Oxidation by trace Cu2+ ions underlies the ability of ascorbate to induce vascular dysfunction in the rat perfused mesentery

Nelli, S., Craig, J. and Martin, W. (2009) Oxidation by trace Cu2+ ions underlies the ability of ascorbate to induce vascular dysfunction in the rat perfused mesentery. European Journal of Pharmacology, 614(1-3), pp. 84-90. (doi: 10.1016/j.ejphar.2009.04.033)

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Publisher's URL: http://dx.doi.org/10.1016/j.ejphar.2009.04.033

Abstract

Ascorbate has both antioxidant and pro-oxidant activity. We have previously shown that plasma levels of ascorbate induce constriction and blockade of dilatation mediated by endothelium-derived hyperpolarizing factor (EDHF). In this study we sought to determine if these detrimental actions were mediated by a pro-oxidant action of ascorbate. Since trace levels of transition metal ions including, Cu<sup>2+</sup> and Fe<sup>3+</sup>, promote oxidation of ascorbate, we examined the effects of the chelating agents, cuprizone and deferoxamine, and of CuSO<sub>4</sub> and FeCl<sub>3</sub> on ascorbate-induced constriction and blockade of EDHF in the perfused rat mesentery. Cuprizone abolished and Cu<sup>2+</sup> but not Fe<sup>3+</sup> ions enhanced both ascorbate (50 μM)-induced constriction and blockade of EDHF. The blockade of EDHF produced by ascorbate in the presence of CuSO<sub>4</sub> (0.5 μM) was abolished by the hydrogen peroxide scavenger, catalase, but unaffected by the scavengers of hydroxyl radical or superoxide anion, mannitol and superoxide dismutase (SOD), respectively. Consistent with these observations, the oxidation of ascorbate by CuSO<sub>4</sub> led to the rapid production of hydrogen peroxide. Catalase, mannitol and SOD had no effect on ascorbate-induced constriction. Thus, in the rat perfused mesentery, both the constrictor and EDHF-blocking actions of ascorbate arise from its oxidation by trace Cu<sup>2+</sup> ions. The blockade of EDHF results from the consequent generation of hydrogen peroxide, but the factor producing constriction remains unidentified. These detrimental actions of ascorbate may help explain the disappointing outcome of clinical trials investigating dietary supplementation with the vitamin on cardiovascular health.

Item Type:Articles
Additional Information:Ascorbate, copper, EDHF, endothelium-derived hyperpolarizing factor, hydrogen peroxide, oxidant stress
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Craig, Mr John and Nelli, Mrs Silvia and Martin, Professor William
Authors: Nelli, S., Craig, J., and Martin, W.
Subjects:Q Science > QH Natural history > QH345 Biochemistry
College/School:College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:European Journal of Pharmacology
Journal Abbr.:Eur. J. Pharmacol.
ISSN:0014-2999
ISSN (Online):1879-0712

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