L-365,260 inhibits in vitro acid secretion by interacting with a PKA pathway.
The aim of this study was to analyse the antisecretory mechanism of L-365,260 in vitro in isolated rabbit gastric glands. We showed that compound L-365,260, described as a non-peptide specific competitive CCK-B receptor antagonist, was able to dose-dependently inhibit [14C]-aminopyrine accumulation induced by histamine (10(-4) M), carbachol (5x10(-5) M), 3-isobutyl-1-methyl-xanthine (IBMX) (5x10(-6) M) and forskolin (5x10(-7) M) with similar IC50 values respectively of 1.1+/-0.6x10(-7) M, 1.9+/-1.2x10(-7) M, 4.2+/-2.0x10(-7) M and 4.0+/-2.8x10(-7) M. We showed that L-365,260 acted beyond receptor activation and production of intracellular second messengers and that it had no action on the H+/K+ -ATPase. We found that L-365,260 inhibited cyclic AMP-induced [14C]-aminopyrine accumulation in digitonin-permeabilized rabbit gastric glands, suggesting that this compound acted, at least in part, as an inhibitor of the cyclic AMP-dependent protein kinase (PKA) pathway.
Oiry
C
C
Laboratoire des Amino Acides, Peptides et Protéines, UMR CNRS 5810, Faculté de Pharmacie, Montpellier, France.
Pannequin
J
J
Cormier
A
A
Galleyrand
J C
JC
Martinez
J
J
D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D009853:Omeprazole / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D054328:Proton Pump Inhibitors; D011817:Rabbits; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D015290:Second Messenger Systems / Q000187:drug effects
D001570:Benzodiazepinones; D004791:Enzyme Inhibitors; D006635:Histamine H2 Antagonists; D007295:Inositol Phosphates; D010671:Phenylurea Compounds; D054328:Proton Pump Inhibitors; D011949:Receptors, Cholecystokinin; D000632:Aminopyrine; C058121:L 365260; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D009853:Omeprazole