Mechanisms Underlying Vasorelaxation Induced in Rat Aorta by Galetin 3,6-Dimethyl Ether, a Flavonoid from Piptadenia stipulacea (Benth.) Ducke

In this study, we investigated the relaxant action of galetin 3,6-dimethyl ether (FGAL) on rat aorta. The flavonoid relaxed both PMA‑ and phenylephrine (Phe)-induced contractions (pD(2) = 5.36 ± 0.11 and 4.17 ± 0.10, respectively), suggesting the involvement of PKC and Phe pathways or α(1) adrenergic receptor blockade. FGAL inhibited and rightward shifted Phe-induced cumulative concentration‑response curves, indicating a noncompetitive antagonism of α(1) adrenergic receptors. The flavonoid was more potent in relaxing 30 mM KCl- than 80 mM KCl-induced contractions (pD(2) = 5.50 ± 0.22 and 4.37 ± 0.12). The vasorelaxant potency of FGAL on Phe-induced contraction was reduced in the presence of 10 mM TEA(+). Furthermore, in the presence of apamin, glibenclamide, BaCl(2) or 4-AP, FGAL-induced relaxation was attenuated, indicating the participation of small conductance calcium-activated K(+) channels (SK(Ca)), ATP-sensitive K(+) channels (K(ATP)), inward rectifier K(+) channels (K(ir)) and voltage-dependent K(+) channels (K(V)), respectively. FGAL inhibited and rightward shifted CaCl(2)-induced cumulative concentration-response curves in both depolarizing medium (high K(+)) and in the presence of verapamil and phenylephrine, suggesting inhibition of Ca(2+) influx through voltage-gated calcium channels (Ca(V)) and receptor operated channels (ROCs), respectively. Likewise, FGAL inhibited Phe-induced contractions in Ca(2+)-free medium, indicating inhibition of Ca(2+) release from the sarcoplasmic reticulum (SR). FGAL potentiated the relaxant effect of aminophylline and sildenafil but not milrinone, suggesting the involvement of phosphodiesterase V (PDE V). Thus, the FGAL vasorelaxant mechanism involves noncompetitive antagonism of α(1) adrenergic receptors, the non-selective opening of K(+) channels, inhibition of Ca(2+) influx through Ca(V) or ROCs and the inhibition of intracellular Ca(2+) release. Additionally, there is the involvement of cyclic nucleotide pathway, particularly through PDE V inhibition.