gastrin-i and loxiglumide

In vitro cholecystokinin (CCK) contracts the human lower oesophageal sphincter by stimulating muscular receptors. The aim of this study was to characterize the muscular CCK receptor subtypes in the human lower oesophageal sphincter. Twenty-five circular strips from six patients were studied. RNA was extracted, reverse transcribed, and cDNAs were amplified with primers for human CCK-A and B receptors. The potency of the contraction induced by CCK-8, desulphated CCK-8, and gastrin-I, and the effect of the CCK-A (loxiglumide and SR 27897) and the CCK-B (YM022 and L-365 260) specific receptor antagonists were compared. Both CCK-A and CCK-B receptor mRNAs were found in functional lower oesophageal sphincter strips. The potency of the CCK-8 concentration-dependent contraction was two and three orders of magnitude higher than that of desulphated CCK-8 and gastrin-I, respectively. The CCK-8-induced contraction was blocked by the CCK-A receptor antagonists loxiglumide (IC50 11 micromol L-1) and SR 27897 (IC50 74 nmol L-1) but not by CCK-B receptor antagonists (1 micromol L-1). Our data suggest that, although the human lower oesophageal sphincter expresses both CCK-A and CCK-B receptors, the contractile effect of CCK-8 on the circular muscle is mainly due to the activation of CCK-A receptors.

Topics: Adult; Aged; Benzodiazepines; Benzodiazepinones; Esophagogastric Junction; Female; Gastric Emptying; Gastrins; Gastrointestinal Agents; Gene Expression; Hormone Antagonists; Humans; In Vitro Techniques; Indoleacetic Acids; Male; Middle Aged; Phenylurea Compounds; Proglumide; Receptors, Cholecystokinin; Restriction Mapping; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sincalide; Thiazoles

Mechanisms for the hypertrophy of rat pancreas induced by long-term administration of bethanechol were investigated. The administration of bethanechol, an acetylcholine receptor agonist, to male Wistar rats for 14 days induced significant increases in the pancreatic weight and contents of protein, amylase and RNA in the pancreas without altering the content of DNA and the incorporation of [3H]thymidine into DNA. Simultaneous administration of atropine with bethanechol suppressed the bethanechol-induced pancreatic hypertrophy. Long-term administration of other acetylcholine receptor agonists also showed similar effects as produced by bethanechol. CR1505 (loxiglumide; D,L-4-(3,4-dichlorobenzoyl-amino)-5-(N-3-methoxypropyl-pentylam ino)-5- oxopentanoic acid), an antagonist of cholecystokinin receptors, inhibited pancreatic growth induced by long-term administation of pentagastrin, whereas pancreatic hypertrophy induced by bethanechol was not inhibited by CR1505. These results suggest that long-term administration of bethanechol induces pancreatic hypertrophy through direct activation of muscarinic receptors in the pancreas.

Topics: Amylases; Animals; Atropine; Bethanechol; Cholinergic Agonists; Cholinergic Antagonists; Drug Administration Schedule; Drug Interactions; Gastrins; Hypertrophy; Male; Organ Size; Pancreas; Pentagastrin; Proglumide; Rats; Rats, Wistar; Receptors, Cholecystokinin; Sincalide