Antisecretory actions of a novel vasoactive intestinal polypeptide (VIP) antagonist in human and rat small intestine.
Vasoactive intestinal peptide (VIP) has been demonstrated in intestinal mucosal neurones and elicits chloride secretion from enterocytes. These findings have led to the proposal that VIP is a secretomotor neurotransmitter. Confirmation of such a role may now be possible with the development of PG 97-269, a high-affinity, selective antagonist of VIP type 1 (VPAC1) receptor, which is expressed by gut epithelial cells. We have evaluated the VIP antagonism and antisecretory potential of this novel compound using in vitro and in vivo models of intestinal secretion. Monolayers of the human colonic cell line (T84) and muscle-stripped preparations of rat jejunum and human ileum were set up in Ussing chambers for recording of transepithelial resistance and short-circuit current. Ussing chambers were modified to allow electrical stimulation of mucosal neurones. Effects of PG 97-269 on enterotoxin-induced secretion were investigated in perfused rat jejunum in vivo. PG 97-269 competitively antagonised VIP in T84 monolayers. In rat jejunum and human ileum, responses to VIP were inhibited as were responses of rat jejunum to electrical stimulation of mucosal neurons. In perfused rat jejunum, PG 97-269 abolished the effects of VIP on fluid and electrolyte transport and attenuated cholera toxin and Escherichia coli heat labile toxin-induced net fluid and electrolyte secretion. PG 97-269 is a competitive antagonist of enterocyte VIP receptors and effectively inhibits responses of rat and human intestinal mucosa to VIP. Antagonism of secretory responses to electrical stimulation of mucosal neurons and lumenal application of enterotoxins imply a secretory role for VIP in these processes.
Banks
Matthew R
MR
Department of Adult and Paediatric Gastroenterology, St Bartholomew's and The Royal London School of Medicine and Dentistry, Clinical Research Centre, Newark Street, London E1 2AD.
Farthing
Michael J G
MJ
Robberecht
Patrick
P
Burleigh
David E
DE
D000818:Animals; D002460:Cell Line; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018005:Receptors, Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014660:Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology
C110307:PG 97-269; D010446:Peptide Fragments; D018005:Receptors, Vasoactive Intestinal Peptide; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014660:Vasoactive Intestinal Peptide