ATP-sensitive potassium (K(ATP)) channels link membrane excitability to metabolism. They are regulated by intracellular nucleotides and by other factors including membrane phospholipids, protein kinases and phosphatases. K(ATP) channels comprise octamers of four Kir6 pore-forming subunits associated with four sulphonylurea receptor subunits. The exact subunit composition differs between the tissues in which the channels are expressed, which include pancreas, cardiac, smooth and skeletal muscle and brain. K(ATP) channels are targets for antidiabetic sulphonylurea blockers, and for channel opening drugs that are used as antianginals and antihypertensives. This review focuses on non-pancreatic K(ATP) channels. In vascular smooth muscle, K(ATP) channels are extensively regulated by signalling pathways and cause vasodilation, contributing both to resting blood flow and vasodilator-induced increases in flow. Similarly, K(ATP) channel activation relaxes smooth muscle of the bladder, gastrointestinal tract and airways. In cardiac muscle, sarcolemmal K(ATP) channels open to protect cells under stress conditions such as ischaemia or exercise, and appear central to the protection induced by ischaemic preconditioning (IPC). Mitochondrial K(ATP) channels are also strongly implicated in IPC, but clarification of their exact role awaits information on their molecular structure. Skeletal muscle K(ATP) channels play roles in fatigue and recovery, K+ efflux, and glucose uptake, while neuronal channels may provide ischaemic protection and underlie the glucose-responsiveness of hypothalamic neurones. Current therapeutic considerations include the use of K(ATP) openers to protect cardiac muscle, attempts to develop openers selective for airway or bladder, and the question of whether block of extra-pancreatic K(ATP) channels may cause adverse cardiovascular side-effects of sulphonylureas.

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The sulphonylurea gliclazide is widely used in the treatment of Type II (non-insulin-dependent) diabetes mellitus because of its ability to stimulate insulin secretion from pancreatic beta-cells. Like other sulphonylureas, its principal target is the ATP-sensitive potassium (K ATP ) channel. This channel plays a major role in controlling the beta-cell membrane potential and thereby insulin release. At low plasma glucose concentrations, K ATP channels are open and the resulting K + efflux holds the beta-cell membrane at a hyperpolarized potential. Closure of K ATP channels by glucose or sulphonylureas causes depolarization of the beta-cell membrane, leading to opening of voltage-gated Ca 2+ channels, Ca 2+ influx and a rise in intracellular Ca 2+ which stimulates the exocytosis of insulin-containing secretory granules [1].K ATP channels are also found in a variety of other cell types including cardiac, smooth and skeletal muscle, and some brain neurones [2]. Although their roles in extrapancreatic tissues are less well characterised, it is likely that they open in response to metabolic stress, such as during cardiac and cerebral is- Abstract Aims/hypothesis. Sulphonylureas stimulate insulin secretion by closing ATP-sensitive potassium (K ATP ) channels in the pancreatic beta-cell membrane. K ATP channels are also found in other tissues, including heart and smooth muscle, where they link cellular metabolism to electrical activity. The sulphonylurea gliclazide blocks recombinant beta-cell K ATP channels (Kir6.2/ SUR1) but not heart (Kir6.2/SUR2A) or smooth muscle (Kir6.2/SUR2B) K ATP channels with high potency. In this study, we examined the specificity of gliclazide for the native (as opposed to recombinant) K ATP channels in beta cells, heart and smooth muscle. Methods. The action of the drug was studied by whole-cell current recordings of native K ATP channels in isolated pancreatic beta-cells and myocytes from heart and smooth muscle. Results. Gliclazide blocked whole-cell beta-cell K ATP currents with an IC 50 of 184 30 nmol/l (n = 6±10) but was much less effective in cardiac and smooth muscle (IC 50 s of 19.5 5.4 mmol/l (n = 6±12) and 37.9 1.0 mmol/l (n = 5±10), respectively). In all three tissues, the action of the drug on whole-cell K ATP currents was rapidly reversible. In inside-out patches on beta-cells, gliclazide (1 mmol/l) produced a maximum of 66 13 % inhibition (n = 5), compared with more than 98 % block in the whole-cell configuration. Conclusion/interpretation. Gliclazide is a high-potency sulphonylurea which shows specificity for the pancreatic beta-cell K ATP channel over heart and smooth muscle. In this respect, it differs from glibenclamide. The difference in the maximal block observed in the excised patch and whole-cell recordings from betacells, may be due to the absence of intracellular Mgnucleotides in the excised patch experiments. [Diabetologia (2001

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