AUGMENTATION OF INTRARENAL ANGIOTENSIN-II LEVELS BY CHRONIC ANGIOTENSIN-II INFUSION

The objective of this study was to investigate the singular role of elevated angiotensin II (ANG II) levels in the development of two-kidney, one-clip (2K1C) Goldblatt hypertension in the rat and specifically in the altered intrarenal ANG II levels that occur in the nonclipped kidney. As a substitute for the clipped kidney, chronic delivery of ANG II (40 ng/min) via an osmotic minipump implanted subcutaneously was used to mimic plasma ANG II levels observed in 2K1C rats during the developmental phase of hypertension. Arterial pressure increased gradually over a period of 14 days, and a pressure profile similar in magnitude and temporal pattern to that of the 2K1C rats was observed. Systemic ANG II was elevated to similar levels in the 2K1C (60 +/- 13 fmol/ml) and ANG II-infused rats (72 +/- 15 fmol/ml) compared with intact two-kidney control animals (31 +/- 6 fmol/ml; P < 0.05) or uninephrectomized rats (13 +/- 1 fmol/ml; P < 0.05). Although renin content was markedly suppressed (80%), intrarenal ANG II content of the contralateral kidneys of the 2K1C groups (86 +/- 12 fmol/g) and the ANG II-infused group (150 +/- 17 fmol/g) was greater than that of the two-kidney control (53 +/- 7 fmol/g; P < 0.05) and uninephrectomized control animals (42 +/- 5 fmol/g; P < 0.05). Additionally, intrarenal angiotensin-converting enzyme activity was significantly enhanced in the contralateral kidneys of the 2K1C (1.7 +/- 0.1 nmol min(-1).mg protein(-1)) and ANG II-infused rats (2.0 +/- 0.1 nmol.min(-1).mg protein(-1)) compared with their respective controls (1.1 +/- 0.2 and 1.5 +/- 0.1 nmol.min(-1).mg protein(-1), respectively; P < 0.05). These results indicate that 1) elevations in circulating ANG II serve as the singular mediator of the hypertensive response in ANG II-infused rats; 2) chronic elevations in circulating and intrarenal ANG II levels are associated with stimulation of intrarenal angiotensin-converting enzyme activity; and 3) in the renin-suppressed contralateral kidneys of the 2K1C and ANG II-infused rats, intrarenal ANG II production is induced via an ANG II-mediated positive amplification mechanism.