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See article on page 696
In a variety of pathological states, notably ischaemia–reperfusion injury, organ infarction, and shock, there are substantial increases in the normally low circulating concentrations of endothelin-1 (ET-1).1 ,2 This is more than just a symptom. ET-1 seems to be an active participant in these disorders as antibodies directed against ET-1 and endothelin receptor antagonists are protective.1 ,2 Interestingly, although studies in isolated cells suggest that the production of ET-1 can only be up-regulated over the course of hours, increases in vivo can be recorded within much shorter periods. For example, intravenous injection of a high dose of endotoxin to anaesthetised rats causes within 5–10 minutes both a dramatic fall in blood pressure and a notable increase in haematocrit. Both of these effects are greatly reduced by treatment with endothelin receptor antagonists active at the ETA receptor.3 Clearly, the speeds of these responses suggest a direct effect of high dose endotoxin. When given in lower doses endotoxin causes increases in plasma ET-1 over periods of hours rather than minutes. These more delayed responses are indirect effects of endotoxin and are secondary to the release of cytokines, particularly tumour necrosis factor (TNF) α and interleukin-1β. Increases in circulating ET-1 caused by endotoxin in both pigs and baboons are noticeably reduced by treatment with anti-TNF-α.4 ,5 Similarly, and more importantly, in human septic shock there is a clear positive correlation between the circulating concentrations of TNF-α and ET-1.6
What, however, are the clinical implications of either direct or cytokine mediated increases in ET-1 caused by endotoxin? In this issue Oldner et al (see page 696) report that in a porcine model of endotoxaemia, administration of bosentan (a non-selective endothelin ETA/B receptor antagonist) restores gut oxygen delivery and reverses intestinal mucosal acidosis. Clearly, these are beneficial effects, but would endothelin receptor antagonists be useful in human endotoxaemia? In their model Oldner et al follow the course of changes in anaesthetised pigs over five hours following endotoxin infusion. Endotoxin causes an early fall in blood pressure and an accompanying rise in blood endothelin concentrations associated with the immediate effects of endotoxin discussed earlier. Over the next few hours the continued fall in blood pressure is unaffected by bosentan. However, bosentan lowers systemic vascular resistance and so improves tissue perfusion. Within the gut these beneficial effects of bosentan are evident as support of portal blood flow, increase in portal venous oxygen saturation and gut oxygen delivery, and prevention of the fall in gastrointestinal mucosal pH. These outcomes seem to indicate that endothelin antagonists would be therapeutically beneficial in human endotoxic shock. However, we should be cautious in drawing such conclusions. In particular the short experimental period chosen by Oldner et al permits study of the initial responses to endotoxaemia, but not the longer term responses that are more relevant to clinical practice. More prolonged exposure to endotoxin leads to many profound effects. These effects follow alterations in the cellular expressions of proteins and so take hours to become apparent. In particular, recent research efforts have examined how excessive nitric oxide, produced by newly synthesised inducible nitric oxide synthase, underlies the vascular hyporesponsiveness found after longer periods of endotoxaemia. At these latter time points much clinical effort is aimed at supporting blood pressure.7 The administration of an agent such as bosentan, which antagonises the pressor effects of endogenously produced ET-1, may precipitate a further critical fall in blood pressure. Indeed, in the rat endothelin receptor antagonists potentiate endotoxaemia associated hypotension8 and increase mortality.9
Weighing up the current evidence leads us to the conclusion that Oldneret al are correct in suggesting that endothelin receptor antagonists would prove useful in reducing gut ischaemia in human septic shock. This could be of benefit as gut mucosal hypoperfusion is well known to be associated with poor prognosis.10However, the administration of endothelin receptor antagonists to humans with established sepsis may well produce dangerous falls in blood pressure that could more than offset any benefits on gut perfusion.