The influence of intravenous peptide YY (PYY) on the gastric injury induced by 45% ethanol was investigated in urethane-anesthetized rats. PYY (25, 75, 125, and 250 pmol ⅐ kg Ϫ1 ⅐ h Ϫ1 ) significantly reduced gastric lesions by 36, 59, 40, and 38%, respectively. Antibody against ratPYY (2 mg/rat) injected intravenously completely prevented the gastroprotective effect of intravenous PYY (75 pmol⅐kg Ϫ1 ⅐h Ϫ1 ), whereas injected intracisternally (460 g/20 l), it significantly prevented intracisternal PYY (24 pmol/rat)-induced 58% reduction of ethanol lesions but not that induced by intravenous PYY. Vagotomy did not influence the gastroprotective effect of intravenous PYY. The Y 1/"PYY-preferring" receptor agonist [Pro 34 ]PYY (75 pmol ⅐ kg Ϫ1 ⅐h Ϫ1 iv) significantly decreased ethanol-induced gastric lesions by 82%, whereas [Leu 31 , Pro 34 ]NPY, a Y1/Y3 agonist, and PYY-(3-36), a Y2 agonist, had no effect. These data indicate that PYY-infused intravenously at doses reported to mimic postprandial peak blood levels prevents ethanol-induced gastric injury through vagal independent pathways and PYY-preferring receptors.neuropeptide Y-receptor subtype; peptide YY antibody; vagotomy; ethanol; gastric lesions PEPTIDE YY (PYY), neuropeptide Y (NPY), and pancreatic peptide (PP) belong to a family of structurally related 36-amino acid peptides. PYY, which was isolated from porcine duodenum (35), is widely distributed in the gastrointestinal tract, predominantly in the endocrine cells of intestine and pancreas (24, 26) and in neuronal elements of the gastrointestinal tract (7).Postprandial release of PYY into the circulation has been established in all species studied so far (36). Doses of PYY infused intravenously, reproducing the circulating postprandial peak levels, are in the range of 50-120 pmol ⅐ kg Ϫ1 ⅐ h Ϫ1 in rats (19,34). Intravenous infusion of PYY at doses within this range inhibits stimulated gastric acid secretion (1,16,28,30) and gastric emptying (3, 29) in humans and dogs and exocrine pancreatic secretion in rats and dogs (19,31,37) and interrupts intestinal propagation in rats (2). PYY is assumed to act as a physiological inhibitor of upper gastrointestinal functions when nutrients reach the distal small intestine (36).PYY is a gut peptide that also acts in the brain to alter gastric secretory and motor functions through vagal pathways. Autoradiographic studies have demonstrated dense concentrations of PYY binding sites in the rat dorsal medulla (25). Saturable PYY binding has been observed in the region of the brain stem containing the dorsal vagal complex (DVC) after the intravenous injection of 125 I-labeled PYY at doses reproducing postprandial blood concentrations in rats (18). We previously reported that intravenous PYY-induced inhibition of gastric acid secretion was prevented by intracisternal injection of PYY antibody, providing evidence for a central action of peripheral PYY (42). In addition, microinjection of PYY or NPY into the DVC at low doses inhibits vagally stimulated gastric contractions, w...