Mesentric hemodynamics and effects of angiotensin II during circulatory stress

Abstract: Mesenteric hypoperfusion and ischemia is considered to be deleterious to the intestinal mucosal barrier function and it is suggested that the renin-angiotensin system plays a pivotal role in the regulation of mesenteric perfusion.The present thesis examines the effects of the specific AT1 receptor blocker candesartan on mesenteric hemodynamics during acute hypovolemia and endotoxinemia. Furthermore, it investigates the degree to which the monitoring of systemic hemodynamics may be used to predict changes in mesenteric and intestinal circulation during hypovolemia and endotoxinemia. It also explores the effects of angiotensin II on mucosal function during moderate hypovolemia and whether such effects are mediated via the AT1 or the AT2 receptor.Experiments were performed on anaesthetized pigs. Pretreatment with candesartan improved mesenteric circulation and mesenteric DO2 and induced a leftward shift of DO2crit during hypovolemia. Furthermore, animals treated with candesartan also maintained mesenteric and intestinal perfusion better when treatment was initiated in moderate hypovolemia. Pretreatment with candesartan resulted in higher mesenteric perfusion initially during endotoxinemia; it also improved survival during severe hypovolemia and retransfusion as well as endotoxinemia. Systemic and mesenteric perfusion correlated well during both hypovolemia and endotoxinemia. A correlation between mesenteric and intestinal perfusion was shown with laser-Doppler flowmetry and capnotonometry during hypovolemia but only with capnotonometry during endotoxinemia. Treatment with candesartan markedly increased intraluminal nitric oxide production during moderate hypovolemia and maintained the intestinal lumen to blood potential difference. This effect was reduced by an AT2 receptor antagonist.It is concluded that AT1 receptor blockade improves mesenteric perfusion during severe hypovolemic stress, whereas in endotoxinemia this potential of AT1 blockade is limited to the early phase. Candesartan pretreatment improved general hemodynamic stability and thus survival in severe hypovolemia and endotoxinemia. AT1 receptor blockade might exert protective effects on the intestinal mucosa even in moderate circulatory stress involving the AT2 receptor. Tonometry and laser-Doppler flowmetry may be useful additions for monitoring the intestinal circulation, particularly in septic conditions.