Statistical analysisData are presented as means with standard www.selleckchem.com/products/MDV3100.html deviations and all comparisons were performed by repeated measures analysis of variance [17]. All analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC, USA). To correct for the effect of multiple comparisons, only a two-sided P < 0.01 was considered statistically significant.ResultsEffects of sepsisAfter administration of E. coli, all animals developed features of sepsis: (temperature of >41��C, a respiratory rate >40 breaths per minute, use of accessory muscles of respiration, hypotension, tachycardia, lassitude, anorexia). Two sheep died following induction of sepsis.The onset of severe sepsis was associated with peripheral vasodilatation, hypotension and an increase in CO (hyperdynamic septic state).

MAP decreased (from 86.3 �� 7.2 to 71.8 �� 7.2 mmHg, P < 0.0001) and total peripheral conductance increased (P < 0.0001; Figure Figure1).1). These changes were accompanied by increases in CO and heart rate (Figure (Figure1)1) and a reduction in stroke volume (67.5 �� 11.6 to 46.4 �� 7.5 ml/beats, P < 0.0001).Figure 1Effect of intravenous angiotensin II or vehicle on systemic hemodynamics. Phase I = control period, two hours before Escherichia coli administration; Phase II = sepsis control period two hours before treatment; Phase III = six hours of treatment with ...Sepsis caused pronounced vasodilatation in all regional vascular beds with increases in renal conductance (3.4 �� 0.8 to 5.2 �� 0.9 ml/min/mmHg, P < 0.0001) and RBF (292.3 �� 60.5 to 396.6 �� 74.1 ml/min, P < 0.0001; Figure Figure2).

2). There were similarly large increases in coronary conductance and blood flow and in iliac conductance and blood flow (Figure (Figure3).3). Mesenteric conductance and mesenteric blood flow also increased (Figure (Figure33).Figure 2Effect of intravenous angiotensin II or vehicle on renal blood flow (RBF) and renal conductance (RC). Phase I = control period, two hours before Escherichia coli administration; Phase II = sepsis control period, two hours before treatment; Phase III = …Figure 3Effect of intravenous angiotensin II or vehicle on regional haemodynamics. Phase I = control period, two hours before Escherichia coli administration; Phase II = sepsis control period, two hours before treatment; Phase III = six hours of treatment with …

Despite the increase in RBF during sepsis, there was a 46% decrease in urine output (102.6 �� 38.1 to 50.5 �� 25.4 ml/h, P < 0.01) and a 43% decrease in creatinine clearance (88.7 �� 19.6 to 47.7 �� 21.0 ml/min, P < 0.01; Figure Figure4).4). GSK-3 Fractional excretion of sodium (FENa), however, did not change (0.47 �� 0.35 to 0.45 �� 0.35%, P > 0.05).Figure 4Effect of intravenous angiotensin II or vehicle on urine output and creatinine clearance.