Tocolytic action and underlying mechanism of galetin 3,6-dimethyl ether on rat uterus

Dec 4, 2017BMC complementary and alternative medicine

How galetin 3,6-dimethyl ether may relax the rat uterus and its possible working process

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Abstract

FGAL demonstrates a greater potency in relaxing the rat uterus induced by oxytocin compared to KCl.

FGAL shifted oxytocin-induced contraction curves to the right, indicating a pseudo-irreversible noncompetitive antagonism of oxytocin receptors.
A rightward shift in CaCl-induced contraction curves suggests FGAL may inhibit calcium influx.
The relaxant effect of FGAL was diminished by a non-selective potassium channel blocker, implying its action involves potassium channels.
Additional inhibitors reduced FGAL's relaxant potency, highlighting the involvement of specific potassium channels.
Aminophylline did not alter the relaxant effect of FGAL, suggesting that cyclic nucleotide pathways are not affected.

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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 Ereduction, indicating a pseudo-irreversible noncompetitive antagonism of oxytocin receptors (OTR) or a downstream pathway target. Moreover, FGAL shifted CaCl-induced cumulative contraction curves to the right in a non-parallel manner in depolarizing medium, nominally without Ca, with Ereduction, suggesting the inhibition of Cainflux through Ca. The relaxant potency of FGAL was reduced by CsCl, a non-selective Kchannel 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, K, Kand highlighting BK. Aminophylline, a non-selective phosphodiesterase (PDE) blocker, did not affect the FGAL relaxant potency, excluding the modulation of cyclic nucleotide PDEs pathway by FGAL. max2max V Ca V ATP Ca2+ 2+ + +

CONCLUSION: Tocolytic effect of FGAL on rat uterus occurs by pseudo-irreversible noncompetitive antagonism of OTR and activation of Kchannels, primarily BK, leading to calcium influx reduction through Ca. + Ca V

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Tocolytic action and underlying mechanism of galetin 3,6-dimethyl ether on rat uterus

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