Role of erythropoietin and nitric oxide in modulating the tone of human renal interlobular and subcutaneous arteries from uraemic subjects

Abstract

This study investigated potential reasons why erythropoietin (EPO) given therapeutically to patients with renal failure may increase peripheral, but not renal, vascular resistance. This was done by comparing the effects of EPO on resting tension in normal renal interlobular and subcutaneous vessels from uraemic patients. In human subcutaneous arteries from uraemic subjects, noradrenaline- and KCl-induced vasoconstrictions were enhanced when nitric oxide (NO) production was blocked with N(G)-nitro-L-arginine methyl ester (L-NAME), but were unaffected by EPO, while acetylcholine- and bradykinin-induced concentration-dependent relaxations were markedly attenuated by L-NAME, but not by EPO. The noradrenaline- and KCl-induced vasoconstrictions of human renal interlobular arteries were unaffected by the presence of L-NAME, but were attenuated by EPO (20 units.ml(-1)) by some 33% (P<0.01); this effect was enhanced by the co-administration of L-NAME. Acetylcholine and bradykinin caused comparable dilatations of the interlobular arteries; the response to the former was attenuated by L-NAME, but none of these responses were changed by EPO. EPO given alone, at a concentration of either 0.1 or 20 units.ml(-1), had no effect on basal resting tone. NO production mediated both acetylcholine- and bradykinin-induced relaxation in this vessel type. In contrast, in the interlobular arteries there was no indication of NO modulating the level of vasoconstriction, and it only mediated acetylcholine-induced dilation. These acute responses to EPO only partially explain its differential effects on the vasculature in renal failure.

The Influence of Erythropoietin on the Vascular Responses of Rat Resistance Arteries

“…Therefore, the fact that EPO attenuated the acetylcholine-induced relaxation but not that of bradykinin suggested that nitric oxide synthase (NOS) was only partly responsible and that some other mechanism was also involved. However this view is not supported by the results obtained from other vascular beds, such as human subcutaneous arteries (Wu et al 1999) or the renal arcuate arteries used in the present study in which neither dose of EPO affected acetylcholine-or bradykinin-induced relaxations. Indeed, it was evident that the renal arcuate arteries were relatively resistant to relaxation induced by acetylcholine and bradykinin even though sodium nitroprusside was a potent vasodilator.…”

Pattern of prepro-endothelin-1 expression revealed by reporter-gene activity in kidneys of erythropoietin-overexpressing mice

“…Replacement therapy with recombinant human Epo increases blood pressure in anaemic patients with chronic renal insufficiency [2]. Besides other mechanisms [3], blood pressure is thought to be increased by the release of endothelium-derived vasoconstrictors by Epo receptors on the surface of vascular endothelial cells [4]. These cells seem to be capable of releasing endothelin-1 (ET-1) under stimulation with Epo [5].…”