Insulinotropic effect of new glibenclamide isosteres

The aim of the present study was to characterize the effects of BM 208 (N-[ 4-(5-chloro-2-metoxybenzamidoethyl)benzensulfonyl]-N'-cyano-N'-cyclohexylgu anidine) and BM 225 (1-[4-(5-chloro-2-methoxybenzamidoethyl)benzene sulfona mido]-1-cyclohexylamino-2-nitroethylene), two newly synthesized isosteres o f glibenclamide, on ionic and secretory events in rat pancreatic islet cell s. Both compounds inhibited Rb-86 (K-42 substitute) outflow from rat pancre atic islets perifused throughout at low (2.8 mM) D-glucose concentration. I n excised inside-out membrane patches, BM 208 and BM 225 reduced the freque ncy of K-ATP(+) channel openings. The inhibition of Rb-86 outflow induced b y BM 208 and BM 225 coincided with an increase in Ca-45 outflow. The latter phenomenon was abolished in islets exposed to Ca2+-free media. Both isoste res of glibenclamide increased the [Ca2+](i) in single pancreatic islet cel ls. This effect was counteracted by verapamil, a Ca2+ entry blocker. In isl ets exposed to 2.8 mM glucose and extracellular Ca2+, BM 208 and BM 225 sti mulated insulin output. The secretory capacity of BM 225 was more marked th an that of BM 208, but the time courses of the cationic and secretory respo nses exhibited obvious dissociations. These data suggest that the secretory capacity of BM 208 and BM 225 results, at least in part, from the inhibiti on of ATP-sensitive K+ channels with subsequent increase in Ca2+ inflow. Th e dissociation between cationic and secretory variables further suggests th at the modifications in Ca2+ handling are not solely attributable to a prim ary inhibition of the ATP-sensitive K+ channels.