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- Title
Potentiation of Glibenclamide Hypoglycaemia in Mice by MK-467, a Peripherally Acting Alpha2-Adrenoceptor Antagonist.
- Authors
Ruohonen, Suvi T.; Ranta‐Panula, Ville; Bastman, Sanna; Chrusciel, Paulina; Scheinin, Mika; Streng, Tomi
- 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.
- Subjects
ADRENERGIC receptors; GLIBENCLAMIDE; RADIO telemetry; TYPE 2 diabetes treatment; HYPERTENSION
- Publication
Basic & Clinical Pharmacology & Toxicology, 2015, Vol 117, Issue 6, p392
- ISSN
1742-7835
- Publication type
Article
- DOI
10.1111/bcpt.12440