Mecanismos da atividade vasodilatadora de xantonas

Abstract

Xanthones are low molecular weight polyphenols commonly found in plants used in folk medicine for the treatment of cardiovascular disorders. Pharmacological effect and potency depends directly of radicals associated its basic skeleton. Previous studies in the literature reported activities of xanthones on the cardiovascular system. However, these studies not showed the mechanisms involved on xanthones effects. The aims of this work were study the mechanism involved on xanthones-inducedvasodilation in mouse aortic rings and correlates small structural differences to activation of different pathways of transduction signals. The 9-xanthenone promoted vasodilator response that does not depend on the presence of functional endothelium (Emax 46.3 ± 2.95 % and pEC50 = 0.01 ± 5.013). The mechanism of vasodilator effect of 9-xanthenone involved the blocking of voltage-dependent Ca2+ channels. The addition of an hydroxyl group in the four position of xanthonic skeleton (4-OHxanthone) produced an increase in Emax (102.5 ± 11.37 %) but not changed pEC50 (4.805 ± 0.06). The addition of OH group in position 4 did not change the mechanism of action of this xanthone. The substitution of the hydroxyl by a methoxyl (OMe) in position 4 (4-OMe-xanthone) did not change the Emax (95.3 ± 3.29 %) and pEC50 (5.159 ± 0.058), in comparation to 4-OH-xanthone but changed the mechanism involved on vasodilator effect of this xanthone. The effect of 4-OMe-xanthone has partly dependent on the endothelium via increased production of nitric oxide (NO). Part of this vasodilator effect was independent of the endothelium by direct activation of smooth muscle cells K+ . The reduction of xanthonic skeleton by a convertion of ketone into hydroxyl produced the xanthydrol. Xanthydrol induced a concentrationdependent vasodilation by two different mechanisms: dependent and independent of vascular endothelium. Xanthydrol produced activation of eNOS and nNOS, with consequent increased production of NO and H2O2. Part of the vasodilator response that is independent of endothelium is mediated by blockade of calcium channels voltage-dependent. In conclusion, our study shows that the xanthones studied in this work, have vasodilator activity. Minor changes in the structure of xanthones are able to change the Emax, as well as the mechanisms involved in the vasodilator response.