DYNAMICS OF THE CATIONIC AND SECRETORY RESPONSES TO A-4166 IN PERIFUSED PANCREATIC-ISLETS

The dynamics of the cationic and secretory response to A-4166, a hypog lycemic meglitinide analogue, was investigated in rat islets prelabell ed with either Rb-86 or Ca-45 and placed in a perifusion system. In th e absence of D-glucose, A-4166 (10 mu M) provoked an immediate, sustai ned and rapidly reversible inhibition of Rb-86 outflow, this contrasti ng with a short-lived stimulation of insulin release. In the presence of 6 mM D-glucose, A-4166 provoked a rapid, sustained and rapidly reve rsible stimulation of both insulin release and Ca-45 efflux. The latte r cationic response was suppressed in the absence of extracellular Ca2 +, in which case A-4166 even caused a modest decrease in effluent radi oactivity. These findings support the view that A-4166 acts mainly in the islet B-cell by closing ATP-responsive K+ channels, leading to sub sequent depolarization of the plasma membrane and gating of voltage-se nsitive Ca2+ channels. Independently of the latter effect, A-4166 may also affect the intracellular distribution of Ca2+ ions. The present d ata 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 o r glimepiride.