M. Migliori et al., Nitric oxide-dependent renal vasodilatation is not altered in rat with rHuEpo-induced hypertension, KIDNEY BL P, 22(3), 1999, pp. 140-145
Background: Recombinant human erythropoietin (rHuEpo) is the treatment of c
hoice in anemia associated with end-stage renal disease. Its major side eff
ect is hypertension, which occurs in 8-30% of uremic patients. The exact me
chanism of rHuEpo-induced hypertension has not been fully elucidated, and s
everal possibilities have been proposed, such as a direct vascular effect o
f the drug with a shift in the balance of constrictor and relaxing endothel
ial factors (endothelins and nitric oxide (NO)). Recent papers suggested an
enhanced rather than reduced activity of endogenous NO system in rats with
normal renal function and rHuEpo-induced hypertension. Our study was desig
ned to verify whether, in spite of enhanced activity of the renal NO system
, rHuEpo may affect endothelium-dependent (acetylcholine-induced) and/or en
dothelium-independent (sodium nitroprusside-induced) vasorelaxation and to
evaluate basal NO release by the infusion of N-G-nitro-L-arginine methyl es
ter (L-NAME) in an isolated and perfused rat kidney model. Methods: To inve
stigate this hypothesis, we have determined systemic and renal NO activity
in Wistar rats treated with a hypertensive dose of rHuEpo (150 IU/kg b.w. e
very other day for 2 weeks) by measuring stable NO metabolites (NO2+NO3) in
the urine and have also evaluated variations in renal vascular resistance
after the injection of Ach, SNP and the infusion of L-NAME. Results: Hemato
crit, hemoglobin concentration and arterial blood pressure were significant
ly increased in the treated group as compared with the controls. Urinary ex
cretion of NO2+NO3 was significantly higher in treated than in the controls
(438+/-66 vs. 294+/-36 nM/ml/min, p<0.01, respectively). There were no sig
nificant differences in the dose-response curves to Ach and SNP between the
two groups. The renal vasoconstriction following the infusion of L-NAME wa
s also similar in the two groups. Conclusions: The analysis of our results
seems to indicate that the endogenous NO system activity was enhanced in rH
uEpo-induced hypertension in rats with normal renal function and a resistan
ce to NO was not developed in renal circulation. Further studies seem to be
necessary to better clarify the exact mechanisms underlying the developmen
t of rHuEpo-induced hypertension.