| مستخلص: |
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. |
