Vol. 289, Issue 2, 625-631, May 1999

Insulinotropic Effect of New Glibenclamide Isosteres¹

R. Ouedraogo, Q.-A. Nguyen, M.-H. Antoine, C. Kane, M.J. Dunne, L. Pochet, B. Masereel and P. Lebrun

Laboratory of Pharmacology, Université Libre de Bruxelles, Bruxelles, Belgium (R.O., Q.-A.N., M.-H.A., P.L.); Department of Pharmacy, Université de Namur, Namur, Belgium (L.P., B.M.); and Department of Biomedical Science, The University of Sheffield, Sheffield, United Kingdom (C.K., M.J.D.)

The aim of the present study was to characterize the effects of BM 208 (N-[4-(5-chloro-2-methoxybenzamidoethyl)benzenesulfonyl]-N'-cyano-N"-cyclohexylguanidine) and BM 225 (1-[4-(5-chloro-2-methoxybenzamidoethyl)benzene sulfonamido]-1-cyclohexylamino-2-nitroethylene), two newly synthesized isosteres of glibenclamide, on ionic and secretory events in rat pancreatic islet cells. Both compounds inhibited ⁸⁶Rb (⁴²K substitute) outflow from rat pancreatic islets perifused throughout at low (2.8 mM) D-glucose concentration. In excised inside-out membrane patches, BM 208 and BM 225 reduced the frequency of K_ATP⁺ channel openings. The inhibition of ⁸⁶Rb outflow induced by BM 208 and BM 225 coincided with an increase in ⁴⁵Ca outflow. The latter phenomenon was abolished in islets exposed to Ca²⁺-free media. Both isosteres of glibenclamide increased the [Ca²⁺]_i in single pancreatic islet cells. This effect was counteracted by verapamil, a Ca²⁺ entry blocker. In islets exposed to 2.8 mM glucose and extracellular Ca²⁺, BM 208 and BM 225 stimulated insulin output. The secretory capacity of BM 225 was more marked than that of BM 208, but the time courses of the cationic and secretory responses exhibited obvious dissociations. These data suggest that the secretory capacity of BM 208 and BM 225 results, at least in part, from the inhibition of ATP-sensitive K⁺ channels with subsequent increase in Ca²⁺ inflow. The dissociation between cationic and secretory variables further suggests that the modifications in Ca²⁺ handling are not solely attributable to a primary inhibition of the ATP-sensitive K⁺ channels.