RECEPTOR-MEDIATED INTRARENAL ANGIOTENSIN-II AUGMENTATION IN ANGIOTENSIN II-INFUSED RATS

Chronic low-dose angiotensin II (Ang II) infusion for 13 days mimics t wo-kidney, one clip Goldblatt hypertension and increases intrarenal An g Il levels. We performed studies to determine the time course for the enhancement of intrarenal Ang II levels and whether the increased int rarenal Ang II is a tissue-specific event and requires a receptor-medi ated step. Male Sprague-Dawley rats were uninephrectomized, and either vehicle or Ang II (40 ng/min) was infused via a subcutaneous osmotic minipump. Plasma and renal Ang II levels were measured 3, 7, 10, and 1 3 days after minipump implantation. Compared with controls (126 +/- 2 mm Hg), systolic pressure in Ang II-infused rats exhibited a detectabl e increase by day 6 (146 +/- 2 mm Hg) and continued to increase to 189 +/- 5 mm Hg by day 12. Plasma Ang II levels were elevated by day 3, w hereas intrarenal Ang II levels were not significantly elevated until 10 days of Ang II infusion. Renal injury characterized by focal and se gmental glomerulosclerosis was evident after 13 days of Ang II infusio n. Losartan (30 mg/kg per day) prevented the development of hypertensi on in the Ang II-infused rats for the duration of the infusion period (125 +/- 1 mm Hg) and reduced the degree of glomerular injury. Plasma renin activity was suppressed in the Ang II-infused group but was elev ated markedly in both losartan-treated groups. Plasma Ang II levels we re elevated in the Ang II-infused rats and were even higher during los artan treatment. Intrarenal Ang II levels were enhanced significantly (354 +/- 60 versus 164 +/- 23 fmol/g) in the Ang II-infused rats. Howe ver, losartan treatment prevented the augmentation of intrarenal Ang I I caused by Ang II infusion. Heart and adrenal Ang II levels were not significantly increased in the Ang II-infused rats but were significan tly elevated during losartan treatment. These results suggest that the tissue-specific elevations of intrarenal Ang II levels caused by chro nic Ang II infusion are mediated by angiotensin type 1 receptor activa tion, which leads to either receptor-mediated internalization of Ang I I, enhancement of intrarenal Ang II formation, or both.