In contrast, in our model of hyperdynamic sepsis, we found intens

In contrast, in our model of hyperdynamic sepsis, we found intense renal vasodilatation and increased RBF, as previously reported [8,9]. Despite renal hyperemia, there was a significant decline in renal function, as shown by the decreased urine output and creatinine clearance. These changes suggest a marked Abiraterone chemical structure reduction in glomerular filtration rate (GFR) and its major determinant, intra-glomerular capillary pressure. The effect of Ang II on urine output, creatinine clearance and natriuresis occurring in the setting of renal vasoconstriction and decreased RBF, as seen in our study, is consistent with the hypothesis that Ang II causes an increase in glomerular filtration pressure, possibly through selective efferent arteriolar vasoconstriction or changes in mesangial cell tone or both.

To our knowledge, this is the first report of such effects in hyperdynamic sepsis. Previous animal studies in rats demonstrated a likely role for Ang II to oppose the hypotensive response to lipopolysaccharide-induced sepsis [20] and a reduced systemic pressor response to Ang II boluses at doses similar to ours, an effect which was associated with a variable renal vasoconstrictor response [21]. None of these studies, however, measured the renal functional effect or systemic and renal hemodynamic effect of extended Ang II infusion.The increase in urinary output, fractional natriuresis and creatinine clearance induced by infusion of Ang II in sepsis seems unlikely to be simply secondary to increases in arterial pressure.

First, the MAP value during Ang II infusion was similar to baseline values and yet urine output and fractional natriuresis were much greater. Second, in previous identical studies, norepinephrine and epinephrine infusion caused similar increases in arterial pressure but produced much smaller and more transient improvements in renal function than Ang II [7,22].The renal effect of Ang II may relate to its selective effects on intrarenal hemodynamics, where it controls tone in the afferent and efferent arterioles [14] and mesangial cells [23]. Infusion of Ang II increases filtration fraction [24-26], which has been proposed to result from a greater sensitivity of the efferent than the afferent arterioles to its vasoconstrictor action, a notion supported by several studies [27-32]. In contrast, the afferent and efferent arterioles have been shown to respond similarly to norepinephrine [27].

If Ang II is to be used in human sepsis, it is important to assess whether this treatment has harmful effects. We found that Ang II caused only limited reductions in blood flow to the heart, gut or skeletal muscle. Additionally, AV-951 we found no evidence of adverse effects on electrolyte or lactate levels. Desensitization to the effects of vasoconstrictor agents, including Ang II, in sepsis is well established.

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