AT1 Receptor-Mediated Augmentation of Urinary Excretion of Endogenous Ang II in Val5-Ang II Infused Rats

摘要

Rats infused chronically with Val⁵-Ang II exhibit increased urinary excretion of endogenous Ile⁵-Ang II by the 12^th day of infusion suggesting the stimulation of endogenous Ang II formation by Val⁵-Ang II infusion. The present study determined the time course of increased urinary Ang II excretion and the effects of AT1 receptor blockade (candesartan, 2 mg/kg/day) on the urinary excretion rates of Ile⁵-Ang II in Val⁵-Ang II-infused (80ng/min) rats. Ile⁵-Ang II was separated from Val⁵-Ang II by HPLC and measured by radioimmunoassay. Systolic blood pressure increased progressively (215 ± 2 mmHg) in Val⁵-Ang II-infused rats (5) while the candesartan treated group (6) remained normotensive (124 ± 3 mmHg). Candesartan treatment significantly increased the level of plasma Ile⁵-Ang II (24.0±7.6 vs. 156.9±24.6 fmol/ml; p<0.01); in contrast, there was a markedly lower intrarenal Ile⁵-Ang II content (357.9±76.6 vs. 21.1±2.8 fmol/g; p<0.01). Urinary Ile⁵-Ang II excretion rates were elevated by day 9 (2185.7 ± 283.2 fmol/24hr) in Val⁵-Ang II-infused rats but not in candesartan treated rats (740.6 ± 110.3 fmol/24hr). Thus, AT1 receptor blockade prevents the increase in urinary excretion of endogenous Ang II in rats subjected to chronic Ang II infusion. These data indicate that the increased urinary excretion of endogenous Ang II in Val⁵-Ang II-infused rats is primarily due to AT1 receptor dependent secretion into and/or de novo formation of Ang II within the tubular lumen.