Flavonoid galetin 3,6-dimethyl ether attenuates guinea pig ileum contraction through K + channel activation and decrease in cytosolic calcium concentration

Abstract

Flavonoid galetin 3,6-dimethyl ether (FGAL) has been isolated from the aerial parts of Piptadenia stipulaceae and has shown a spasmolytic effect in guinea pig ileum. Thus, we aimed to characterize its relaxant mechanism of action. FGAL exhibited a higher relaxant effect on ileum pre-contracted by histamine (EC50=1.9±0.4×10(-7) M) than by KCl (EC50=2.6±0.5×10(-6) M) or carbachol (EC50=1.8±0.4×10(-6) M). The flavonoid inhibited the cumulative contractions to histamine, as well as to CaCl2 in depolarizing medium nominally Ca(2+)-free. The flavonoid relaxed the ileum pre-contracted by S-(-)-Bay K8644 (EC50=9.5±1.9×10(-6) M) but less potently pre-contracted by KCl or histamine. CsCl attenuated the relaxant effect of FGAL (EC50=1.1±0.3×10(-6) M), but apamin or tetraethylammonium (1mM) had no effect (EC50=2.6±0.2×10(-7) and 1.6±0.3×10(-7) M, respectively), ruling out the involvement of small and big conductance Ca(2+)-activated K(+) channels (SKCa and BKCa, respectively). Either 4-aminopyridine or glibenclamide attenuated the relaxant effect of FGAL (EC50=1.8±0.2×10(-6) and 1.5±0.5×10(-6) M, respectively), indicating the involvement of voltage- and ATP-sensitive K(+) channels (KV and KATP, respectively). FGAL did not alter the viability of intestinal myocytes in the MTT assay and decreased (88%) Fluo-4 fluorescence, indicating a decrease in cytosolic Ca(2+) concentration. Therefore, the relaxant mechanism of FGAL involves pseudo-irreversible noncompetitive antagonism of histaminergic receptors, KV and KATP activation and blockade of CaV1, thus leading to a reduction in cytosolic Ca(2+) levels.

Quercetin relaxes human gastric smooth muscles directly through ATP‐sensitive potassium channels and not depending on the nitric oxide pathway

“…We found that quercetin concentration dependently reduced the carbachol‐induced contractions and the resting tension in all concentrations used in the isolated human gastric smooth muscle. This observation is consistent with those reported for the effects of flavonoids on GI smooth muscles of rats and guinea pigs 9,10,36,39,40 …”

“…This observation is consistent with those reported for the effects of flavonoids on GI smooth muscles of rats and guinea pigs. 9,10,36,39,40 Modulation of NO metabolism is one of the possible mechanisms that may contribute to the explanation of polyphenol activity observed in vivo. In the stomach, polyphenols in the diet may not only promote the reduction of nitrites toward NO, but also deal with a complex network of chemical reactions to produce NO with its signaling functions.…”

“…This observation is consistent with those reported for the effects of flavonoids on GI smooth muscles of rats and guinea pigs. 9 , 10 , 36 , 39 , 40 …”

Relaxant effects of Azadirachta indica A. Juss var. siamensis Valeton flower extract on isolated rat ileum contractions and the mechanisms of action

“… 24 Furthermore, the flavonoid known as galetin 3,6-dimethyl ether has shown to decrease guinea pig ileum contraction through K + channel activation and decrease in cytosolic calcium concentration. 25 Therefore, the relaxant effect demonstrated by SNF might possibly due to the presence of these bioactive compounds in the extract.…”

Study of Antispasmodic and Antidiarrheal Activities of Tagetes lucida (Mexican Tarragon) in Experimental Models and Its Mechanism of Action

“…It is known that contractions induced by high concentrations of KCl are due to an increase in intracellular calcium by opening of L-type Ca 2+ voltage-dependent channels, which leads to the activation of the myosin light chain on the smooth muscle [30,31]. Meanwhile, ACh induces contraction by activation of muscarinic receptors (M 3 ) on the membrane of smooth muscle and the activation of phospholipase C. is generates inositol triphosphate (IP 3 ) that stimulates calcium release from the sarcoplasmic reticulum and induces an increase in the cytosolic levels of calcium [32].…”