Losartan-sensitive renal damage caused by chronic NOS inhibition does not involve increased renal angiotensin II concentrations

Background. Chronic nitric oxide synthase (NOS) inhibition results in hyper tension, proteinuria, and renal morphological changes. Continuous angiotens in II (Ang II) blockade prevents these effects, suggesting an essential rol e of Ang II, However, it is not known whether renal Ang II concentrations a re primarily increased or whether the scarcity of NO allows normal concentr ations of Ang II to cause these detrimental effects. Therefore, we measured renal Ang II concentrations before and during the development of renal dam age. Methods. Group 1 served as controls. Groups 2 through 5 received the NOS in hibitor N omega-nitro-L-arginine (L-NNA: 40 mg/kg/day) for 4, 7, 14, and 21 days, respectively. Systolic blood pressure (SBP), proteinuria. glomerular filtration rate (GFR). and renal and blood Ang II were measured. In a sepa rate experiment, rats were treated with L-NNA + the Ang II AT(1) receptor b locker losartan to determine the functional effects of endogenous Ang II du ring chronic NOS inhibition. Results. L-NNA treatment resulted in an increase in SEP from day 4 (161 +/- 4 vs. 135 +/- 4 mm Hg in control, P < 0.05) to day 21 (230 +/- 9 mm Hg). G FR was decreased from day 4 (1.9 +/- 0.2 vs. 2.5 +/- 0.2 ml/min in control, P < 0.05) to day 21 (1.2 +/- 0.2 ml/min). Proteinuria was increased from d ay 14 (85 +/- 14 vs. 6 +/- 1 mg/day in control, P < 0.05) to day 21 (226 +/ - 30 mg/day). L-NNA treatment during four days resulted in a significant de crease in renal Ang II (183 +/- 32 vs. 454 +/- 40 fmol/g in control, P < 0. 05). On day 7, 14, and 21, renal Ang II was not significantly different fro m the control. Blood Ang II was not significantly different from the contro l on days 4,7, and 14 but was significantly increased after 21 days of L-NN A treatment (215 +/- 35 vs. 78 +/- 13 fmol/ml in control, P < 0.05). Ang II type-1 (AT(1)) receptor blockade prevented the severe renal injury and hyp ertension induced by chronic NOS inhibition. Conclusions. Losartan-sensitive renal damage caused by chronic NOS inhibiti on does not involve increased renal Ang II concentrations. This suggests th at the detrimental effects of endogenous Ang II are increased during chroni c NOS inhibition. Thus, when NO levels are low, normal Ang II concentration s can cause renal injury and hypertension.