Modulatory Effect of 2‐(4‐Hydroxyphenyl)amino‐1,4‐naphthoquinone on Endothelial Vasodilation in Rat Aorta

Abstract

The vascular endothelium plays an essential role in the control of the blood flow. Pharmacological agents like quinone (menadione) at various doses modulate this process in a variety of ways. In this study, Q7, a 2-phenylamino-1,4-naphthoquinone derivative, significantly increased oxidative stress and induced vascular dysfunction at concentrations that were not cytotoxic to endothelial or vascular smooth muscle cells. Q7 reduced nitric oxide (NO) levels and endothelial vasodilation to acetylcholine in rat aorta. It also blunted the calcium release from intracellular stores by increasing the phenylephrine-induced vasoconstriction when CaCl2 was added to a calcium-free medium but did not affect the influx of calcium from extracellular space. Q7 increased the vasoconstriction to BaCl2 (10−3 M), an inward rectifying K+ channels blocker, and blocked the vasodilation to KCl (10−2 M) in aortic rings precontracted with BaCl2. This was recovered with sodium nitroprusside (10−8 M), a NO donor. In conclusion, Q7 induced vasoconstriction was through a modulation of cellular mechanisms involving calcium fluxes through K+ channels, and oxidative stress induced endothelium damage. These findings contribute to the characterization of new quinone derivatives with low cytotoxicity able to pharmacologically modulate vasodilation.

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

“…Nevertheless, sodium nitroprusside (SNP), a NO donor compound, caused a complete vasodilation even in the presence of 10 −5 M Q7. These data were recently published from our laboratory [ 19 ].…”

“…In fact, Q7 significantly increased lipid peroxidation (TBARS) and decreased the SOD-like activity in serum of rats. In previous studies, we demonstrated increased TBARS levels in rat aorta tissue [ 19 ] and in calf thymus DNA treated with Q7 [ 21 ]. These findings are in agreement with other reports showing that oral administration of high-dose ascorbate reduced the blood pressure and heart rate in dogs displaying ROS-induced myocardial damage [ 31 ].…”

“…For groups 2, 3, and 4, the doses of Q7 and ascorbate were selected according to previous experiments using ECG of the normotensive rats in our laboratory and antitumor activity in mice was also observed [ 21 ]. For in vitro studies, the concentration of Q7 and ascorbate was selected according to our vascular reactivity experiments in the rat aorta [ 19 ].…”

“…A7r5 cells were cultured in 35 mm culture dish according to the methodology described by Palacios et al [ 19 ]. The cells were washed with Krebs-Ringer bicarbonate buffer (KRB) containing (×10 −3 M) 4.2 KCl, 1.19 KH 2 PO 4 , 120 NaCl, 25 Na 2 HCO 3 , 1.2 MgSO 4 , 1.3 CaCl 2 , and 5 D-glucose (pH 7.4).…”

“…A previous study from our group showed that arylamino-naphthoquinone derivatives like Q7 (2-(4-hydroxyphenyl) amino-1,4-naphthoquinone) increased the formation of ROS and impaired the endothelial vasodilation in the rat aorta [ 19 ]. The objective of this investigation was to evaluate possible cardioprotective effects of ascorbate on the cardiotoxic response induced through chronic treatment with a naphthoquinone derivative Q7.…”