SUPRAMAXIMAL DECREASE OF SULFONYLUREA-INDUCED ACCUMULATION OF SODIUM IN PANCREATIC-ISLETS

Sodium was measured in beta-cell-rich pancreatic islets of mice under steady state conditions or after 6 min of exposure to 1 mM ouabain, Th e islet content of sodium increased when 100 mu M tolbutamide or 1 mu M glipizide were added to an albumin-containing (1 mg ml(-1)) medium, but remained unaffected at 10-fold higher concentrations, Both sulphon ylurea compounds promoted the uptake of Na+ in the presence of ouabain , Whereas tolbutamide was stimulatory at 10 mu M or above in a medium containing 10 mg ml(-1) albumin, only 0.1 mu M was required in the abs ence of albumin, In the latter situation there was a reduction of the stimulatory action with increase of the tolbutamide concentration from 100 to 1000 mu M. The inhibitory component in the sulphonylurea actio n on the Na+ uptake was particularly impressive with glipizide, maxima l stimulation being reached at 10 mu M in the presence of 1 mg ml(-1) albumin. Diazoxide (400 mu M) modified the glipizide action on Na+ upt ake, making 1000 mu M stimulatory instead of 1 mu M. The latter concen tration of glipizide became inhibitory after removal of K+. Glipizide stimulated the Na+ uptake both at low and high concentrations in a med ium deficient in Ca2+ or when the cotransport of Na+, K+ and Cl- was b locked by 20 mu M bumetanide. The observation that the sulphonylurea-i nduced islet accumulation of sodium is diminished at supramaximal conc entrations reinforces existing arguments for additional effects of hig h concentrations of hypoglycemic sulphonylureas.