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The vasorelaxant profile of quercetin 3,7-dimethyl ether, a flavonoid isolated from Croton schiedeanus Schlecht (Euphorbiaceae), was assessed in aortic rings isolated from Wistar rats. To gain insight into its structure-activity relationship, we compared this substance with quercetin 3,4',7-trimethyl ether (ayanin), another flavonoid isolated from this plant, quercetin 3,3',4',7-tetramethyl ether, a flavonoid synthesized by us, and quercetin. In addition we examined the interaction of quercetin 3,7-dimethyl ether with the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. According to their pEC50 values (concentration producing a 50% inhibition of the maximal contractile response) to phenylephrine-induced precontraction in rat isolated aorta, the potency order was quercetin 3,7-dimethyl ether > quercetin > quercetin 3,4',7-trimethyl ether > quercetin 3,3',4',7-tetramethyl ether (4.70+/-0.18; 3.96+/-0.07; 3.64+/-0.02; 3.11+/-0.16). The relaxant effect of quercetin 3,7-dimethyl ether was significantly decreased by the removal of endothelium as well as by methylene blue, an inhibitor of guanylyl cyclase, and by N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME), an NO-synthase inhibitor. Therefore, quercetin 3,7-dimethyl ether has a NO/cGMP pathway-related profile, with increased vasorelaxant activity due to hydroxylation at positions 3 and 4 of the B ring. In addition, methylation at positions 3 and 7 with respect to quercetin of the C and A rings, respectively, seems to further enhance the vasorelaxant activity of quercetin 3,7-dimethyl ether.

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In this study we evaluated the anti-adrenergic response elicited by ayanin, a flavonoid compound isolated from Croton schiedeanus Schlecht, in the pithed rat, and the inhibitory effect of NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), and its acute toxicity profile in mice. In pithed rats ayanin (5 - 50 mg/kg i. v.) caused a dose-dependent decrease in the pressor and chronotropic responses induced by intravenous noradrenaline administration (0.25 microg/kg). This anti-adrenergic response was completely abolished by prior treatment with L-NAME (10 mg/kg i.v ) and the inhibitory effect of L-NAME was reversed after intravenous administration of L-arginine (100 mg/kg, i. v.). No lethal or major toxic effects were observed in mice receiving i. p. administration of ayanin up to a dose of 500 mg/kg. Our findings confirm that ayanin exerts protective cardiovascular effects against the increase in blood pressure and heart rate mainly through a mechanism that depends on the NO/cyclic guanosine monophosphate (cGMP) pathway without acute toxic effects. These results suggest that extracts of Croton schiedeanus, the native south American plant from which ayanin was isolated, might be beneficial in cardiovascular disease.

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