Effect of tetrahydrobiopterin on blood pressure in rats after subtotal nephrectomy.
BACKGROUND
Previous studies have shown that endothelial dysfunction after 5/6 nephrectomy (5/6 Nx) in rats is associated with decreased nitric oxide (NO) bioavailability and increased vascular superoxide production. Blood pressure is significantly increased by day 10 after surgery. Tetrahydrobiopterin (BH4) is a key cofactor of NO synthase. Suboptimal levels of BH4 result in uncoupling of NO synthase, low NO synthesis and augmented production of superoxide anions. The aim of this study was to evaluate whether BH4 supplementation may improve NO production and prevent the increase of blood pressure after 5/6 Nx.


METHODS
Three groups were evaluated: 5/6 Nx (untreated rats), BH4 (5/6 Nx rats treated with BH4, 10 mg/day i.p. for 10 days) and L-ARG (5/6 Nx rats treated with L-arginine, 260 mg/kg BW, p.o for 10 days). Systolic blood pressure (SBP), urinary nitrate excretion (UNO(3)) and creatinine clearance (CCR) were measured before surgery and on days 3 and 10 after surgery. Endothelial NO synthase (eNOS) protein content of mesenteric resistance vessels was measured at the end of the study.


RESULTS
SBP increased from 107 +/- 2 to 127 +/- 4 mm Hg in untreated 5/6 Nx rats (p < 0.01). By contrast, rats treated with BH4 or L-ARG remained normotensive. Ten days after 5/6 Nx, creatinine clearance decreased similarly in all groups. Both BH4 and L-ARG supplementation markedly increased UNO(3) excretion. The mesenteric vascular expression of eNOs protein was significantly higher in BH4 but not in L-ARG, compared with Nx rats.


CONCLUSIONS
BH4 supplementation prevents the earlier increase in blood pressure observed in rats after 5/6 Nx, possibly by upregulating eNOS in resistance vessels.
Podjarny
Eduardo
E
Department of Nephrology and Hypertension, Meir Hospital, Sapir Medical Center, Kfar-Saba, and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
Benchetrit
Sidney
S
Rathaus
Mauro
M
Pomeranz
Avishalom
A
Rashid
Gloria
G
Shapira
Janice
J
Bernheim
Jacques
J
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D003404:Creatinine / Q000097:blood / Q000378:metabolism / Q000652:urine; D006973:Hypertension / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology / Q000601:surgery*; D008297:Male; D008638:Mesenteric Arteries / Q000201:enzymology; D009392:Nephrectomy; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency
D009566:Nitrates; D001708:Biopterins; D009569:Nitric Oxide; D001120:Arginine; D003404:Creatinine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C003402:sapropterin