Macêdo Cibério L, Vasconcelos Luiz H C, de Correia Ana C C, Martins Italo R R, de Lira Daysianne P, de O Santos Bárbara V, de A Cavalcante Fabiana, Silva Bagnólia A da
Programa de Pós-graduação em Produtos Naturais e Sintéticos Bioativos, Centro de Ciências da Saúde, Universidade Federal da Paraíba, João Pessoa, PB 58051-900, Brazil.
Departamento de Farmácia, Faculdade Santa Maria (FSM), Cajazeiras, PB 58900-000, Brazil.
Molecules. 2014 Nov 27;19(12):19678-95. doi: 10.3390/molecules191219678.
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 contraction‑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 contraction-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.
在本研究中，我们研究了3,6 - 二甲基醚芹菜素（FGAL）对大鼠主动脉的舒张作用。该类黄酮可舒张由佛波醇酯（PMA）和去氧肾上腺素（Phe）诱导的收缩（pD2分别为5.36±0.11和4.17±0.10），提示蛋白激酶C（PKC）和去氧肾上腺素途径或α1肾上腺素能受体阻断参与其中。FGAL抑制并使去氧肾上腺素诱导的累积收缩 - 反应曲线右移，表明其对α1肾上腺素能受体具有非竞争性拮抗作用。该类黄酮舒张30 mM氯化钾诱导的收缩比80 mM氯化钾诱导的收缩更有效（pD2分别为5.50±0.22和4.37±0.12）。在存在10 mM四乙铵（TEA +）的情况下，FGAL对去氧肾上腺素诱导收缩的血管舒张效力降低。此外，在存在蜂毒明肽、格列本脲、氯化钡或4 - 氨基吡啶（4 - AP）的情况下，FGAL诱导的舒张作用减弱，分别表明小电导钙激活钾通道（SKCa）、ATP敏感性钾通道（KATP）、内向整流钾通道（Kir）和电压依赖性钾通道（KV）参与其中。FGAL在去极化介质（高钾）以及存在维拉帕米和去氧肾上腺素的情况下，均抑制并使氯化钙诱导的累积收缩 - 反应曲线右移，分别提示其抑制通过电压门控钙通道（CaV）和受体操纵通道（ROC）的钙离子内流。同样，FGAL在无钙介质中抑制去氧肾上腺素诱导的收缩，表明其抑制肌浆网（SR）释放钙离子。FGAL增强了氨茶碱和西地那非的舒张作用，但对米力农无此作用，提示磷酸二酯酶V（PDE V）参与其中。因此，FGAL的血管舒张机制涉及对α1肾上腺素能受体的非竞争性拮抗作用、钾通道的非选择性开放、抑制通过CaV或ROC的钙离子内流以及抑制细胞内钙离子释放。此外，还涉及环核苷酸途径，特别是通过抑制PDE V。
