A comparison of the effects of gastrin, somatostatin and dopamine receptor ligands on rat gastric enterochromaffin-like cell secretion and proliferation.
Gastrin regulates ECL cell histamine release and is a critical determinant of acid secretion. ECL cell secretion and proliferation is inhibited by gastrin antagonists and somatostatin but little is known about the role of dopamine agonists in this process. Since the ECL cell exhibits all three classes of receptor we evaluated and compared the effects of the gastrin receptor antagonist, (YF476), lanreotide (SST agonist) and novel dopaminergic agents (BIM53061 and BIM27A760) on ECL cell histamine secretion and proliferation. Highly enriched (>98%) ECL cell preparations prepared from rat gastric mucosa using a FACS approach were studied. Real-time PCR confirmed presence of the CCK2, SS2 and SS5 and D1 receptors on ECL cells. YF476 inhibited histamine secretion and proliferation with IC(50)s of 1.25 nM and 1.3 x 10(-11) M respectively, values 10-1000x more potent than L365,260. Lanreotide inhibited secretion and proliferation (2.2 nM, 1.9 x 10(-10) M) and increased YF476-inhibited proliferation a further 5-fold. The dopamine agonist, BIM53061, inhibited gastrin-mediated ECL cell secretion and proliferation (17 nM, 6 x 10(-10) M) as did the novel dopamine/somatostatin chimera BIM23A760 (22 nM, 4.9 x 10(-10) M). Our studies demonstrate that the gastrin receptor antagonist, YF476, is the most potent inhibitor of ECL cell histamine secretion and proliferation. Lanreotide, a dopamine agonist and a dopamine/somatostatin chimera inhibited ECL cell function but were 10-1000x less potent than YF476. Agents that selectively target the CCK2 receptor may provide alternative therapeutic strategies for gastrin-mediated gastrointestinal cell secretion and proliferation such as evident in the hypergastrinemic gastric carcinoids associated with low acid states.
Kidd
M
M
Department of Surgery, Yale University School of Medicine New Haven, Connecticut 06520-8062, United Sates.
Modlin
I M
IM
Black
J W
JW
Boyce
M
M
Culler
M
M
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019861:Enterochromaffin-like Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005755:Gastrins / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006636:Histamine Release / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000235:genetics / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology
D001570:Benzodiazepinones; D018491:Dopamine Agonists; D005755:Gastrins; D010456:Peptides, Cyclic; D010671:Phenylurea Compounds; D043887:Receptor, Cholecystokinin B; D011954:Receptors, Dopamine; D017481:Receptors, Somatostatin; C060347:lanreotide; D013004:Somatostatin; C104428:YF 476