Angiotensin II type 1 receptor-mediated augmentation of urinary excretion of endogenous angiotensin II in Val5-angiotensin II-infused rats

Abstract

Rats infused chronically with Val(5)-Angiotensin (Ang) II exhibit increased urinary excretion of endogenous Ile(5)-Ang II by the 12th day of infusion, suggesting the stimulation of endogenous Ang II formation by Val(5)-Ang II infusion. The present study determined the time course of increased urinary Ang II excretion and the effects of Ang II type 1 receptor blockade (candesartan, 2 mg/kg per day) on the urinary excretion rates of Ile(5)-Ang II in Val(5)-Ang II-infused (80 ng/min) rats. Ile(5)-Ang II was separated from Val(5)-Ang II by high-performance liquid chromatography and measured by radioimmunoassay. Systolic blood pressure increased progressively (215+/-2 mm Hg) in Val(5)-Ang II-infused rats (n=5), whereas the candesartan-treated group (n=6) remained normotensive (124+/-3 mm Hg). Candesartan treatment significantly increased the level of plasma Ile(5)-Ang II (24.0+/-7.6 versus 156.9+/-24.6 fmol/mL; P<0.01); in contrast, there was a markedly lower intrarenal Ile(5)-Ang II content (357.9+/-76.6 versus 21.1+/-2.8 fmol/g; P<0.01). Urinary Ile(5)-Ang II excretion rates were elevated by day 9 (2185.7+/-283.2 fmol/24 hours) in Val(5)-Ang II-infused rats but not in candesartan-treated rats (740.6+/-110.3 fmol/24 hours). Thus, Ang II type 1 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 Val(5)-Ang II-infused rats is primarily attributed to Ang II type 1 receptor-dependent secretion into and/or de novo formation of Ang II within the tubular lumen.

Figure 1

Comparison of systolic blood pressures between Val⁵-Ang II infused rats (n = 5) and Val⁵-Ang II infused rats treated with candesartan (n = 6). Values are mean ± SE. * p < 0.01 vs. Val⁵-Ang II infused rats + candesartan.

Figure 2

Comparison of plasma renin activity between Val⁵-Ang II infused rats (n = 5) and Val⁵-Ang II infused rats treated with candesartan (n = 6). Values are mean ± SE. # p< 0.05 vs. Val⁵-Ang II infused rats.

Figure 3

Comparison of kidney prorenin and renin content between Val⁵-Ang II infused rats (n = 5) and Val⁵-Ang II infused rats treated with candesartan (n = 6). Values are mean ± SE.

Figure 4

Comparison of plasma Val⁵-Ang II and Ile⁵-Ang II levels between Val⁵-Ang II infused rats (n = 5) and Val⁵-Ang II infused rats treated with candesartan (n = 6). Values are mean ± SE. * p < 0.01 vs. Val⁵-Ang II infused rats.

Figure 5

Comparison of kidney Val⁵-Ang II and Ile⁵-Ang II levels between Val⁵-Ang II infused rats (n = 5) and Val⁵-Ang II infused rats treated with candesartan (n = 6). Values are mean ± SE. * p < 0.01 vs. Val⁵-Ang II infused rats.

Figure 6

Comparison of urinary Val⁵-Ang II and Ile⁵-Ang II excretion rates between Val⁵-Ang II infused rats (n = 5) and Val⁵-Ang II infused rats treated with candesartan (n = 6). Values are mean ± SE. * p< 0.01, ** p< 0.05, *** p<0.01 vs. Val⁵-Ang II infused rats + candesartan. # p< 0.01 vs. Val⁵-Ang II infused rats at day -1.