title: Dynamics of the cationic and secretory responses to A-4166 in perifused pancreatic islets.
abstract: The dynamics of the cationic and secretory response to A-4166, a hypoglycemic meglitinide analogue, was investigated in rat islets prelabelled with either 36Rb or 45Ca and placed in a perifusion system. In the absence of D-glucose, A-4166 (10 microM) provoked an immediate, sustained and rapidly reversible inhibition of 36Rb 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 45Ca efflux. The latter cationic response was suppressed in the absence of extracellular Ca2+, 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 Ca2+ channels. Independently of the latter effect, A-4166 may also affect the intracellular distribution of Ca2+ 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.
authors.affiliation: Laboratory of Experimental Medicine, Brussels Free University, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Jijakli
authors.forename: S
authors.initials: S
authors.lastname: Ulusoy
authors.forename: W J
authors.initials: WJ
authors.lastname: Malaisse
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D003510:Cyclohexanes / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D000077715:Nateglinide; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012413:Rubidium / Q000378:metabolism*; D013997:Time Factors
chemical_list: D001549:Benzamides; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007328:Insulin; D000077715:Nateglinide; D010649:Phenylalanine; C030516:meglitinide; D005947:Glucose; D012413:Rubidium; D002118:Calcium