Premium
α 2A ‐Adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice
Author(s) -
Fagerholm V,
Scheinin M,
Haaparanta M
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.186
Subject(s) - phentolamine , glibenclamide , endocrinology , medicine , insulin , imidazoline receptor , chemistry , diabetes mellitus , receptor
Background and purpose: The imidazoline‐type α 2 ‐adrenoceptor antagonists (±)‐efaroxan and phentolamine increase insulin secretion and reduce blood glucose levels. It is not known whether they act by antagonizing pancreatic β‐cell α 2 ‐adrenoceptors or by α 2 ‐adrenoceptor‐independent mechanisms. Many imidazolines inhibit the pancreatic β‐cell K ATP channel, which is the molecular target of sulphonylurea drugs used in the treatment of type II diabetes. To investigate the mechanisms of action of (±)‐efaroxan and phentolamine, α 2A ‐adrenoceptor knockout (α 2A ‐KO) mice were used. Experimental approach: Effects of (±)‐efaroxan, 5 mg kg −1 , and phentolamine, 1 mg kg −1 , on blood glucose and insulin levels were compared with those of the non‐imidazoline α 2 ‐adrenoceptor antagonist [8a R ,12a S ,13a S ]‐5,8,8a,9,10,11,12,12a,13,13a‐decahydro‐3‐methoxy‐
12‐(ethylsulphonyl)‐6 H ‐isoquino[2,1‐g][1,6]naphthyridine (RS79948‐197), 1 mg kg −1 , and the sulphonylurea glibenclamide, in α 2A ‐KO and control (wild type (WT)) mice. Key results: In fed WT mice, (±)‐efaroxan, phentolamine and RS79948‐197 reduced blood glucose and increased insulin levels. Fasting abolished these effects. In fed α 2A ‐KO mice, (±)‐efaroxan, phentolamine and RS79948‐197 did not alter blood glucose or insulin levels, and in fasted α 2A ‐KO mice, blood glucose levels were increased. Glibenclamide, at a dose only moderately efficacious in WT mice (5 mg kg −1 ), caused severe hyperinsulinaemia and hypoglycaemia in α 2A ‐KO mice. This was mimicked in WT mice by co‐administration of RS79948‐197 with glibenclamide. Conclusions and implications: These results suggest that (±)‐efaroxan and phentolamine increase insulin secretion by inhibition of β‐cell α 2A ‐adrenoceptors, and demonstrate a critical role for α 2A ‐adrenoceptors in limiting sulphonylurea‐induced hyperinsulinaemia and hypoglycaemia. British Journal of Pharmacology (2008) 154 , 1287–1296; doi: 10.1038/bjp.2008.186 ; published online 19 May 2008