Lack of Ca2+ ionophoretic activity of hypoglycemic sulfonylureas in excitable cells and isolated secretory granules.

Beta-Cell-rich pancreatic islets, neurohypophyses, and adrenal medullae were used for exploring whether hypoglycemic sulfonylureas exhibit Ca2+ ionophoretic properties. Exposure of these excitable organs to depolarizing concentrations of K+ resulted in stimulation both of 45Ca uptake and efflux. Although tolbutamide does not bind preferentially to pancreatic islets, this sulfonylurea was specific in stimulating the fluxes of 45Ca in these endocrine specimens. A chromaffin granule preparation was used for studies of both the net transport of Ca2+ with the metallochromic indicator arsenazo III and the proton concentration gradient (delta pH) with the fluorescent probe 9-aminoacridine. Even at high concentrations, tolbutamide and glibenclamide did not mediate Ca2+ -H+ exchange diffusion whether or not the granules were made permeable to protons by the addition of the protonophore carbonyl cyanide rho-trifluoromethoxyphenylhydrazone, nor did the sulfonylureas affect Ca2+ -H+ exchange diffusion induced by the addition of A-23187. The data indicate that the Ca2+ fluxes associated with sulfonylurea-stimulated insulin secretion do not result from the Ca2+ -ionophoretic properties of the drugs but rather reflect depolarization of the beta-cells.