Supramaximal decrease of sulphonylurea-induced accumulation of sodium in pancreatic islets

Abstract

Sodium was measured in β-cell-rich pancreatic islets of mice under steady state conditions or after 6 min of exposure to I mm ouabain. The islet content of sodium increased when 100,μ M tolbutamide or 1 μ M glipizide were added to an albumin-containing (1 mg ml −1) medium, but remained unaffected at 10-fold higher concentrations. Both sulphonylurea compounds promoted the uptake of Na + in the presence of ouabain. Whereas tolbutamide was stimulatory at 10μ M or above in a medium containing 10 mg ml − albumin, only 0.1 μ M was required in the absence of albumin. In the latter situation there was a reduction of the stimulatory action with increase of the tolbutamide concentration from 100 to 1000 μ M. The inhibitory component in the sulphonylurea action on the Na + uptake was particularly impressive with glipizide, maximal stimulation being reached at 10 μ M in the presence of 1 mg ml − albumin. Diazoxide (400 μ M) modified the glipizide action on Na + uptake, making 1000 μ M stimulatory instead of 1 μ M. The latter concentration of glipizide became inhibitory after removal of K +. Glipizide stimulated the Na + uptake both at low and high concentrations in a medium deficient in Ca 2+ or when the cotransport of Na +, K + and Cl − was blocked by 20 μ M bumetanide. The observation that the sulphonylurea-induced islet accumulation of sodium is diminished at supramaximal concentrations reinforces existing arguments for additional effects of high concentrations of hypoglycemic sulphonylureas.