Dynamics of the cationic and secretory responses to A-4166 in perifused pancreatic islets

Fundam Clin Pharmacol. 1997;11(4):300-4. doi: 10.1111/j.1472-8206.1997.tb00842.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Calcium / metabolism*
  • Cyclohexanes / pharmacology*
  • Female
  • Glucose / pharmacology
  • Hypoglycemic Agents / pharmacology*
  • Insulin / metabolism*
  • Insulin Secretion
  • Nateglinide
  • Pancreas / drug effects*
  • Pancreas / metabolism
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / pharmacology
  • Rats
  • Rats, Wistar
  • Rubidium / metabolism*
  • Time Factors


  • Benzamides
  • Cyclohexanes
  • Hypoglycemic Agents
  • Insulin
  • Nateglinide
  • Phenylalanine
  • meglitinide
  • Glucose
  • Rubidium
  • Calcium