Specific angiotensin II receptor blockade improves intestinal perfusion during graded hypovolemia in pigs

Objective: To investigate the potential of specific angiotensin II subtype 1 (AT1) receptor blockade to modify the mesenteric hemodynamic response to acute hypovolemia and retransfusion. Design: Prospective, randomized, controlled experimental study. Setting: University-affiliate animal research laboratory. Subjects: Fasted, anesthetized, ventilated, juvenile domestic pigs of both sexes. Interventions: Acute, graded hypovolemia by 20% and 40% of the total estima ted blood volume followed by retransfusion in control animals (CTRL; n = 10 ) and animals pretreated with the AT1 receptor blocker candesartan (CAND; n = 10). Measurements and Main Results: Invasive monitoring of arterial and central venous blood pressures, cardiac output, portal venous blood flow, and jejun al mucosal blood flow. Blood gases were repeatedly analyzed to calculate ox ygen delivery and consumption. Thirty minutes after each level of hypovolem ia at 20% and 40%, cardiac output was decreased in CTRL animals from a base line of 2.9 +/- 0.1 to 1.8 +/- 0.2 and 1.1 +/- 0.2 L/min, with no differenc es compared with CAND animals. Cardiac output was restored to 3.0 +/- 0.3 L /min 30 mins after retransfusion in CTRL animals, with no significant inter group differences. Baseline portal venous blood Row (Q(MES)) and jejunal mu cosal perfusion (PUJEJ) were greater in CAND animals compared with CTRL ani mals. During graded hypovolemia, CAND animals maintained Q(MES) and PUJEJ a t significantly higher levels compared with CTRL animals, particularly afte r 40% hemorrhage (+221% and + 244%, respectively, relative to the mean valu es in CTRL animals). The same pattern was observed after retransfusion. Mor eover, the calculated mesenteric critical oxygen delivery was significantly greater in CTRL animals (74 mL/min) compared with CAND animals (34 mL/min) . No animals died in the CAND group, whereas four animals died during 40% h ypovolemia or retransfusion in the CTRL group. Conclusions: Specific AT1 blockade before acute hypovolemia significantly a meliorated mesenteric and, in particular, jejunal mucosal hypoperfusion. In addition, cardiovascular stability was improved, and mortality in conjunct ion with acute hypovolemia and retransfusion could be completely avoided. T hese findings support a fundamental role of the renin-angiotensin system in the mesenteric response to acute hypovolemia and indicate a substantial in terventional potential for candesartan in conjunction with circulatory stre ss.