Potentiation of Glibenclamide Hypoglycaemia in Mice by MK-467, a Peripherally Acting Alpha2-Adrenoceptor Antagonist.
| Title: | Potentiation of Glibenclamide Hypoglycaemia in Mice by MK-467, a Peripherally Acting Alpha2-Adrenoceptor Antagonist. |
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| Authors: | Ruohonen ST; Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.; Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Ranta-Panula V; Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.; Bastman S; Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.; Chrusciel P; Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.; Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Scheinin M; Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.; Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland.; Streng T; Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.; Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Department of Biology, Laboratory of Animal Physiology, University of Turku, Turku, Finland. |
| Source: | Basic & clinical pharmacology & toxicology [Basic Clin Pharmacol Toxicol] 2015 Dec; Vol. 117 (6), pp. 392-8. Date of Electronic Publication: 2015 Jul 30. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Blackwell Country of Publication: England NLM ID: 101208422 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1742-7843 (Electronic) Linking ISSN: 17427835 NLM ISO Abbreviation: Basic Clin Pharmacol Toxicol Subsets: MEDLINE |
| Imprint Name(s): | Publication: : Oxford : Blackwell; Original Publication: Copenhagen, Denmark : Oxford, UK : Nordic Pharmacological Society Distributed by Blackwell Munksgaard, 2004- |
| MeSH Terms: | Adrenergic alpha-2 Receptor Antagonists/*pharmacology ; Blood Glucose/*drug effects ; Glyburide/*pharmacology ; Hypoglycemia/*chemically induced ; Hypoglycemic Agents/*pharmacology ; Quinolizines/*pharmacology; Adrenergic alpha-2 Receptor Agonists/pharmacology ; Adrenergic alpha-2 Receptor Antagonists/toxicity ; Arterial Pressure/drug effects ; Biomarkers/blood ; Blood Glucose/metabolism ; Glyburide/toxicity ; Heart Rate/drug effects ; Hypoglycemia/blood ; Hypoglycemic Agents/toxicity ; Insulin/blood ; Medetomidine/pharmacology ; Quinolizines/toxicity ; Animals ; Dose-Response Relationship, Drug ; Drug Synergism ; Drug Therapy, Combination ; Male ; Mice, Inbred C57BL ; Telemetry ; Time Factors |
| Abstract: | Pharmacological antagonism and genetic depletion of pancreatic α2A-adrenoceptors increase insulin secretion in mice and enhance the insulinotropic action of glibenclamide, a representative of the sulphonylurea class of insulin secretagogues used in the therapy of type 2 diabetes. Antagonism of α2-adrenoceptors in the central nervous system (CNS) causes tachycardia and hypertension, making generalized α2-adrenoceptor blockade unfavourable for clinical use despite its potential to decrease blood glucose levels. The purpose of this study was to test the acute effects of the peripherally acting α2-adrenoceptor antagonist MK-467 alone and in combination with glibenclamide in non-diabetic C57BL/6N mice. Cardiovascular safety was assessed in freely moving mice with radiotelemetry. Dose-dependent decreases in blood glucose and increases in plasma insulin concentrations were seen with the combination of MK-467 and glibenclamide; the combinations were much more potent than glibenclamide or MK-467 alone. Furthermore, MK-467 had no effect on mean arterial pressure or heart rate in freely moving mice and did not prevent the centrally mediated hypotensive effect of the α2-adrenoceptor agonist medetomidine. Thus, peripheral blockade of α2-adrenoceptors does not evoke the same cardiovascular adverse effects as antagonism of CNS α2-adrenoceptors. The current results indicate that the combined use of small doses of a peripherally acting α2-adrenoceptor antagonist with a sulphonylurea drug could provide a novel option for the treatment of type 2 diabetes, especially in patients with increased tonic α2-adrenoceptor-mediated inhibition of insulin secretion.; (© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).) |
| Substance Nomenclature: | 0 (Adrenergic alpha-2 Receptor Agonists); 0 (Adrenergic alpha-2 Receptor Antagonists); 0 (Biomarkers); 0 (Blood Glucose); 0 (Hypoglycemic Agents); 0 (Insulin); 0 (Quinolizines); 342EYN0QFD (vatinoxan); MR15E85MQM (Medetomidine); SX6K58TVWC (Glyburide) |
| Entry Date(s): | Date Created: 20150702 Date Completed: 20161031 Latest Revision: 20191210 |
| Update Code: | 20260130 |
| DOI: | 10.1111/bcpt.12440 |
| PMID: | 26132275 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't