Mo2102 Gastric Emptying Rate and CCK and GLP-1 Release After a Solid Test Meal Are Dependent on Body Mass Index

Abstract

G A A b st ra ct s both transcriptional levels through stimulating its classical nuclear receptors: ER α and ERβ. On the other hand, a G protein coupled receptor, GPR30 responds to estrogen with rapid signaling. Whether estrogen has a direct physiologic role in the exacerbation of GI symptoms by altering GI motility or visceral sensation has not been sufficiently explored. We designed this study to see if: a) estrogen alters GI motility and pain sensation and b) its effects are mediated by GPR30. Methods: CD1 female mice (4-5 weeks old) were used in this study. The effects of cumulative concentrations (100 nM-3μM) of β-Estradiol and a potent and selective GPR30 agonist, G-1 on the contractility of the longitudinal colonic preparations induced by electrical field stimulation (EFS; 4Hz, 10Sec, 24V, 50Sec intervals) or, at the highest concentration (3μM), on the muscarinic agonist bethanechol (10μM) induced contractions were studied in vitro. Colonic propulsion of a glass bead after administration of β-Estradiol or G-1 was studied in vivo. The effects of either compound on visceral pain, induced by intracolonic mustard oil (MO) were characterized by recording spontaneous behaviors. Results: G-1 and β-Estradiol inhibited colonic EFS and bethanechol induced contractilities. G-15, a selective GPR30 antagonist, blocked the effects of G-1 but not βEstradiol on the colonic contractility. MPP dihydrochloride, a highly selective ERα antagonist partially reversed the effects of G-1 and β-Estradiol; however, PHTPP, an ERβ antagonist, did not alter the effects of either G-1 or β-Estradiol on the colonic contractility. In vivo, βEstradiol and G-1, both at the dose of 10-20 mg. i.v., prolonged colonic propulsion. The effects of β-Estradiol on colonic propulsion were significantly reversed by G-15 (5 mg, i.v.) or MPP dihydrochloride (5 mg, i.v.). The effects of G-1 were significantly reversed by G15 and partially by the ER antagonists. The number of MO induced pain related behaviors was decreased by G-1 or β-Estradiol (20 mg, i.v.). G-15 and MPP dihydrochloride, but not PHTPP (5 mg, i.v.) reversed the effects of G-1 on visceral pain. The antinociceptive effect of β-Estradiol was only blocked by G-15 and not by ER antagonists. Conclusion: GPR30 is involved in the regulation of GI motility and visceral sensation. Our data suggests that GPR30 may be a promising target for the treatment of functional GI disorders with impaired GI motility or visceral sensation.