AT1 Receptor Antagonist Combats Oxidative Stress in the JGA of the SHR
The tubuloglomerular feedback (TGF) responses of the SHR are under exaggerated regulation by angiotensin II (Ang II) type 1 receptors (AT1-R). Since AT1-R 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 (n=6-9) of SHR and control WKY rats received vehicle (Veh), the AT1-R antagonist candesartan (Cand; 3 mg·kg-1·d-1) or non-specific therapy with hydralazine + hydrochlorothiazide + reserpine (HHR) for two weeks. Compared to WKY, the elevated mean arterial pressure of SHR (WKY: 125±2 vs. SHR: 163±9 mmHg; p<0.001) was reduced (p<0.001) similarly in SHR by Cand and HHR (121±5 and 116±5 mmHg, 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 mmHg; p<0.01) and a reduced TGF response to blockade of neuronal (n) NOS in the MD with luminal 7-nitroindazole (7-NI: ΔTGF in WKY: +2.8±0.4 vs. SHR +1.1±0.6 mmHg; 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 (ΔTGF with 7-NI: +1.8±0.4 vs. Cand +3.4±0.5 mmHg; 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 (ΔTGF with 7-NI during tempol: Veh, +6.3±1.0 and HHR, +4.5±0.8 mmHg; 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 (ΔTGF with 7-NI during tempol: +2.9±0.9; ns compared to no tempol). In conclusion, TGF responses of SHR are exaggerated due to effects of hypertension and AT1-R. AT1-R blockade specifically diminishes oxidative stress and restores NO signaling in the JGA of the SHR.