The endothelin receptor antagonist bosentan restores gut oxygen delivery and reverses intestinal mucosal acidosis in porcine endotoxin shock.
BACKGROUND
Endothelin-1, the most potent vasoconstrictor known, is produced in septic states and may be involved in the pathophysiology of the deteriorated splanchnic circulation seen in septic shock.


OBJECTIVE
To elucidate the capability of bosentan, a non-peptide mixed endothelin receptor antagonist, to attenuate splanchnic blood flow disturbances and counteract intestinal mucosal acidosis in endotoxic shock.


METHODS
In 16 anaesthetised pigs, central and regional haemodynamics were monitored by thermodilution and ultrasonic flow probes, respectively. A tonometer in the ileum was used for measurement of mucosal pH. Onset of endotoxin challenge was followed by bosentan administration (to eight pigs) two hours later.


RESULTS
Endotoxin infusion reduced cardiac index and systemic oxygen delivery; bosentan restored these parameters. The reduced mean arterial blood pressure and renal blood flow remained unaffected by bosentan. The profound reduction in gut oxygen delivery in response to endotoxin was completely abolished by bosentan. Bosentan significantly improved the notably deteriorated intestinal mucosal pH and mucosal-arterial PCO2 gap. The mucosal-portal vein PCO2 gap, used to monitor the mucosa in relation to the gut as a whole (including the spleen and pancreas), was also greatly increased by endotoxaemia and significantly reversed by bosentan.


CONCLUSIONS
Bosentan completely restored the profound endotoxin induced reductions in systemic and gut oxygen delivery with a concomitant reversal of intestinal mucosal acidosis. Results suggest that endothelin is involved in the pronounced perfusion disturbances seen in the gut in endotoxic shock. Bosentan may prove useful in reducing gut ischaemia in septic shock.
Oldner
A
A
Department of Anaesthesiology and Intensive Care, Karolinska Institute, Stockholm, Sweden.
Wanecek
M
M
Goiny
M
M
Weitzberg
E
E
Rudehill
A
A
Alving
K
K
Sollevi
A
A
D000138:Acidosis / Q000188:drug therapy; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D004926:Escherichia coli; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000098:blood supply; D007511:Ischemia / Q000188:drug therapy; D008070:Lipopolysaccharides; D010100:Oxygen / Q000378:metabolism*; D012772:Shock, Septic / Q000188:drug therapy* / Q000503:physiopathology; D013152:Splanchnic Circulation / Q000187:drug effects; D013449:Sulfonamides / Q000627:therapeutic use*; D013552:Swine
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D008070:Lipopolysaccharides; D013449:Sulfonamides; D000077300:Bosentan; D010100:Oxygen