| Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K(ATP) channels. | |
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MedLine Citation:
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PMID: 22167524 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Here, we examined the chronic effects of two cannabinoid receptor-1 (CB1) inverse agonists, rimonabant and ibipinabant, in hyperinsulinemic Zucker rats to determine their chronic effects on insulinemia. Rimonabant and ibipinabant (10 mg·kg⁻¹·day⁻¹) elicited body weight-independent improvements in insulinemia and glycemia during 10 wk of chronic treatment. To elucidate the mechanism of insulin lowering, acute in vivo and in vitro studies were then performed. Surprisingly, chronic treatment was not required for insulin lowering. In acute in vivo and in vitro studies, the CB1 inverse agonists exhibited acute K channel opener (KCO; e.g., diazoxide and NN414)-like effects on glucose tolerance and glucose-stimulated insulin secretion (GSIS) with approximately fivefold better potency than diazoxide. Followup studies implied that these effects were inconsistent with a CB1-mediated mechanism. Thus effects of several CB1 agonists, inverse agonists, and distomers during GTTs or GSIS studies using perifused rat islets were unpredictable from their known CB1 activities. In vivo rimonabant and ibipinabant caused glucose intolerance in CB1 but not SUR1-KO mice. Electrophysiological studies indicated that, compared with diazoxide, 3 μM rimonabant and ibipinabant are partial agonists for K channel opening. Partial agonism was consistent with data from radioligand binding assays designed to detect SUR1 K(ATP) KCOs where rimonabant and ibipinabant allosterically regulated ³H-glibenclamide-specific binding in the presence of MgATP, as did diazoxide and NN414. Our findings indicate that some CB1 ligands may directly bind and allosterically regulate Kir6.2/SUR1 K(ATP) channels like other KCOs. This mechanism appears to be compatible with and may contribute to their acute and chronic effects on GSIS and insulinemia. |
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Authors:
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Christopher J Lynch; Qing Zhou; Show-Ling Shyng; David J Heal; Sharon C Cheetham; Keith Dickinson; Peter Gregory; Michael Firnges; Ulrich Nordheim; Stephanie Goshorn; Dania Reiche; Lechoslaw Turski; Jochen Antel |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-12-13 |
Journal Detail:
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Title: American journal of physiology. Endocrinology and metabolism Volume: 302 ISSN: 1522-1555 ISO Abbreviation: Am. J. Physiol. Endocrinol. Metab. Publication Date: 2012 Mar |
Date Detail:
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Created Date: 2012-02-23 Completed Date: 2012-04-13 Revised Date: 2012-05-08 |
Medline Journal Info:
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Nlm Unique ID: 100901226 Medline TA: Am J Physiol Endocrinol Metab Country: United States |
Other Details:
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Languages: eng Pagination: E540-51 Citation Subset: IM |
Affiliation:
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Dept. of Cellular & Molecular Physiology, Pennsylvania State College of Medicine, Hershey, PA 17033, USA. clynch@psu.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
/
agonists*,
genetics,
metabolism Allosteric Regulation Animals Anti-Obesity Agents / adverse effects, chemistry, pharmacology*, therapeutic use Cell Line, Transformed Cercopithecus aethiops Cricetinae Glucose Intolerance / chemically induced, metabolism Humans Hypoglycemic Agents / adverse effects, chemistry, pharmacology*, therapeutic use Islets of Langerhans / drug effects, metabolism, secretion Ligands Male Membrane Transport Modulators / adverse effects, chemistry, pharmacology*, therapeutic use Mice Mice, Knockout Mice, Obese Potassium Channels, Inwardly Rectifying / agonists*, genetics, metabolism Rats Rats, Zucker Receptor, Cannabinoid, CB1 / agonists*, antagonists & inhibitors*, genetics, metabolism Receptors, Drug / agonists*, genetics, metabolism Recombinant Proteins / agonists, antagonists & inhibitors, metabolism Stereoisomerism |
| Grant Support | |
ID/Acronym/Agency:
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DK-084428/DK/NIDDK NIH HHS; DK-57699/DK/NIDDK NIH HHS; R01 DK084428/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ATP-Binding Cassette Transporters; 0/Anti-Obesity Agents; 0/Hypoglycemic Agents; 0/Ligands; 0/Membrane Transport Modulators; 0/Potassium Channels, Inwardly Rectifying; 0/Receptor, Cannabinoid, CB1; 0/Receptors, Drug; 0/Recombinant Proteins; 0/sulfonylurea receptor |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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