Endogenous ghrelin and 5-HT regulate interdigestive gastrointestinal contractions in conscious rats

Abstract

Endogenous ghrelin causes interdigestive contractions of the stomach in rats. In contrast, previous studies showed that 5-HT3 and 5-HT4 receptors were involved in regulating intestinal interdigestive contractions. We studied the possible role of endogenous ghrelin and 5-HT regulating interdigestive gastrointestinal (GI) contractions in rats. Four strain gauge transducers were implanted on the antrum, duodenum, and proximal and distal jejunum. After an overnight fast, GI contractions were recorded in freely moving conscious rats and ghrelin receptor antagonists [(D-lys3)GHRP6; 1 mol/kg], 5-HT3 antagonists (Ondansetron; 0.5 mg/kg) and 5-HT 4 antagonists (GR 125,487; 1 mg/kg) were administered (bolus iv). To evaluate the relationship between the luminal concentrations of 5-HT and phase III-like contractions of the duodenum, duodenal juice was collected via the intraduodenal catheter. 5-HT content of the duodenal juice was measured by HPLC. (D-lys3)GHRP6 significantly attenuated the occurrence and amplitude of phase III-like contractions of the antrum, but not the duodenum and jejunum. 5-HT 4 antagonists significantly reduced spontaneous phase III-like contractions of the jejunum, without affecting those of the antrum and duodenum. In contrast, 5-HT 3 antagonists did not affect phase III-like contractions in GI tract. Luminal concentration of 5-HT at the phase III-like contraction (36.0 Ϯ 13.3 ng/ml, n ϭ 9) was significantly higher than that at the phase I-like contractions of the duodenum (4.9 Ϯ 1.6 ng/ml, n ϭ 9, P Ͻ 0.05). It is suggested that released ghrelin from the gastric mucosa mediates gastric phase III-like contractions, whereas 5-HT released from enterochromaffin cells of the duodenal mucosa mediates intestinal phase III-like contractions via 5-HT 4 receptors. 5-HT3 receptors; 5-HT4 receptors; enterochromaffin cells DURING THE INTERDIGESTIVE state, the stomach and small intestine show a remarkable motor pattern, known as the migrating motor complex (MMC) in dogs (51) and humans (56). MMC consists of three phases: phase I (period of motor quiescence), phase II (period of irregular low-amplitude contractions), and phase III (period of regular high-amplitude contractions). Phase III contractions of MMC have physiological importance for clearance of secretions, debris, and microbes during fasting and let the stomach be ready to receive a next meal (56). Plasma motilin levels are highly associated with the appearance of gastric phase III in dogs (34). Motilin administration caused phase III contractions in human and dogs (33, 60).The characteristic feature of gastric MMC is different among species. In humans and dogs, MMC is usually observed every 90 -120 min the interdigestive state. In contrast, MMC cycle is short (less than 20 min) in rats and not so regular as that of humans and dogs (2, 18, 53). Since it is rather difficult to distinguish three phases in rats, these phases are called as phase I-like contractions and phase III-like contractions in rats (3,18,53).Ghrelin, a 28-amino acid peptide, was discov...

Effects of ghrelin on interdigestive contractions of the rat gastrointestinal tract

“…Our recent study showed that phase Ⅲ-like contractions at the jejunum, not the antrum and duodenum, were significantly attenuated by 5-HT 4 antagonists. In contrast, 5-HT 3 antagonists did not affect phase Ⅲ-like contractions in all of upper GI tract [11] . These suggest that spontaneous phase Ⅲ-like contractions at the jejunum is mediated via 5-HT 4 receptors, but not 5-HT 3 receptors.…”

“…Previous report showed that ghrelin stimulates motility in the rat small intestine and that the stimulatory effect of ghrelin is mediated via cholinergic neurons of the myenteric plexus [12] . Our recent study showed that GHS-R antagonists inhibited phase Ⅲ-like contractions at the antrum, but not the duodenum and the jejunum [11] . Previous studies also showed that GHS-R antagonists did not affect phase Ⅲ-like contractions in the duodenum [8] .…”

“…Ghrelin-induced acid secretion is also abolished by bilateral vagotomy [26] . Our recent study showed that spontaneous phase Ⅲ-like contractions were completely disappeared in vagotomized rats [11] . These results suggest that ghrelin-induced spontaneous phase-Ⅲ like is mediated via vagal pathways.…”

“…Spontaneous phase Ⅲ-like contractions were observed at every 13-16 min in rat GI tract. The fasted motor patterns were replaced by the fed motor pattern immediately after food intake [11] . Two minutes after finishing the spontaneous phase Ⅲ-like contractions in the antrum, acyl ghrelin (0.8, 2.4 and 8.0 µg/kg per min) was continuously infused for 30 min.…”

Extrinsic Orexin-A in Lateral Hypothalamic Area Regulates Gastric Motility in Rats

“…Under the dissecting microscope, the lower part of the esophagus was exposed and anterior and posterior branches of the vagal nerves were incised above the hepatic and celiac branches, as previously reported [15] . In sham operation rats, the vagal trunks were similarly exposed but not cut [16] .…”