Serotonergic modulation of murine fundic tone.

Fundic tone is maintained through a balance of excitatory and inhibitory input to fundic smooth muscle. The aim of this study was to determine the role of serotonin (5-HT) and 5-HT receptors in modulating murine fundic tone. Muscle strips were prepared from the murine fundus. Intracellular recordings were made from circular smooth muscle cells, and the effects of 5-HT on tone and excitatory and inhibitory junction potentials evoked by electrical field stimulation (EFS) were determined. 5-HT induced a concentration-dependent contraction and smooth muscle depolarization that was tetrodotoxin resistant. The 5-HT(1B/D) receptor antagonists GR-127935 and BRL-155172 significantly inhibited 5-HT-induced contractions. The 5-HT(1B/D) agonist sumatriptan contracted murine fundic muscle. The 5-HT(1A) receptor agonist buspirone relaxed fundic smooth muscle, and the relaxation was inhibited by WAY-100135 but not by N(omega)-nitro-l-arginine or tetrodotoxin. 5-HT enhanced both the excitatory and inhibitory responses to EFS. The 5-HT(3) receptor antagonist MDL-72222 partly inhibited both the excitatory and inhibitory response elicited by EFS, whereas the 5-HT(4) receptor antagonist GR-113808 partly inhibited the EFS-evoked inhibitory response. The 5-HT reuptake inhibitor fluoxetine contracted smooth muscle strips, a contraction that was partially inhibited by GR-127935 and abolished by tetrodotoxin. In conclusion, the data suggest that 5-HT modulates murine fundic contractile activity through several different receptor subtypes. Sustained release of 5-HT maintains fundic tone through postjunctional 5-HT(1B/D) receptors. 5-HT(3) receptors modulate excitatory neural input to murine fundic smooth muscle, and both 5-HT(3) and 5-HT(4) receptors modulate inhibitory neural input to murine fundic smooth muscle.

Effect of modulation of serotonergic, cholinergic, and nitrergic pathways on murine fundic size and compliance measured by ultrasonomicrometry.

Reduced fasting or postprandial gastric volumes have been implicated in the pathophysiology of functional dyspepsia. The mechanisms that underlie the control of gastric fundic volume are incompletely understood, partly because of an inability to accurately measure fundic volume in vivo in small animals. Small animals are useful models to evaluate mechanisms, e.g., in knockout animals. The aim of this study was to determine whether an ultrasonometric technique accurately monitors fundic contraction and relaxation in mice in vivo and to determine the effect of modulation of cholinergic, nitrergic, and serotonergic pathways on fundic size and compliance in the intact mouse innervated stomach. Two to four piezoelectric crystals (diameter 1 mm, 24-microm resolution) were glued to the serosal side of fundus and used to measure distance. Validation studies showed excellent correlation between measured changes and actual changes in distances between crystals and excellent reproducibility. The expected responses to pharmacological modulation with bethanechol and nitroglycerin were demonstrated. Atropine increased the distance between the crystals, suggesting a baseline cholinergic regulation of fundic volume. Bethanechol, Nomega-nitro-L-arginine, and the 5-HT1B/D agonist sumatriptan decreased the distance between the crystals, suggesting fundic contraction. Atropine, nitroglycerin, and buspirone caused an increase in intercrystal distance consistent with fundic relaxation. Fundic compliance was investigated by changing intragastric pressure via an implanted catheter. Sumatriptan increased compliance, whereas buspirone increased the distance between crystals but did not change compliance. The data suggest that ultrasonomicrometry is a useful tool that can reproducibly and accurately measure changes in fundic size and the response to pharmacological agents.