Effects of putative activators of K+ channels in mouse pancreatic beta-cells

Abstract

1 The vasodilator and antihypertensive properties of pinacidil, cromakalim (BRL 34915), nicorandil and minoxidil sulphate may be due, at least in part, to their ability to open K+ channels in vascular smooth muscles. In this study, mouse pancreatic islets were used to determine whether these drugs affect insulin release by acting on K+ channels of beta-cells. Their effects were compared to those of diazoxide. 2 Diazoxide caused a dose-dependent inhibition of insulin release by islets incubated with 15 mM glucose (93% at 100 microM). Pinacidil inhibited release by 36 and 72% at 100 and 500 microM, respectively. Cromakalim and nicorandil were less effective (35 and 25% inhibition at 500 microM). Minoxidil sulphate increased insulin release at 500 microM. 3 In the presence of 7 mM glucose and in the absence of Ca2+ (to avoid activation of Ca2+-dependent K+ channels), 86Rb efflux from islet cells was increased by 100-500 microM pinacidil and 500 microM nicorandil, which were, however, less potent than diazoxide. Cromakalim was ineffective, whereas 500 microM minoxidil sulphate decreased the efflux rate. In the absence of glucose and presence of Ca2+, 500 microM cromakalim and minoxidil sulphate inhibited 86Rb efflux. 4 Like diazoxide, pinacidil (500 microM) abolished glucose-induced electrical activity in beta-cells and hyperpolarized the membrane. 5 ATP-sensitive K+ currents were studied in single beta-cells by the whole cell patch-clamp technique. Pinacidil increased the current less than did diazoxide. In contrast, cromakalim and minoxidil sulphate decreased K+-currents whilst nicorandil was without effect. 6. It is concluded that pinacidil, like diazoxide, inhibits insulin release from beta l-cells by opening ATP-sensitive K+ channels, whereas the smaller inhibitory effects of cromakalim and nicorandil may involve actions other than on K+ channels in these cells. Minoxidil sulphate potentiates glucose-induced insulin release, probably by inhibiting ATP-sensitive K+ channels. However, all these effects of the vasodilators are only seen at high concentrations and are thus unlikely to occur in vivo.