Persistent hypertension and progressive renal injury induced by salt overload after short term nitric oxide inhibition.
BACKGROUND
Administration of the NO inhibitor N(wdelta)-nitro-L-arginine methyl ester (NAME) and a high-salt diet (HS) promotes severe albuminuria and renal injury, which regresses upon discontinuation of treatments.


OBJECTIVE
We investigated whether these changes reappear after reinstitution of HS, and whether they are prevented by treatment with the antilymphocyte agent mycophenolate mofetil (MMF) or the AT-1 receptor blocker losartan (L). Adult male Munich-Wistar rats received NAME and HS. A control Group (C) received only HS. After 20 days, rats receiving HS and NAME exhibited severe hypertension and albuminuria. After a 30-day recovery period, hypertension was attenuated and albuminuria had virtually disappeared.


METHODS
Rats were then distributed among the following groups: HS, receiving HS; NS, receiving a normal salt (NS) diet; HS-MMF, receiving HS and MMF; HS-LOS, receiving HS and L; HS-HDZ, receiving HS and hydralazine (HDZ). Sixty days later, NS rats showed only slight albuminuria and renal damage or inflammation. In contrast, HS rats developed severe hypertension, marked glomerulosclerosis with interstitial expansion and renal infiltration by macrophages and angiotensin II-positive cells. The group treated with losartan had lowered blood pressure and a lack of albuminuria or renal injury. MMF provided similar protection without altering blood pressure, suggesting a nonhemodynamic effect, a hypothesis reinforced by the finding that HDZ lowered blood pressure without preventing renal injury.


RESULTS
These results indicate that treatment with HS and NAME predisposes to the development of hypertension and renal injury upon salt overload, characterizing a new model of chronic nephropathy.


CONCLUSIONS
The response to MMF or L, but not HDZ, suggests a key role for inflammatory rather than hemodynamic factors.
Mattar
Ana Lúcia
AL
Renal Division, Department of Clinical Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
Machado
Flávia Gomes
FG
Fujihara
Clarice Kazue
CK
Malheiros
Denise Maria Avancini Costa
DM
Zatz
Roberto
R
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006830:Hydralazine / Q000627:therapeutic use; D006973:Hypertension / Q000139:chemically induced* / Q000517:prevention & control; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D017673:Sodium Chloride, Dietary / Q000633:toxicity*
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D007166:Immunosuppressive Agents; D017673:Sodium Chloride, Dietary; D006830:Hydralazine; D009569:Nitric Oxide; D009173:Mycophenolic Acid; D019808:Losartan