ACTIVATION OF ATP-DEPENDENT K- EFFECT OF BPDZ-62( CHANNELS AND INHIBITION OF INSULIN RELEASE )

The present study was undertaken to characterize the effects of BPDZ 6 2, an original pyridothiadiazine derivative structurally related to bo th diazoxide and pinacidil, on ionic and secretory events in rat pancr eatic islet cells. BPDZ 62 increased the rate of Rb-86 outflow from is lets perfused in the presence or absence of extracellular glucose. The se effects persisted in the absence of extracellular Ca++ but were abo lished by glibenclamide. Such data support the view that BPDZ 62 activ ates ATP-sensitive K+ (K-ATP) channels. This proposal was substantiate d by the finding that the drug enhanced the flow of current through K- ATP channels in excised inside-out membrane patches. BPDZ 62 markedly decreased Ca-45 uptake, Ca-45 outflow and insulin output from islets i ncubated in the presence of 16.7 mM glucose. By contrast, the drug did not affect the increase in Ca-45 outflow and Ca-45 uptake mediated by K+ depolarization. In single B cells, BPDZ 62 inhibited the glucose b ut not the KCl-induced rise in [Ca++](i). It is concluded that the inh ibitory effect of BPDZ 62 on the insulin-releasing process results fro m the activation of K-ATP channels leading to a decrease in Ca++ influ x and [Ca++](i). Last, BPDZ 62 was shown to be five times more potent than diazoxide at inhibiting the insulin-releasing process. This sugge sts that BPDZ 62 could be a valuable pharmacological tool for further characterization of B-cell K-ATP channels.