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Dynamics of the cationic and secretory responses to A‐4166 in perifused pancreatic islets
Author(s) -
Jijakli H,
Ulusoy S,
Malaisse WJ
Publication year - 1997
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.1997.tb00842.x
Subject(s) - chemistry , extracellular , pancreatic islets , depolarization , stimulation , intracellular , medicine , islet , insulin , endocrinology , biochemistry , biophysics , biology
Summary— The dynamics of the cationic and secretory response to A‐4166, a hypoglycemic meglitinide analogue, was investigated in rat islets prelabelled with either 86 Rb or 45 Ca and placed in a perifusion system. In the absence of D‐glucose, A‐4166 (10 μM) provoked an immediate, sustained and rapidly reversible inhibition of 86 Rb outflow, this contrasting with a short‐lived stimulation of insulin release. In the presence of 6 mM D‐glucose, A‐4166 provoked a rapid, sustained and rapidly reversible stimulation of both insulin release and 45 Ca efflux. The latter cationic response was suppressed in the absence of extracellular Ca 2+ , in which case A‐4166 even caused a modest decrease in effluent radioactivity. These findings support the view that A‐4166 acts mainly in the islet B‐cell by closing ATP‐responsive K + channels, leading to subsequent depolarization of the plasma membrane and gating of voltage‐sensitive Ca 2+ channels. Independently of the latter effect, A‐4166 may also affect the intracellular distribution of Ca 2+ ions. The present data further indicate that A‐4166 belongs to those hypoglycemic agents that cause rapidly reversible changes in cationic and secretory events, at variance with highly potent sulfonylureas such as glibenclamide or glimepiride.