Paradoxical inhibitory effect of cromakalim on 86Rb outflow from pancreatic islet cells.

Cromakalim appears to be the most potent pharmacologic agent belonging to the new class of smooth muscle relaxants: the "K+ channel openers." The present study aimed at characterizing the effects of cromakalim on 86Rb outflow, 45Ca outflow and insulin release from prelabeled and perifused rat pancreatic islets. Cromakalim provoked a concentration-dependent reduction in 86Rb outflow. This inhibitory effect was attenuated in islets exposed throughout to glibenclamide or to a Ca+(+)-free medium. In islets exposed to glucose and extracellular Ca++, cromakalim induced a dose-dependent reduction in 45Ca outflow. The drug also inhibited the increase in 45Ca outflow mediated by K+ depolarization. Lastly, cromakalim elicited a concentration-dependent inhibition of insulin release from islets perifused in the presence of glucose and extracellular Ca++. The present data suggest that the paradoxical inhibitory effect of cromakalim on 86Rb outflow probably reflects the capacity of the drug to reduce the activity of the ATP-sensitive K+ channels and to indirectly inhibit the Ca+(+)-activated K+ channels. Furthermore, the cromakalim-induced changes in 45Ca outflow are compatible with an inhibitory effect of the drug on the voltage-dependent Ca++ channels.

Effect of a new xanthine derivative on the release of insulin from rat pancreatic islets.

S 9795 (1-methyl-3-isobutyl-8-[2-ethyl 1-(4-diphenylmethylpiperazinyl)]- 3,7-dihydro(1H)purine-2,6-dione) is a new xanthine derivative displaying antiasthmatic properties in animals. The drug might exert its pharmacological actions either by inhibiting phosphodiesterases, or by inhibiting cellular Ca2+ movements or antagonizing purinoreceptors. Since the process of glucose-induced insulin release is markedly influenced by xanthine derivatives, the effect of S 9795 was compared to that of two other xanthine derivatives (theophylline and 3-isobutyl-1-methylxanthine (IBMX] on glucose-induced insulin release and ionic fluxes in rat pancreatic islets. Theophylline and IBMX potentiated glucose-induced insulin release, as expected, while S 9795 inhibited the insulinotropic effect of glucose. The effect of S 9795 was observed at a concentration of 10(-5) mol/l, lower concentrations (10(-6) to 10(-9) mol/l) failing to affect glucose-induced insulin release. At 10(-5) mol/l, the drug also inhibited the secondary rise in 45Ca efflux evoked by glucose from preloaded islets and the uptake of 45Ca by incubated islets stimulated either by glucose or potassium. The drug failed to alter 86Rb fluxes in stimulated and unstimulated islets labelled with the radioisotope. These data show that S 9795 inhibits glucose-induced insulin release, possibly by blocking glucose-stimulated Ca2+ inflow into the B-cell.

Similarities between the effects of pinacidil and diazoxide on ionic and secretory events in rat pancreatic islets.

The present study aimed at comparing the effects of pinacidil, a putative K+ channel opener, and diazoxide on ionic and secretory events in rat pancreatic islets. Pinacidil and diazoxide provoked a dose-dependent increase in 86Rb outflow from pancreatic islets perifused in the presence of glucose. Both drugs inhibited the glucose- and tolbutamide-induced increase in 45Ca outflow and insulin release whereas failing to affect the ionic and secretory responses to K+ depolarization. Pinacidil and diazoxide, in contrast to quinine, failed to affect 86Rb outflow from pancreatic islets stimulated by the Ca++-ionophore A23187. Pinacidil as well as diazoxide abolished the glucose-induced increase in [Ca++]i but did not modify the rise in [Ca++]i provoked by KCl. Lastly, both drugs were shown to stimulate an ouabain-resistant modality of 86Rb inflow into the islet cells. The close similarities between the ionic and secretory events mediated by pinacidil and diazoxide suggest that pinacidil could interfere with the same target site as diazoxide; namely the beta-cell ATP-sensitive K+ channel.

Pinacidil inhibits insulin release by increasing K+ outflow from pancreatic B-cells.

Pinacidil, a putative K+ channel opener, increased 86Rb outflow from rat pancreatic islets perifused in the presence of glucose, 2-ketoisocaproate or tolbutamide. Furthermore, the drug markedly inhibited 45Ca outflow and insulin release from glucose-stimulated islets. These results represent the first indication of an effect of pinacidil on ionic and secretory events in endocrine cells. Indirect findings suggest that, in pancreatic islet cells, pinacidil could affect ATP-sensitive K+ channels.