Mechanism of the Vasodilator Effect of Mono-oxygenated Xanthones: A Structure-Activity Relationship Study

Abstract

The present study characterized the mechanisms involved in the vasodilator effect of two mono-oxygenated xanthones, 4-hydroxyxanthone and 4-methoxyxanthone. 9-Xanthenone, the base structure of xanthones, was used for comparison. 4-Hydroxyxanthone and 9-xanthenone induced a concentration-dependent and endothelium-independent vasodilator effect in arteries precontracted with phenylephrine (0.1 µmol · L⁻¹) or KCl (50 mmol · L⁻¹). 4-Methoxyxanthone induced a concentration-dependent vasodilator effect in arteries precontracted with phenylephrine, which was partially endothelium-dependent, and involved production of nitric oxide. In endothelium-denuded arteries precontracted with KCl, the vasodilator effect of 4-methoxyxanthone was abolished. The vasodilator effect of 4-hydroxyxanthone (96.22 ± 2.10 %) and 4-methoxyxanthone (96.57 ± 12.40 %) was significantly higher than observed with 9-xanthenone (53.63 ± 8.31 %). The presence of an oxygenated radical in position 4 made 4-hydroxyxanthone (pIC₅₀ = 4.45 ± 0.07) and 4-methoxyxanthone (pIC₅₀ = 5.04 ± 0.09) more potent as a vasodilator than 9-xanthenone (pIC₅₀ = 3.92 ± 0.16). In addition, 4-methoxyxanthone was more potent than the other two xanthones. Ca²⁺ transients in vascular smooth muscle cells elicited by high K⁺ were abolished by 4-hydroxyxanthone and 9-xanthenone. The endothelium-independent effect of 4-methoxyxanthone was abolished by inhibition of K⁺ channels by tetraethylammonium. The current work shows that an oxygenated group in position 4 is essential to achieve E_max and to increase the potency of xanthones as vasodilators. Substitution of an OH by OCH₃ in position 4 increases the potency of the vasodilator effect and changes the underling mechanism of action from the blockade of L-type calcium channels to an increase in NO production and activation of K⁺ channels.

Key words

xanthones - 4-hydroxyxanthone - 4-methoxyxanthone - vasodilation - Ca²⁺ channels - nitric oxide - K⁺ channels

• References

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