Renal nitric oxide production is decreased in diabetic rats and improved by AT1 receptor blockade.
OBJECTIVE
Diabetes mellitus is associated with increased incidence of cardiovascular complications. Lack of nitric oxide production may exacerbate these complications. We hypothesized that diabetes decreases renal nitric oxide (NO) production, an effect that is reversed via inhibition of angiotensin subtype-1 receptor.


METHODS
We monitored changes in renal interstitial fluid nitric oxide by a microdialysis technique in the renal cortex of conscious Sprague-Dawley rats. Rats (n = 8 each group) were given streptozotocin 30 mg/kg intravenously to induce diabetes. Changes in renal interstitial fluid angiotensin II and NO were evaluated at baseline before and over 12 weeks during the development of diabetes and at 4 and 8 h after oral administration of the angiotensin subtype-1 (AT1) receptor blockers, losartan (30 mg/kg) or valsartan (10 mg/kg).


RESULTS
Renal interstitial fluid angiotensin II significantly increased after development of diabetes. In contrast, basal renal interstitial fluid nitric oxide decreased significantly over 12 weeks after development of diabetes. Both losartan and valsartan caused a further increase in renal angiotensin II levels. Some 4 h after administration, there was significantly greater increase in renal nitric oxide after administration of valsartan than of losartan. At 8 h post- treatment, only valsartan caused a significant increase in renal nitric oxide levels.


CONCLUSIONS
These results demonstrate that diabetes mellitus is associated with an increase in renal production of angiotensin II, while renal production of nitric oxide is reduced. The decrease in renal NO is reversed by AT1 receptor blockade.
Awad
Alaa S
AS
Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Webb
Randy L
RL
Carey
Robert M
RM
Siragy
Helmy M
HM
D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001786:Blood Glucose; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D009569:Nitric Oxide; D000068756:Valsartan; D014633:Valine; D019808:Losartan