin-angiotensin systems (RAS) in the endotoxin-induced metabolic and haemodynamic changes in the splanchnic region and systemically. All experiments were conducted in anaesthetised, mechanically ventilated pigs. Catheters, ultrasonic flow probes, intestinal tonometry and in some cases microdialysis probes were used to measure systemic and regional haemodynamics and metabolic changes in response to endotoxin infusion. All interventive drugs were administered after two hours of endotoxaemia when a state of shock was established. Endotoxin induced a hypodynamic shock characterised by reductions in regional and systemic perfusion. Signs of splanchnic metabolic deterioration were seen in the ileum and liver as increased tissue levels of hypoxanthine and lactate as well as ileal mucosal acidosis obtained by tonometry. In addition, endotoxaemia induced a notable mucosal injury as evident by microscopical examination. A more limited increase was seen in tissue hypoxanthine levels in the lung and only moderate changes were evident in subcutaneous fat and arterial blood. Moreover, the endotoxin- induced hypoperfusion was more pronounced in the splanchnic region than at the systemic level. Furthermore, ileal mucosal acidosis was more prominent than pH changes in arterial blood. Thus, systemic variables did not fully reflect changes seen in the splanchnic region in response to endotoxin, suggesting obvious limitations in relying on systemic monitoring only. Plasma levels of endothelin-1-like immunoreactivity (ET-1-LI) and plasma renin activity were both markedly increased in response to endotoxin, indicating strong activation of the ET- and RAS. Intervention with non-selective ET receptor antagonists (RA) effectively counteracted endotoxin-induced reductions in systemic and gut oxygen delivery as well as ileal mucosal acidosis. Selective ETA RA did not result in any beneficial effects in the splanchnic region whereas selective ETB RA proved to be fatal. In contrast, simultaneous administration of the selective ETA and ETB RA improved systemic and gut oxygen delivery as well as systemic metabolic acidosis, but not ileal mucosal acidosis, indicating that antagonism of both ETA and ETB receptors is necessary to counteract endotoxin-induced perfusion disturbances. Only treatments involving ETB RA increased the already high arterial plasma levels of ET-1-LI suggesting an important role for this receptor in plasma clearance of ET-1. The fatal effect of separate ETB RA may be explained by increased ETA receptor activity from increased levels of ET-1. Antagonism of the angiotensin II type 1 (AT1) receptor improved gut oxygen delivery and reduced pulmonary hypertension whereas no beneficial effects were seen on systemic oxygen delivery, systemic metabolic acidosis or ileal mucosal acidosis, suggesting a limited contribution of AT1 receptor activity to endotoxin-induced perfusion disturbances. AT1 RA did not affect plasma renin activity or plasma levels of ET- I -LI, suggesting that activation of the AT1 receptor was of minor importance for ET- 1 release in this endotoxaemic model. In conclusion: Endotoxin- induced metabolic and haemodynamic changes in the splanchnic region were not fully reflected at the systemic level. The ET system seems to play an important role in the endotoxin- induced disturbances in splanchnic homeostasis as well as regional and systemic haemodynamics in the current model. AT1 receptor activity seems to be of limited importance for these disturbances.