Potentiation of Glibenclamide Hypoglycaemia in Mice by MK-467, a Peripherally Acting Alpha2-Adrenoceptor Antagonist
| Autor: | Tomi Streng, Ville Ranta-Panula, Paulina Chrusciel, Mika Scheinin, Sanna Bastman, Suvi T. Ruohonen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Agonist
Blood Glucose Male medicine.medical_specialty Mean arterial pressure Time Factors medicine.drug_class medicine.medical_treatment Type 2 diabetes Pharmacology Toxicology ta3111 Glibenclamide Heart Rate Internal medicine Glyburide medicine Adrenergic alpha-2 Receptor Agonists Animals Hypoglycemic Agents Insulin Telemetry Arterial Pressure ta317 Dose-Response Relationship Drug business.industry Antagonist Drug Synergism General Medicine Adrenergic alpha-2 Receptor Antagonists Medetomidine medicine.disease Hypoglycemia Blockade Mice Inbred C57BL Endocrinology Drug Therapy Combination business Antagonism Biomarkers Quinolizines medicine.drug |
| Zdroj: | Basic and clinical pharmacology and toxicology. 117(6):392-398 |
| ISSN: | 1742-7835 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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