title: Mechanisms underlying the relaxant effect of Galetin 3,6- dimethyl ether, from Piptadenia stipulacea (Benth.) Ducke, on guinea-pig trachea.
abstract: Galetin 3,6-dimethyl ether (FGAL), a flavonoid from the aerial parts of Piptadenia stipulacea (Benth.) Ducke, was found to exert a relaxant effect on carbachol (CCh)-pre-contracted guinea-pig trachea. Based on cumulative concentration-response curves to CCh, FGAL antagonized muscarinic receptors pseudo-irreversibly and noncompetitively, since it inhibited and shifted these curves towards higher concentrations in a nonparallel manner. In addition, FGAL was more potent in relaxing contractions induced by 18 mM as compared to 60 mM KCl (pD2 = 5:50 ±0:36 and 4.80 ±0.07, respectively), indicating the participation of K+ channels. In the presence of 10 mM tetraethylammonium (TEA+) chloride, a nonselective K+ channel blocker, the relaxant potency of FGAL was reduced (from pD2 = 5:12 ±0:07 to 4.87 ±0.02). Among several selective blockers of K+ channel subtypes, only apamin, an SKCa (small-conductance Ca2+-activated K+ channels) blocker, attenuated the relaxant potency of FGAL (pD2 = 4:85±0:06), suggesting SKCa activation. FGAL was equipotent in relaxing trachea contracted by 60 mM KCl (pD2 =4:80 ±0:07) or 10-6 M CCh (pD2 = 5:02 ±0:07), suggesting CaV (voltage-gated calcium channel), but not ROCs (receptor-operated calcium channels) participation. Furthermore, aminophylline-induced relaxation (pD2 = 4:12 ±0:06) was potentiated around 4-fold (pD2 = 4:80 ±0:44) in the presence of FGAL. Moreover, forskolininduced relaxation (pD2 = 6:51 ±0:06) was potentiated around 2.5-fold (pD2 = 6:90 ±0:05) by FGAL. Conversely, sodium nitroprusside-induced relaxation was unaffected, indicating that the AC/cAMP/PKA pathway, but not the NO pathway, may be modulated by the flavonoid. These results suggest that, in guinea-pig trachea, FGAL induces relaxation by pseudo-irreversible noncompetitive antagonism on muscarinic receptors, modulation of K+ and Ca2+ channels, as well as activation of the AC/cAMP/PKA pathway.
authors: Cibério Landim
authors: CL
authors: Macêdo
authors: Luiz Henrique César
authors: LH
authors: Vasconcelos
authors: Ana Carolina de Carvalho
authors: AC
authors: Correia
authors: Italo Rossi Roseno
authors: IR
authors: Martins
authors: Daysianne Pereira de
authors: DP
authors: Lira
authors: Bárbara Viviana de Oliveira
authors: BV
authors: Santos
authors: Bagnólia Araújo da
authors: BA
authors: Silva
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D007887:Fabaceae / Q000737:chemistry; D005419:Flavonoids / Q000008:administration & dosage* / Q000737:chemistry; D006168:Guinea Pigs; D009126:Muscle Relaxation / Q000187:drug effects*; D009465:Neuromuscular Agents / Q000008:administration & dosage* / Q000737:chemistry; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
chemical_list: D015220:Calcium Channels; D005419:Flavonoids; D009465:Neuromuscular Agents; D010936:Plant Extracts; C570563:galetin 3,6-dimethyl ether