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Pancreatic vasopressin V_1b receptors: characterization in In-R1-G9 cells and localization in human pancreas

Exploratory Research Department Sanofi-Synthélabo Recherche ¹31036 Toulouse and ²67080 Strasbourg, France

Submitted 7 April 2003 ; accepted in final form 29 April 2003

Vasopressin (AVP) receptors present in In-R1-G9 cells, a hamster glucagon-secreting -pancreatic cell line, were characterized using SSR-149415, a selective nonpeptide V_1b receptor antagonist, and reference AVP compounds. Binding experiments, using [³H]AVP as a ligand, identified a single population of high-affinity binding sites. SSR-149415 competitively inhibited this binding and exhibited nanomolar and stereospecific affinity for these sites. The affinity of various AVP/oxytocin ligands confirmed a V_1b binding profile. In functional studies, AVP was a potent stimulant in inducing intracellular Ca²⁺ increase, glucagon secretion, and cell proliferation. These effects were fully antagonized by SSR-149415 with a nanomolar potency, whereas its diasteroisomer as well as two selective V_1a and V₂ receptor antagonists were much less potent. Additionally, the order of potency of AVP agonists and antagonists was in agreement with V_1b-mediated effects. By RT-PCR, we confirmed the presence of V_1b receptor mRNA in both In-R1-G9 cells and in human pancreas. The distribution pattern of V_1b receptors investigated in human pancreas by immunohistochemistry showed strong labeling in islets of Langerhans, and colocalization studies indicated that this receptor was expressed in -glucagon, -insulin, and somatostatin pancreatic cells. Thus, in In-R1-G9 cells, AVP mediates intracellular Ca²⁺ increase, glucagon secretion, and cell proliferation by activating V_1b receptors, and these effects are potently antagonized by SSR-149415. Moreover, the presence of V_1b receptors also found in human Langerhans islets could suggest hormonal control of AVP in human pancreas.

arginine vasopressin V_1b receptors; glucagon; SSR-149415

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