Ascorbate Attenuates Oxidative Stress and Increased Blood Pressure Induced by 2-(4-Hydroxyphenyl) Amino-1,4-naphthoquinone in Rats.

Javier Palacios,Chukwuemeka R Nwokocha,José Luis Vega,José Miguel Fonseca,Fernando Ayavire,Iván Barría,Ewaldo Zavala,Mirko Ortiz,Julio Benites,Felipe Salas,Juan Marcelo Sandoval,Fredi Cifuentes,Adrián Paredes

doi:10.1155/2018/8989676

Abstract

Quinone derivatives like 2-(4-hydroxyphenyl) amino-1,4-naphthoquinone (Q7) are used as antitumor agents usually associated with adverse effects on the cardiovascular system. The objective of this study was to evaluate the cardioprotective effect of ascorbate on Q7-induced cardiovascular response in Wistar rats. In this study, blood pressure, vascular reactivity, and intracellular calcium fluxes were evaluated in cardiomyocytes and the rat aorta. We also measured oxidative stress through lipid peroxidation (TBARS), superoxide dismutase- (SOD-) like activity, and H2O2 generation. Oral treatment of rats with ascorbate (500 mg/kg) for 20 days significantly (p < 0.05) reduced the Q7-induced increase (10 mg/kg) in blood pressure and heart rate. The preincubation with ascorbate (2 mM) significantly (p < 0.05) attenuated the irregular beating of the atrium induced by Q7 (10−5 M). In addition, ascorbate induced endothelial vasodilation in the presence of Q7 in the intact aortic rings of a rat and reduced the cytosolic calcium levels in vascular smooth muscle cells. Ascorbate also reduced the Q7-induced oxidative stress in vivo. Ascorbate also attenuated Q7-induced SOD-like activity and increased TBARS levels. These results suggest a cardioprotective effect in vivo of ascorbate in animals treated orally with a naphthoquinone derivative by a mechanism involving oxidative stress.

Highlights

Naphthoquinone derivatives are widely distributed molecules in nature
We found that oral treatment with ascorbate at physiological concentrations reduced the Q7-induced blood pressure in rats
This decrease in blood pressure was as a result of decreased HR and improved endothelial vasodilation in the intact aortic rings of the rat

Summary

Introduction

Naphthoquinone derivatives are widely distributed molecules in nature. Numerous antitumor therapeutic drugs are quinone-bearing molecules; these include anthracyclines, the 1,4-naphthoquinone pharmacophore group, and several synthetic compounds [1,2,3,4]. The therapeutic spectrum of action of quinone derivatives is very wide: leukemia, breast and lung cancer, lymphomas, and others [5]. Treatment of cancer with anthracycline derivatives has been very successful. These treatments generate increased cardiotoxic effects such as hypertension, heart failure, vascular complications, and cardiac arrhythmia [6]. Cytotoxic and cardiotoxic effects of naphthoquinone derivatives involve the generation of reactive oxygen species (ROS) by a redox-cycling reaction [8,9,10,11].

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