Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, D.C., USA

Correspondence: Christopher S. Wilcox, M.D., Ph.D., Division of Nephrology and Hypertension, Georgetown University Medical Center, 3800 Reservoir Road, NW, PHC-F6003, Washington, D.C. 20007, USA. E-mail: wilcoxch@gunet.georgetown.edu

Received 23 December 1999; Revised 6 September 2000; Accepted 10 October 2000.

Abstract

AT₁ receptor antagonist combats oxidative stress and restores nitric oxide signaling in the SHR. The tubuloglomerular feedback (TGF) responses of the spontaneously hypertensive rat (SHR) are under exaggerated regulation by angiotensin II (Ang II) type 1 receptors (AT₁-R). Since AT₁-Rs enhance oxygen radical (O₂^-) generation, we tested the hypothesis that the exaggerated TGF was due to a diminished blunting by macula densa (MD)-derived nitric oxide (NO) because of excessive AT₁-R–dependent generation of O₂^-. Groups of SHR and control Wistar-Kyoto (WKY) rats received vehicle (Veh), the AT₁-R antagonist candesartan (Cand; 3 mg kg^-1 day^-1), or nonspecific therapy with hydralazine + hydrochlorothiazide + reserpine (HHR) for two weeks. Compared with WKY rats, the elevated mean arterial pressure of SHR (WKY 125 2 vs. SHR 163 to 779 mm Hg, P < 0.001) was reduced (P < 0.001) similarly in SHR by Cand and HHR (121 5 and 116 5 mm Hg, P = NS). The SHR had an increased maximal TGF response (change in stop flow pressure during luminal perfusion of fluid: SHR 11.2 0.5 vs. WKY 8.3 0.4 mm Hg, P < 0.01) and a reduced TGF response to blockade of neuroneal NO synthase (nNOS) in the MD with luminal 7-nitroindazole (7-NI: TGF in WKY 2.8 0.4 vs. SHR 1.1 0.6 mm Hg, P < 0.05). Although the elevated TGF responses of SHR were normalized by both HHR and Cand, only Cand restored a normal TGF response to luminal perfusion of the MD with 7-NI (TGF with 7-NI in SHR: Veh + 1.8 0.4 vs. Cand + 3.4 0.5 mm Hg, P < 0.05). To abrogate the local effects of O₂^-, tempol (a membrane-permeable superoxide dismutase mimetic) was perfused into the efferent arteriole. During tempol, SHR given vehicle or HHR had a much increased response to blockade of nNOS with 7-NI (TGF in SHR with 7-NI during tempol: Veh 6.3 1.0 and HHR 4.5 0.8 mm Hg, P < 0.01 vs. no tempol for both), implying that the effects of NO had been prevented because of excessive O₂^-. In contrast, the TGF response to 7-NI in SHR given Cand was unaffected by tempol (TGF with 7-NI during tempol: 2.9 0.9, P = NS, compared with no tempol). In conclusion, TGF responses of SHR are exaggerated because of the effects of hypertension and AT₁-R. AT₁-R blockade specifically diminishes oxidative stress and restores NO signaling in the juxtaglomerular apparatus of the SHR.