title: Potentiation of Glibenclamide Hypoglycaemia in Mice by MK-467, a Peripherally Acting Alpha2-Adrenoceptor Antagonist.
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.
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.|Turku Center for Disease Modeling, University of Turku, Turku, Finland.
authors.forename: Suvi T
authors.initials: ST
authors.lastname: Ruohonen
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Ranta-Panula
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Bastman
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.|Turku Center for Disease Modeling, University of Turku, Turku, Finland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Chrusciel
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.|Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
authors.affiliation: 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.
authors.forename: Tomi
authors.initials: T
authors.lastname: Streng
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005905:Glyburide / Q000494:pharmacology* / Q000633:toxicity; D006339:Heart Rate / Q000187:drug effects; D007003:Hypoglycemia / Q000097:blood / Q000139:chemically induced*; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000633:toxicity; D007328:Insulin / Q000097:blood; D008297:Male; D020926:Medetomidine / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D011807:Quinolizines / Q000494:pharmacology* / Q000633:toxicity; D013686:Telemetry; D013997:Time Factors
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D011807:Quinolizines; C055732:vatinoxan; D020926:Medetomidine; D005905:Glyburide