Imidazoline antagonists of α2‐adrenoceptors increase insulin release in vitro by inhibiting ATP‐sensitive K+ channels in pancreatic β‐cells

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Abstract
1 Islets from normal mice were used to study the mechanisms by which imidazoline antagonists of α2-adrenoceptors increase insulin release in vitro. 2 Alinidine, antazoline, phentolamine and tolazoline inhibited 86Rb efflux from islets perifused with a medium containing 3 mm glucose, i.e. under conditions where many adenosine 5′-triphosphate (ATP)-sensitive K+ channels are open in the β-cell membrane. They also reduced the acceleration of 86Rb efflux caused by diazoxide, an opener of ATP-sensitive K+ channels. 3 ATP-sensitive and voltage-sensitive K+ currents were measured in single β-cells by the whole-cell mode of the patch-clamp technique. Antazoline more markedly inhibited the ATP-sensitive than the voltage-sensitive current, an effect previously observed with phentolamine. Alinidine and tolazoline partially decreased the ATP-sensitive K+ current. 4 The four imidazolines reversed the inhibition of insulin release caused by diazoxide (through opening of ATP-sensitive K+ channels) or by clonidine (through activation of α2-adrenoceptors) in a concentration-dependent manner. Only the former effect correlated with the ability of each drug to increase control insulin release stimulated by 15 mm glucose alone. 5 It is concluded that the ability of imidazoline antagonists of α2-adrenoceptors to increase insulin release in vitro can be ascribed to their blockade of ATP-sensitive K+ channels in β-cells rather than to their interaction with the adrenoceptor.