Renal Accumulation of Circulating Angiotensin II in Angiotensin II–Infused Rats

Abstract

Abstract Previous studies have demonstrated that low-dose angiotensin II (Ang II) infusion for 14 days mimics two-kidney, one clip Goldblatt hypertension and increases intrarenal Ang II levels. The objective of the present study was to determine whether the augmented intrarenal Ang II is due to intrarenal accumulation of the infused Ang II and/or to an increase in intrarenal formation of endogenous Ang II. Male Sprague-Dawley rats were uninephrectomized and divided into three groups: control (n=6), those infused with [Ile 5 ]Ang II (endogenous form) (n=6), and those infused with [Val 5 ]Ang II (n=8). [Ile 5 ]Ang II or [Val 5 ]Ang II was infused at 40 ng/min via an osmotic minipump implanted subcutaneously. By day 12, systolic blood pressure increased significantly in both [Val 5 ]Ang II–infused rats (197±7 mm Hg) and [Ile 5 ]Ang II–infused rats (173±3 mm Hg). Blood and kidney samples were harvested, subjected to high-performance liquid chromatography to separate [Val 5 ]Ang II from [Ile 5 ]Ang II, and then measured by radioimmunoassay. Plasma renin activity was markedly suppressed in both [Ile 5 ]Ang II– and [Val 5 ]Ang II–infused rats. Plasma Ang II levels were elevated in rats infused with both [Ile 5 ]Ang II (121±24 fmol/mL) and [Val 5 ]Ang II (119±14 fmol/mL) compared with controls (69±15 fmol/mL). Both [Ile 5 ]Ang II– and [Val 5 ]Ang II–infused rats exhibited an enhancement of total intrarenal Ang II. Only [Ile 5 ]Ang II (358±53 fmol/g) was detected in the kidneys of rats infused with [Ile 5 ]Ang II. In [Val 5 ]Ang II–infused rats, a significant portion of total renal Ang II (371±57 fmol/g) was in the form of [Val 5 ]Ang II (256±44 fmol/g). Renal [Ile 5 ]Ang II levels were maintained in the [Val 5 ]Ang II–infused rats (116±15 fmol/g) compared with control rats (116±11 fmol/g) despite marked suppression of renin release. These results support the hypothesis that infused circulating Ang II is bound to receptor or taken up intrarenally in a manner that protects against degradation.