3-Morpholinosydnonimine as instigator of a glibenclamide-sensitive reduction of the insulin secretory rate

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Hydroxylamine, a nitric oxide donor, inhibits insulin release and activates K+ATP channels.

The present study was undertaken to assess the effects of hydroxylamine, a nitric oxide (NO) donor, on ionic and secretory events in rat pancreatic islets. Hydroxylamine provoked a concentration-dependent inhibition of the glucose-induced insulin release. This inhibitory action was counteracted by glibenclamide. Moreover, hydroxylamine increased the rate of 86Rb outflow from perifused islets. This effect persisted in the absence of external Ca2+ but was impaired by glibenclamide. Hydroxylamine decreased 45Ca outflow, [Ca2+]i and insulin output from islets exposed to 16.7 mM glucose and extracellular Ca2+. By contrast, hydroxylamine did not affect the increase in 45Ca outflow and [Ca2+]i evoked by K+ depolarization. These experimental results suggest that the negative insulinotropic action of the NO donor results, at least in part, from the activation of ATP-sensitive K+ channels leading to a decrease in Ca2+ influx and [Ca2+]i. Additional mechanisms, however, could also be involved in the NO donor modulation of the secretory process.In VitroJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

In vitro and in vivo effects of new insulin releasing agents.

The present study aimed at characterizing in vitro and in vivo 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 new isosteres of the hypoglycemic sulfonylurea glibenclamide. In rat pancreatic islets perifused at close to normal (8.3mM) D-glucose concentration, both BM 208 and BM 225 (10 and 25 microM) increased 45Ca outflow and insulin release. The compounds did not affect the 45Ca outflow rate from islets exposed to Ca(2+)-free media. In single pancreatic islet cells loaded with the fluorescent Ca(2+) indicator fura-2 and incubated in the presence of 8.3mM glucose, BM 208 and BM 225 raised the [Ca(2+)](i). All these findings indicate that, in islet cells exposed to a physiological concentration of D-glucose, the secretory capacity of the new glibenclamide isosteres is related to a facilitation of Ca(2+) entry. The potency and duration of action of BM 225 was, however, more pronounced than that of BM 208. Successive additions of BM 208 provoked repeated increments in 45Ca outflow and insulin release, without evidence of tachyphylaxis. Lastly, intraperitoneal injection of BM 208 and BM 225 to fed rats lowered plasma glucose concentration in a dose-dependent manner. BM 225 was more potent and acting faster than BM 208. Our results indicate that appropriate structural modification can generate isosteres of glibenclamide with different features and activity profiles.In VitroJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe