Phentolamine and yohimbine inhibit ATP‐sensitive K+ channels in mouse pancreatic β‐cells

1 The effects of phentolamine and yohimbine on adenosine 5‐triphosphate (ATP)‐sensitive K + channels were studied in normal mouse β‐cells. 2 In the presence of 3 mM glucose, many ATP‐sensitive K + channels are open in the β‐cell membrane. Under these conditions, phentolamine inhibited 86 Rb efflux from the islets. This inhibition was faster with 100 than with 20 μ m phentolamine but its steady‐state magnitude was similar with both concentrations. Yohimbine (20–100 μ m ) also inhibited the efflux rate but was not as potent as phentolamine. 3 In the presence of 6 mM glucose, most ATP‐sensitive K + channels are closed in the β‐cell membrane. Their opening by 100 μ m diazoxide caused a marked acceleration of 86 Rb efflux from the islets. This acceleration was almost entirely prevented by 20 μ m phentolamine. It was barely affected by 20 μ m yohimbine and reduced by 50% by 100 μ m yohimbine. 4 ATP‐sensitive K + currents were studied in single β‐cells by the whole cell patch‐clamp technique. Phentolamine (20–100μ m ) caused a progressive but almost complete and irreversible inhibition of the current. The effects of yohimbine were faster but smaller; the inhibition was still incomplete with 100 μ m yohimbine. 5 The increase in ATP‐sensitive K + current produced by 100 μ m diazoxide was prevented by 100 μ m phentolamine but only partially attenuated by 100 μ m yohimbine. 6 It is concluded that phentolamine inhibits ATP‐sensitive K + channels in pancreatic β‐cells. This novel effect of phentolamine resembles that of hypoglycaemic sulphonylureas. It may account for previously unexplained effects of the drug. These observations also call for reinterpretation of many studies in which phentolamine was used as an allegedly specific blocker of α‐adrenoceptors.