Neural modulation of the antisecretory effect of peptide YY in the rat jejunum

Abstract

The endocrine and neural peptide, peptide YY, inhibits intestinal secretion of water and electrolytes in several animal species and in man. Peptide YY receptors have been evidenced on isolated rat jejunal crypt cells, but neural receptors are also likely to participate in the antisecretory effect of peptide YY in vivo. The aim of the present study was to investigate the mechanisms of the peptide YY effect on vasoactive intestinal peptide (VIP)-stimulated jejunal net water flux in the rat. Antagonist experiments using several drugs affecting neurally mediated processes were done for the purpose. A small peptide YY dose (10 pmol/kg) inhibited significantly (P<0.005) the jejunal net water flux produced by 30 μg/kg·h of VIP. The inhibitory effect of peptide YY was suppressed, or strongly and significantly reduced, by tetrodotoxin, hexamethonium, lidocaine, idazoxan and BMY14,802 (51-(4-fluorophenyl)-4-(-4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl)-1-butanol), whereas devazepide and l-NAME (l-ω-N-arginine methyl ester) had no effect. These results suggest that peptide YY inhibits VIP-stimulated jejunal net water flux in vivo through a neural mechanism implicating the participation of nicotinic synapses, α₂-adrenoceptors and σ receptors.

Introduction

Peptide YY is a 36-amino-acid gut peptide mainly produced in L type endocrine cells of the distal small intestine, colon and rectum (Tatemoto, 1982). More recently, the presence of peptide YY has also been evidenced in gut intrinsic neurons in the dog (Mc Donald et al., 1993). Peptide YY has a number of pharmacological effects on the digestive tract, including inhibition of gastrointestinal motility and secretions (Sheikh, 1991). In the small intestine, peptide YY potently inhibits electrolyte and water secretion in different animal species and in man (Saria and Beubler, 1985; Cox et al., 1988; Playford et al., 1990).

Although the antisecretory effect of peptide YY on small intestine has been described repeatedly, little is known about its exact mechanism in vivo.

In vitro data indicate that neuropeptide Y Y₂ receptor-like, peptide YY-preferring receptors are present on baso-lateral membranes of rat jejunal crypt cells (Laburthe et al., 1986; Servin et al., 1989). However, it is not clear whether peptide YY effects in vivo take place only through the occupation of enterocyte receptors, or rather by activating indirect neural mechanisms modulating epithelial cell function. Such a hypothesis rests upon two lines of evidence.

First, the inhibition of jejunal secretion in vivo by a series of peptide YY derivatives with various specificities for neuropeptide Y receptor subtypes indicates that neuropeptide Y Y₁ receptor agonists, as well as neuropeptide Y Y₂ receptor agonists and to some extent pancreatic polypeptide, all inhibit rat jejunal secretion while the enterocyte receptors have very little affinity for neuropeptide Y Y₁ receptor agonists and for pancreatic polypeptide (Souli et al., 1997).

Second, the effect of peptide YY and of neuropeptide Y on intestinal secretion is seriously affected by neural antagonists under several conditions. In mouse jejunum in Ussing chambers, the peptide YY-induced decrease of basal short-circuit current is blocked by tetrodotoxin, chlorisondamine and haloperidol (Rivière et al., 1993). In the rat, the jejunal antisecretory effect of neuropeptide Y in vivo is decreased by tetrodotoxin and the somatostatin receptor antagonist, cyclosomatostatin (Rivière et al., 1995), while in human volunteers, haloperidol suppresses peptide YY inhibition of prostaglandin E₂-induced jejunal secretion (Rozé et al., 1997).

The purpose of the present work was to investigate whether intrinsic or extrinsic neurons participate in the antisecretory effect of peptide YY in the rat jejunum in vivo. We used as a model vasoactive intestinal peptide (VIP)-stimulated jejunal loops in situ and investigated whether a series of neural antagonists would interfere with the peptide YY effect. In order to avoid difficulties of interpretation, we first determined the effects of these various neural antagonists on basal and VIP-stimulated jejunal net water flux. We then tested against peptide YY only the antagonists which had sufficiently small effects of their own on basal or VIP-stimulated net water flux to allow a clear interpretation of their modulation of the peptide YY effect.

Part of these results have appeared in abstract form (Souli et al., 1996b).