ITERATIVE STIMULATION OF PANCREATIC-ISLETS BY GLIPIZIDE

Iterative administrations of glipizide (2 mumol/l) for 10 min each to perifused rat pancreatic islets provoked at low glucose concentration (2.8 mmol/l) rapid and rapidly reversible decreases in Rb-86 outflow, rapid and rapidly reversible increases in Ca-45 outflow and modest stimulations of insulin release. In the presence of Ca2+, the reascension in Rb-86 outflow was preceded by a transient fall in effluent radioactivity upon withdrawal of the sulfonylurea. At a higher concentration of D-glucose (8.3 mmol/l), glipizide provoked, each time, biphasic and rapidly reversible increases in both Rb-86 and Ca-45 outflow, as well as in insulin release. These results are compatible with the view that glipizide decreases K+ conductance, leading to depolarization of the B-cell plasma membrane and gating of voltage-sensitive Ca2+ channels. In the presence of 8.3 mmol/l D-glucose, however, the inhibitory effect of glipizide on effluent K+ permeability may be masked by activation of Ca2+-sensitive K+ channels. The present data also indicate that glipizide is able to evoke, at the occasion of iterative administrations, biphasic ionic and secretory responses, without evidence of tachyphylaxis.