Role of Y₂ receptors in the regulation of gastric tone in rats

Abstract

We set out to determine the effect of peptide YY(3-36) (PYY(3-36)) on the gastric muscle tone in conscious rats by measuring intragastric pressure (IGP) during intragastric nutrient drink infusion. After an overnight fast, a chronically implanted gastric fistula was connected to a custom-made nutrient drink infusion system and a catheter to measure IGP. IGP was measured before and during the infusion of a nutrient drink (Nutridrink; 0.5 ml/min) until 10 ml was infused. Rats were treated with PYY(3-36) (0, 33, and 100 pmol·kg(-1)·min(-1)) in combination with a subcutaneous injection of the Y(2) receptor antagonists JNJ31020028 (10 mg/kg) or BIIE0246 (2 mg/kg). Experiments were also performed after subdiaphragmatic vagotomy and after pretreatment with 3 ml of nutrient drink (to mimic a fed state). IGP was compared as the average IGP during nutrient infusion, represented as means ± SE and compared using ANOVA. PYY(3-36) dose dependently increased the IGP during nutrient infusion (4.7 ± 0.3, 5.7 ± 0.5 and 7.3 ± 0.7 mmHg; P < 0.01) while JNJ31020028 and BIIE0246 could block this increase [4.4 ± 0.5 (P < 0.001) and 4.8 ± 0.4 (P < 0.05) mmHg, respectively]. Also in vagotomized rats, PYY(3-36) was able to significantly increase the IGP during, an effect attenuated by JNJ31020028. BIIE0246 and JNJ31020028 were not able to decrease the IGP when no PYY(3-36) was administered. PYY(3-36) increased gastric tone through an Y(2) receptor-mediated mechanism that does not involve the vagus nerve. Y(2) receptor antagonists were not able to decrease gastric tone without exogenous administration of PYY(3-36), indicating that Y(2) receptors do not play a crucial role in the determination of gastric tone in physiological conditions.

The gastrointestinal tract in hunger and satiety signalling

“…[2][3][4] First in animal studies, a minimally invasive method to quantify gastric accommodation was developed and validated using intra-gastric pressure (IGP) monitoring. 5,6 In man, contrary to what is written in physiology textbooks ('gastric accommodation serves to prevent a rise in IGP during food intake'), it was observed that nutrient ingestion induces an initial drop in IGP, followed by gradual recovery 7 (Figure 2). Fasting IGP in man fluctuates with the phases of the interdigestive migrating motor complex (MMC), 8 with maximum value during gastric Phase 3 and minimum value during Phase 1.…”

“…In animals, peptide YY and pancreatic polypeptide inhibit the pressure drop during nutrient infusion. 5,6 In healthy human controls, GLP-1 infused at physiological and supra-physiological levels dose-dependently diminished fundic tone and inhibited fundic volume waves, increased gastric volumes and suppressed gastric emptying rate, possibly through inhibition of vagal function. 29,30 Somewhat paradoxically, the GLP-1 analogue liraglutide inhibits gastric accommodation and this is associated with early satiation.…”

“…The site of gastric accommodation and hence the site of most likely satiation signalling is the proximal stomach 2–4 . First in animal studies, a minimally invasive method to quantify gastric accommodation was developed and validated using intra‐gastric pressure (IGP) monitoring 5,6 . In man, contrary to what is written in physiology textbooks (‘gastric accommodation serves to prevent a rise in IGP during food intake’), it was observed that nutrient ingestion induces an initial drop in IGP, followed by gradual recovery 7 (Figure 2).…”

Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut–brain axis

“…Plasma concentrations roughly equivalent to postprandial levels inhibit gastric acid secretion, gastric emptying, the cephalic phase of gallbladder contraction and mouth-to-caecum transit time (Field et al, 2010). The inhibition of gastric acid secretion involves Y1 and Y2 receptors and is mediated both by an action in the brainstem and stomach (Yang, 2002), while the effect of PYY 3–36 to increase gastric pressure via stimulation of Y2 receptors does not involve the vagus nerve (Janssen et al, 2012). PYY released by SCFAs (administered exogenously or produced by the intestinal microbiota) inhibits gastrointestinal motility and electrolyte and water secretion by neural and non-neural mechanisms (Cox, 2007b).…”

“…There is also growing evidence that PYY and NPY exert a tonic influence on gastrointestinal motor and secretory activity. While Y2 receptor antagonists per se do not alter gastric motor tone (Janssen et al, 2012), Y1 and Y2 receptor antagonism as well as PYY and NPY knockout modify colonic ion transport and motility (Tough et al, 2011). The pertinent findings indicate that, both in the human and mouse colonic mucosa, PYY and NPY exert a tonic antisecretory effect mediated by epithelial Y1 and neural Y2 receptors.…”