Effect of chronic tetrahydrobiopterin supplementation on blood pressure and proteinuria in 5/6 nephrectomized rats.
BACKGROUND
Tetrahydrobiopterin (BH4) is a key cofactor of nitric oxide (NO) synthase. Reduced BH4 levels may mediate endothelial NO synthase uncoupling, resulting in reduced NO synthesis and enhanced oxidative stress. In rats after 5/6 nephrectomy (Nx), administration of BH4 prevents the onset of hypertension, typically observed 10 days after Nx. This effect is associated with an increased synthesis of NO. The aim of the present study was to evaluate the effect of chronic BH4 therapy on blood pressure and renal morphology.


METHODS
During an 8 week period, five groups of rats were studied: untreated 5/6 Nx rats, BH4-treated Nx rats (BH4, 10 mg/kg body weight/day administered intraperitoneally), l-arginine treated Nx rats (LA, 130 mg/kg/day), diltiazem-treated Nx rats (DILT, 30 mg/kg/day) and sham-operated rats. Treatments were commenced 24 h after surgery. Systolic blood pressure values (SBP), 24 h proteinuria (UP) and creatinine clearance rate (CCR) were assessed before and at weeks 4 and 8 of the study period. Histological changes in the kidney were evaluated at the end of the study (week 8).


RESULTS
Compared with baseline, in Nx rats both SBP and UP increased significantly (112+/-1 to 136+/- 1.4 mmHg, P<0.01 and 23+/-2 to 127 +/- 26 mg/day, P<0.01, respectively). Treatment with BH4 normalized SBP values as did treatment with LA and DILT (109+/-3, 115+/-2 and 114+/-2 mmHg, respectively). UP was markedly reduced by BH4, the reduction being similar to that obtained by LA and significantly more marked than that of DILT rats (20+/-2, 28+/-3 and 62+/- 14 mg/day, respectively). CCR was equally decreased in all Nx groups. Histological evaluation showed the development of mesangial expansion in Nx rats, an effect that was significantly blunted by all treatments.


CONCLUSIONS
In rats after 5/6 nephrectomy, BH4 supplementation initiated 24 h after surgery and maintained for 8 weeks preserved SBP, reduced UP and prevented the development of glomerular mesangial expansion.
Podjarny
Eduardo
E
Department of Nephrology and Hypertension, Meir Hospital, Kfar Saba 44281, Israel. podjarny@post.tau.ac.il
Hasdan
Galit
G
Bernheim
Joelle
J
Rashid
Gloria
G
Green
Janice
J
Korzets
Zeev
Z
Bernheim
Jacques
J
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001120:Arginine / Q000494:pharmacology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004110:Diltiazem / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000187:drug effects / Q000503:physiopathology; D006973:Hypertension / Q000188:drug therapy; D007676:Kidney Failure, Chronic / Q000188:drug therapy*; D008297:Male; D023421:Models, Animal; D009392:Nephrectomy; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011507:Proteinuria / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D000975:Antioxidants; D014665:Vasodilator Agents; D001708:Biopterins; D009569:Nitric Oxide; D001120:Arginine; D004110:Diltiazem; C003402:sapropterin