l-365260 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

We examined the effect of peripheral administration of cholecystokinin (CCK)-8S on spontaneous acetylcholine (ACh) release from the frontal cortex and its prevention by loxiglumide, L-364,718 and L-365,260 in freely moving rats using intracerebral microdialysis. Subcutaneously (s.c.) administered CCK-8S at 10 and 30 micrograms/kg significantly decreased the release of ACh. The inhibitory effect of 10 micrograms/kg (s.c.) CCK-8S was prevented by loxiglumide, a mixed type of CCK-A and -B-receptor antagonist, at 1 mg/kg (intraperitoneal) and 40 micrograms/rat (intracerebroventricular, i.c.v.); L-364,718, a CCK-A-receptor antagonist, at 125 and 250 ng/rat (i.c.v.); and L-365,260, a CCK-B-receptor antagonist at 250 ng/rat (i.c.v.). These results demonstrate that peripherally administered CCK-8S inhibits spontaneous ACh release from the frontal cortex through both central CCK-A (mainly) and -B receptors.

Topics: Acetylcholine; Animals; Benzodiazepinones; Cerebral Cortex; Cholecystokinin; Devazepide; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Phenylurea Compounds; Proglumide; Rats; Rats, Wistar; Receptors, Cholecystokinin

The role of gastrin in the control of growth of renal G401 cells isolated from a human nephroblastoma (Wilms' tumour) was investigated. G401 cell growth was enhanced in the presence of exogenous gastrin. Addition of anti-gastrin antibodies to serum-free medium significantly inhibited the growth of G401 cells. G401 cells contained the equivalent of 4.3 pg/10(6) cells of gastrin, and serum-free medium collected over 48 hr from G401 cells contained the equivalent of 38 ng/10(6) cells of gastrin, as determined by radioimmunoassay. Growth of G401 cells was inhibited in a concentration-related way by a variety of gastrin/CCK receptor antagonists. Devazepide and proglumide were, respectively, the most and the least potent inhibitors of G401 cell growth (potency order devazepide > L-365,260 = lorglumide > loxiglumide > benzotript > proglumide). These gastrin/CCK receptor antagonists had similar growth-inhibitory activities in human colonic adenocarcinoma HCT-116 cells. Growth of HCT-116 cells was stimulated to a lesser extent, as compared with G401 cells, by exogenous gastrin, and endogenous gastrin was not detectable in HCT-116 cells. The results are consistent with a role for a gastrin-like peptide in the control of growth of a renal cell line. The data suggest that gastrin/CCK receptor antagonists warrant further investigation as therapeutic agents for the control of gastrin-responsive tumours derived from outside, as well as inside, the gastrointestinal tract, including tumours derived from the kidney.

Topics: Benzamides; Benzodiazepinones; Cell Division; Devazepide; Gastrins; Humans; Indoles; Kidney Neoplasms; Meglumine; Phenylurea Compounds; Proglumide; Receptors, Cholecystokinin; Tumor Cells, Cultured; Wilms Tumor