Abstract
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 (pD2 = 5.36 ± 0.11 and 4.17 ± 0.10, respectively), suggesting the involvement of PKC and Phe pathways or α1 adrenergic receptor blockade. FGAL inhibited and rightward shifted Phe-induced cumulative concentration‑response curves, indicating a noncompetitive antagonism of α1 adrenergic receptors. The flavonoid was more potent in relaxing 30 mM KCl- than 80 mM KCl-induced contractions (pD2 = 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, BaCl2 or 4-AP, FGAL-induced relaxation was attenuated, indicating the participation of small conductance calcium-activated K+ channels (SKCa), ATP-sensitive K+ channels (KATP), inward rectifier K+ channels (Kir) and voltage-dependent K+ channels (KV), respectively. FGAL inhibited and rightward shifted CaCl2-induced cumulative concentration-response curves in both depolarizing medium (high K+) and in the presence of verapamil and phenylephrine, suggesting inhibition of Ca2+ influx through voltage-gated calcium channels (CaV) and receptor operated channels (ROCs), respectively. Likewise, FGAL inhibited Phe-induced contractions in Ca2+-free medium, indicating inhibition of Ca2+ 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 α1 adrenergic receptors, the non-selective opening of K+ channels, inhibition of Ca2+ influx through CaV or ROCs and the inhibition of intracellular Ca2+ release. Additionally, there is the involvement of cyclic nucleotide pathway, particularly through PDE V inhibition.
Highlights
Flavonoids are a large class of polyphenolic substances found in plants [1] known for their interesting activities in vascular diseases [2,3,4]
The endothelium plays an important role in regulating vascular smooth muscle tone by releasing endothelium-derived relaxing factors (EDRF) [11], including endothelium-derived hyperpolarizing factor (EDHF), nitric oxide (NO), prostacyclins and epoxyeicosatrienoic acids [12]
It was previously demonstrated that the vasorelaxation induced by FGAL is independent of endothelium-derived relaxant factors (EDRF), since it relaxed aorta in both the absence and presence of endothelium in an equipotent manner [10]
Summary
Flavonoids are a large class of polyphenolic substances found in plants [1] known for their interesting activities in vascular diseases [2,3,4]. Galetin 3,6-dimethyl ether (FGAL) (Figure 1), a flavonoid isolated from the plant Piptadenia stipulacea (Benth.) Ducke, has exhibited some pharmacological activities, such as antiviral [9], antinociceptive and anti-inflammatory activities in mice [2], as well as non-selective spasmolytic activity in smooth muscles (e.g., guinea-pig ileum and trachea and rat uterus and aorta). This flavonoid has shown the highest relaxant potency in rat aorta, and this effect is independent of endothelium-derived relaxant factors (EDRF) [10]. The aim of this work was to characterize the mechanisms involved in vasorelaxation induced by the flavonoid FGAL in rat aorta
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