title: Mechanisms underlying vasorelaxation induced in rat aorta by galetin 3,6-dimethyl ether, a flavonoid from Piptadenia stipulacea (Benth.) Ducke.
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 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.
authors.affiliation: 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. ciberiolandim@hotmail.com.
authors.forename: Cibério L
authors.initials: CL
authors.lastname: Macêdo
authors.affiliation: 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. henrique.luiz89@ltf.ufpb.br.
authors.forename: Luiz H C
authors.initials: LH
authors.lastname: Vasconcelos
authors.affiliation: 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. anacarolinacc@yahoo.com.br.
authors.forename: Ana C C
authors.initials: AC
authors.lastname: de Correia
authors.affiliation: 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. italo_rossi_@hotmail.com.
authors.forename: Italo R R
authors.initials: IR
authors.lastname: Martins
authors.affiliation: Departamento de Farmácia, Faculdade Santa Maria (FSM), Cajazeiras, PB 58900-000, Brazil. daysianneplira@ltf.ufpb.br.
authors.forename: Daysianne P
authors.initials: DP
authors.lastname: de Lira
authors.affiliation: 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. barbara@ltf.ufpb.br.
authors.forename: Bárbara V
authors.initials: BV
authors.lastname: de O Santos
authors.affiliation: 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. fabianacavalcante@ltf.ufpb.br.
authors.forename: Fabiana
authors.initials: F
authors.lastname: de A Cavalcante
authors.affiliation: 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. barbara@ltf.ufpb.br.
authors.forename: Bagnólia A da
authors.initials: BA
authors.lastname: Silva
mesh_terms: D000628:Aminophylline / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology*; D002122:Calcium Chloride / Q000494:pharmacology; D007887:Fabaceae / Q000737:chemistry*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D020105:Milrinone / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D005419:Flavonoids; D010879:Piperazines; D026902:Potassium Channel Blockers; D011687:Purines; D013449:Sulfonamides; C570563:galetin 3,6-dimethyl ether; D010656:Phenylephrine; D000628:Aminophylline; D000068677:Sildenafil Citrate; D014700:Verapamil; D020105:Milrinone; D002122:Calcium Chloride