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Blockade of peripheral α 2 ‐adrenoceptors by L‐659,066 enhances glucose tolerance and insulin release in mice
Author(s) -
Goldman M. E.,
Pettibone D. J.,
Reagan J. E.,
Clineschmidt B. V.,
Baldwin J. J.,
Huff J. R.
Publication year - 1989
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430170206
Subject(s) - medicine , endocrinology , insulin , clonidine , antagonist , imidazoline receptor , prazosin , adrenergic , chemistry , receptor
The purpose of this study was to compare the effects of a peripherally selective (L‐659,066) vs. a centrally and peripherally active (L‐657,743; MK‐912) α 2 ‐adrenergic antagonist on murine plasma glucose and insulin levels following fasting or administration of hyperglycemic agents (α 2 ‐adrenergic agonists, glucose). The intravenous administration of L‐657,743 or L‐659,066 alone did not cause major alterations in plasma glucose or insulin levels. Pretreatment of mice with either of these agents, however, at selective α 2 ‐adrenoceptor blocking doses (0.3–3 mg/kg) prevented the elevations of plasma glucose levels induced by the α 2 ‐adrenoceptor agonists clonidine or 3,4‐dihydroxyphenylimino‐2‐imidazoline (DPl). Prazosin, an α 1 ‐adrenergic antagonist, did not alter clonidine‐induced elevations of plasma glucose levels. Pretreatment of fasted mice with L‐657,743 or L‐659,066 (1 mg/kg) 5 min before receiving intravenous glucose resulted in higher plasma insulin levels and improved glucose tolerance compared to saline‐pretreated animals. Moreover, both α 2 ‐adrenergic antagonists enhanced the acute insulin response to glucose. These findings indicate that, under conditions of hyperglycemia, insulin release is enhanced by the blockade of peripheral α 2 ‐adrenoceptors α 2 ‐Adrenoceptor antagonists, such as L‐657,743 or the peripherally selective agent L‐659,066, may prove effective in treating noninsulin‐dependent diabetes mellitus.