Abstract
BACKGROUND: Galetin 3,6-dimethyl ether (FGAL) is a flavonoid isolated from aerial parts of Piptadenia stipulacea. Previously, FGAL was shown to inhibit both carbachol- and oxytocin-induced phasic contractions in the rat uterus, which was more potent with oxytocin. Thus, in this study, we aimed to investigate the tocolytic action mechanism of FGAL on the rat uterus. METHODS: Segments of rat uterus ileum were suspended in organ bath containing modified Locke-Ringer solution at 32 °C, bubbled with carbogen mixture under a resting tension of 1 g. Isotonic contractions were registered using kymographs and isometric contractions using force transducer. RESULTS: FGAL was more potent in relaxing uterus pre-contracted with oxytocin than with KCl. Additionally, FGAL shifted oxytocin-induced cumulative contractions curves to the right in a non-parallel manner, with E(max) reduction, indicating a pseudo-irreversible noncompetitive antagonism of oxytocin receptors (OTR) or a downstream pathway target. Moreover, FGAL shifted CaCl(2)-induced cumulative contraction curves to the right in a non-parallel manner in depolarizing medium, nominally without Ca(2+), with E(max) reduction, suggesting the inhibition of Ca(2+) influx through Ca(V). The relaxant potency of FGAL was reduced by CsCl, a non-selective K(+) channel blocker, suggesting positive modulation of these channels. Furthermore, in presence of apamin, 4-aminopyridine, glibenclamide or 1 mM TEA(+), the relaxant potency of FGAL was attenuated, indicating the participation of SK(Ca), K(V), K(ATP) and highlighting BK(Ca). Aminophylline, a non-selective phosphodiesterase (PDE) blocker, did not affect the FGAL relaxant potency, excluding the modulation of cyclic nucleotide PDEs pathway by FGAL. CONCLUSION: Tocolytic effect of FGAL on rat uterus occurs by pseudo-irreversible noncompetitive antagonism of OTR and activation of K(+) channels, primarily BK(Ca), leading to calcium influx reduction through Ca(V).