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-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 KATP+ 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.
Ouedraogo
R
R
Laboratory of Pharmacology, Université Libre de Bruxelles, Bruxelles, Belgium.
Nguyen
Q A
QA
Kane
M H
MH
Dunne
M J
MJ
Pochet
L
L
Masereel
B
B
Lebrun
P
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D005260:Female; D005456:Fluorescent Dyes; D016257:Fura-2; D005905:Glyburide / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012414:Rubidium Radioisotopes; D013268:Stimulation, Chemical
C118843:BM 208; C118844:BM 225; D005456:Fluorescent Dyes; D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D012414:Rubidium Radioisotopes; D000255:Adenosine Triphosphate; D005905:Glyburide; D002118:Calcium; D016257:Fura-2