peptide-yy and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol

Basal short circuit current (Isc) was measured in stripped rat jejunum after addition of neural antagonists and of peptide YY (PYY). Basal Isc was slightly (by 10-21%) but significantly inhibited by tetrodotoxin, hexamethonium, idazoxan, and the sigma antagonist BMY 14,802. PYY (10(-7) M) reduced basal Isc by approximately 54%. This inhibition was unchanged by hexamethonium but reduced by 44-68% in the presence of tetrodotoxin, idazoxan, haloperidol, BMY 14,802, and atropine. The Y2 agonist pYY(3-36) was more potent than the Y1 agonist (Leu31,Pro34)PYY. In conclusion, PYY reduces basal Isc in rat jejunum in part through a neural mechanism involving muscarinic receptors, alpha2 adrenoceptors, and sigma receptors and, in part, through a direct effect on enterocytes. The PYY effect seems mainly carried out through Y2-receptor activation.

Topics: Animals; Atropine; Haloperidol; Hexamethonium; Idazoxan; In Vitro Techniques; Jejunum; Male; Peptide YY; Pyrimidines; Rats; Rats, Wistar; Tetrodotoxin

1. The Y receptor subtype involved in the antagonism by neuropeptide Y (NPY) of intracisternal corticotropin-releasing factor (CRF)-induced inhibition of gastric acid secretion was studied in urethane-anaesthetized rats by use of peptides with various selectivity for Y1, Y2 and Y3 subtypes: NPY, a Y1, Y2 and Y3 agonist, peptide YY (PYY), a Y1 and Y2 agonist, [Leu31, Pro34]-NPY, a Y1 and Y3 agonist, NPY(3-36) and PYY(3-36), highly selective Y2 agonists and NPY(13-36) a weak Y2 and Y3 agonist. Peptides were injected intracisternally 10 min before intracisternal injection of CRF (10 micrograms) and gastric acid secretion was measured by the flushed technique for 1 h before and 2 h after pentagastrin-(10 micrograms kg-1 h-1, i.v.) infusion which started 10 min after CRF injection. 2. Intracisternal injection of CRF (10 micrograms) inhibited by 56% gastric acid secretion stimulated by pentagastrin. Intracisternal injection of NPY and PYY (0.1-0.5 microgram) did not influence the acid response to pentagastrin but blocked CRF-induced inhibition of pentagastrin-stimulated acid secretion. NPY(3-36) (0.5 microgram) and PYY(3-36) (0.25 and 0.5 microgram) also completely blocked the inhibitory action of CRF on pentagastrin-stimulated acid secretion. 3. [Leu31, Pro34]-NPY (0.5-5 micrograms) and NPY(13-36) (0.5-5 micrograms) injected intracisternally did not modify gastric acid secretion induced by pentagastrin or CRF inhibitory action. 4. The sigma antagonist, BMY 14802 (1 mg kg-1, s.c.) did not influence the acid response to pentagastrin but prevented the antagonism by PYY(3-36) (0.5 microgram) of the CRF antisecretory effect. 5. These results show that both PYY and NPY and the 3-36 forms of PYY and NPY are equipotent in blocking central CRF-induced inhibition of pentagastrin-stimulated gastric acid secretion. The structure-activity profile suggests a mediation through Y2 receptor subtype and the involvement of sigma binding sites.

Topics: Animals; Corticotropin-Releasing Hormone; Gastric Acid; Gastric Mucosa; Male; Neuropeptide Y; Peptide Fragments; Peptide YY; Peptides; Pyrimidines; Rats; Rats, Sprague-Dawley