Exaggerated tubuloglomerular feedback activity in genetic hypertension is mediated by ANG II and AT1 receptors

Abstract

The purpose of the present study was to determine the role of endogenous angiotensin II in exaggerated tubuloglomerular feedback (TGF) in young euvolemic spontaneously hypertensive rats (SHR). TGF was characterized by measuring proximal tubular stop-flow pressure (Psf) responses to loop of Henle perfusion before and during losartan infusion in 7-wk-old SHR and Wistar-Kyoto rats (WKY). In the control period, TGF responses were exaggerated in SHR compared with WKY. This was evidenced by a larger flow-induced maximum decrease in Psf (19 vs. 13 mmHg), lower turning point (8 vs.12 nl/min), and higher reactivity (-6.4 vs. -3.0 mmHg.nl-1.min-1) in SHR. Losartan (DuP-753) was infused into the renal artery to antagonize angiotensin AT1 receptors in the experimental period. This was verified by losartan inhibiting > 90% of the decrease in whole kidney and superficial cortical blood flow produced by exogenous angiotensin II in both strains. Losartan infusion significantly attenuated TGF activity in SHR but not in WKY. In SHR losartan reduced the maximum Psf response (from 19 to 10 mmHg) and increased the turning point (from 8 to 11 nl/min). SHR values during losartan administration were similar to those obtained in WKY. WKY values were unaffected by losartan. The lack of change in maximum TGF responses after losartan treatment was not unique to WKY, inasmuch as similar results were obtained in euvolemic Munich-Wistar rats (-2.0 +/- 0.7 and -1.1 +/- 1.0 mmHg vs. -8.4 +/- 0.7 mmHg in SHR). Thus angiotensin II does not appear to play an essential role in basal TGF activity during euvolemia in normotensive animals when there is minimal stimulation of the renin-angiotensin system. In contrast, our observations indicate that the exaggerated TGF in young euvolemic SHR represents a functional resetting that is dependent on angiotensin II and losartan-sensitive AT1 receptors during the development of genetic hypertension.