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Losartan-sensitive renal damage caused by chronic NOS inhibition does not involve increased renal angiotensin II
A M Verhagen1, B Braam, P Boer
1Department of Nephrology, University Hospital Utrecht, The Netherlands.
Background:
Chronic nitric oxide synthase (NOS) inhibition results in hypertension, proteinuria, and renal morphological changes. Continuous angiotensin II (Ang II) blockade prevents these effects, suggesting an essential role of Ang II. However, it is not known whether renal Ang II concentrations are primarily increased or whether the scarcity of NO allows normal concentrations of Ang II to cause these detrimental effects. Therefore, we measured renal Ang II concentrations before and during the development of renal damage.
Methods:
Group 1 served as controls. Groups 2 through 5 received the NOS inhibitor Nomega-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 separate experiment, rats were treated with L-NNA + the Ang II AT1 receptor blocker losartan to determine the functional effects of endogenous Ang II during chronic NOS inhibition.
Results:
L-NNA treatment resulted in an increase in SBP from day 4 (161 +/- 4 vs. 135 +/- 4 mm Hg in control, P < 0.05) to day 21 (230 +/- 9 mm Hg). GFR 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 day 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 decrease 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 from the control. Blood Ang II was not significantly different from the control on days 4, 7, and 14 but was significantly increased after 21 days of L-NNA treatment (215 +/- 35 vs. 78 +/- 13 fmol/ml in control, P < 0.05). Ang II type-1 (AT1) receptor blockade prevented the severe renal injury and hypertension induced by chronic NOS inhibition.
Conclusions:
Losartan-sensitive renal damage caused by chronic NOS inhibition does not involve increased renal Ang II concentrations. This suggests that the detrimental effects of endogenous Ang II are increased during chronic NOS inhibition. Thus, when NO levels are low, normal Ang II concentrations can cause renal injury and hypertension.
Insights
Chronic nitric oxide synthase (NOS) inhibition causes hypertension and kidney damage, but not by increasing renal angiotensin II (Ang II) levels. This suggests that reduced nitric oxide potentiates the harmful effects of normal Ang II concentrations.
Area of Science:
- Nephrology
- Cardiovascular Physiology
- Pharmacology
Background:
- Chronic inhibition of nitric oxide synthase (NOS) leads to hypertension and renal damage.
- Angiotensin II (Ang II) blockade prevents these effects, highlighting its crucial role.
- The precise mechanism by which NOS inhibition causes renal damage, specifically whether it involves increased renal Ang II, remains unclear.
Purpose of the Study:
- To investigate whether chronic NOS inhibition increases renal Ang II concentrations.
- To determine the role of renal Ang II in the development of hypertension and renal damage during NOS inhibition.
Main Methods:
- Rats were treated with the NOS inhibitor Nomega-nitro-L-arginine (L-NNA) for up to 21 days.
- Systolic blood pressure, glomerular filtration rate (GFR), proteinuria, and renal and blood Ang II levels were measured.
- The effect of Ang II AT1 receptor blockade (losartan) during NOS inhibition was assessed.
Main Results:
- L-NNA treatment induced significant hypertension, decreased GFR, and increased proteinuria.
- Renal Ang II concentrations were significantly decreased during the initial phase of L-NNA treatment and not significantly different from controls later.
- Blood Ang II levels were only significantly increased after 21 days of L-NNA treatment.
- Losartan administration prevented the hypertension and renal injury caused by chronic NOS inhibition.
Conclusions:
- Renal damage and hypertension resulting from chronic NOS inhibition are mediated by Ang II but do not involve increased renal Ang II concentrations.
- These findings suggest that reduced nitric oxide bioavailability enhances the detrimental effects of normal Ang II levels.
- Under conditions of low nitric oxide, physiological concentrations of Ang II can precipitate renal injury and hypertension.