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      Nitric Oxide–Dependent Renal Vasodilatation Is Not Altered in Rat with rHuEpo–Induced Hypertension

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          Background: Recombinant human erythropoietin (rHuEpo) is the treatment of choice in anemia associated with end–stage renal disease. Its major side effect is hypertension, which occurs in 8–30% of uremic patients. The exact mechanism of rHuEpo–induced hypertension has not been fully elucidated, and several possibilities have been proposed, such as a direct vascular effect of the drug with a shift in the balance of constrictor and relaxing endothelial 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 designed to verify whether, in spite of enhanced activity of the renal NO system, rHuEpo may affect endothelium–dependent (acetylcholine–induced) and/or endothelium–independent (sodium nitroprusside–induced) vasorelaxation and to evaluate basal NO release by the infusion of N<sup>G</sup>–nitro–L–arginine methyl ester (L–NAME) in an isolated and perfused rat kidney model. Methods: To investigate 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. every other day for 2 weeks) by measuring stable NO metabolites (NO<sub>2</sub>+NO<sub>3</sub>) 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: Hematocrit, hemoglobin concentration and arterial blood pressure were significantly increased in the treated group as compared with the controls. Urinary excretion of NO<sub>2</sub>+NO<sub>3</sub> was significantly higher in treated than in the controls (438±66 vs. 294±36 nM/ml/min, p<0.01, respectively). There were no significant differences in the dose–response curves to Ach and SNP between the two groups. The renal vasoconstriction following the infusion of L–NAME was also similar in the two groups. Conclusions: The analysis of our results seems to indicate that the endogenous NO system activity was enhanced in rHuEpo–induced hypertension in rats with normal renal function and a resistance to NO was not developed in renal circulation. Further studies seem to be necessary to better clarify the exact mechanisms underlying the development of rHuEpo–induced hypertension.

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          Most cited references 2

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          Hypertension in mice lacking the gene for endothelial nitric oxide synthase.

          Nitric oxide (NO), a potent vasodilator produced by endothelial cells, is thought to be the endothelium-dependent relaxing factor (EDRF) which mediates vascular relaxation in response to acetylcholine, bradykinin and substance P in many vascular beds. NO has been implicated in the regulation of blood pressure and regional blood flow, and also affects vascular smooth-muscle proliferation and inhibits platelet aggregation and leukocyte adhesion. Abnormalities in endothelial production of NO occur in atherosclerosis, diabetes and hypertension. Pharmacological blockade of NO production with arginine analogues such as L-nitroarginine (L-NA) or L-N-arginine methyl ester affects multiple isoforms of nitric oxide synthase (NOS), and so cannot distinguish their physiological roles. To study the role of endothelial NOS (eNOS) in vascular function, we disrupted the gene encoding eNOS in mice. Endothelium-derived relaxing factor activity, as assayed by acetylcholine-induced relaxation, is absent, and the eNOS mutant mice are hypertensive. Thus eNOS mediates basal vasodilation. Responses to NOS blockade in the mutant mice suggest that non-endothelial isoforms of NOS may be involved in maintaining blood pressure.
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            • Abstract: not found
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            Direct vasopressor effects of erythropoietin in genetically hypertensive rats


              Author and article information

              Kidney Blood Press Res
              Kidney and Blood Pressure Research
              S. Karger AG
              25 June 1999
              : 22
              : 3
              : 140-145
              Departments of aInternal Medicine and bNeuroscience (Pharmacology Section), University of Pisa, and cNephrology and Dialysis Unit, Hospital of Massa, Italy
              25920 Kidney Blood Press Res 1999;22:140–145
              © 1999 S. Karger AG, Basel

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              Figures: 5, Tables: 1, References: 37, Pages: 6
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