Proximal Tubular Angiotensin II Levels and Renal Functional Responses to AT 1 Receptor Blockade in Nonclipped Kidneys of Goldblatt Hypertensive Rats

Abstract

Abstract —Previous studies have shown that whereas the nonclipped kidney in two-kidney, one clip (2K1C) rats undergoes marked depletion of renin content and renin mRNA, intrarenal angiotensin II (Ang II) levels are not suppressed; however, the distribution and functional consequences of intrarenal Ang II remain unclear. The present study was performed to assess the plasma, kidney, and proximal tubular fluid levels of Ang II and the renal responses to intrarenal Ang II blockade in the nonclipped kidneys of rats clipped for 3 weeks. The Ang II concentrations in proximal tubular fluid averaged 9.19±1.06 pmol/mL, whereas plasma Ang II levels averaged 483±55 fmol/mL and kidney Ang II content averaged 650±66 fmol/g. Thus, as found in kidneys from normal rats with normal renin levels, proximal tubular fluid concentrations of Ang II are in the nanomolar range. To avoid the confounding effects of decreases in mean arterial pressure (MAP), we administered the nonsurmountable AT 1 receptor antagonist candesartan directly into the renal artery of nonclipped kidneys (n=10). The dose of candesartan (0.5 μg) did not significantly decrease MAP in 2K1C rats (152±3 versus 148±3 mm Hg), but effectively prevented the renal vasoconstriction elicited by an intra-arterial bolus of Ang II (2 ng). Candesartan elicited significant increases in glomerular filtration rate (GFR) (0.65±0.06 to 0.83±0.11 mL · min −1 · g −1 ) and renal blood flow (6.3±0.7 to 7.3±0.9 mL · min −1 · g −1 ), and proportionately greater increases in absolute sodium excretion (0.23±0.07 to 1.13±0.34 μmol · min −1 · g −1 ) and fractional sodium excretion (0.38±0.1% to 1.22±0.35%) in 2K1C hypertensive rats. These results show that proximal tubular fluid concentrations of Ang II are in the nanomolar range and are much higher than can be explained on the basis of plasma levels. Further, the data show that the intratubular levels of Ang II in the nonclipped kidneys of 2K1C rats remain at levels found in kidneys with normal renin content and could be exerting effects to suppress renal hemodynamic and glomerular function and to enhance tubular reabsorption rate.