ATP-dependent potassium channels

Repaglinide en nateglinide are not sulfonylurea agents but their mechanism of action is very alike. Repaglinide is the first carbamoylmethyl-benzoic acid derivative that has been registred for the treatment of diabetes mellitus. It closes ATP-dependent potassium channels in the beta cell membrane with consequent depolarization, opening of calcium channels and increased insulin release. It is rapidly absorbed with peak plasma levels after 1 hour. It has a protein binding of over 98%. 

Ocana, M., Del Pozo, E., Barrios, M., Robles, L. I., Baeyens, J. M. An ATP-dependent potassium channel blocker antagonizes morphine analgesia, European Journal of Pharmacology 1990, 186, 377-378. 

The meglitinides bind with high affinity to a site, distinct from the sulfonylurea receptor site, on the ATP-sensitive potassium channels in pancreatic beta cells and stimulate insulin secretion. After binding, the ATP-dependent potassium channels are closed, reducing potassium efflux and depolarizing the cell membrane. The meglitinides do not have to be internalized in the membrane, in contrast to the sulfonylureas. This may explain their rapid onset of... 

New data on the sulfonylurea receptor as part of the ATP-dependent potassium channel (SUR-1 in the beta pancreatic cells, involved in insulin secretion, and SUR-2 in the myocardium, involved in cardiac adaptation during ischemia) has still not yielded a definitive answer. The available experimental and clinical data have been systematically reviewed (29). The conclusion was that experimentally the effects of sulfonylureas on heart muscle are both deleterious and protective for glibenclamide while tolbutamide, glimepiride, and gliclazide have no effects. There seem to be no adverse cardiac consequences of chronic treatment with sulfonylureas. 

Minoxidil is a vasodilator selective for arterioles rather than for veins, similar to diazoxide and hydralazine. Like the former, it acts through its sulphate metabolite as an ATP-dependent potassium channel opener. It is highly effective in severe hypertension, but causes increased cardiac output, tachycardia, fluid retention and hypertrichosis. The hair growth is generalised and although a cosmetic problem in women, it has been exploited as a topical solution for the treatment of baldness in men. 

Diazoxide is chemically a thiazide but has no appreciable diuretic effect indeed, like other potent arterial vasodilators it causes salt and water retention. It reduces peripheral arteriolar resistance through activation of the ATP-dependent potassium channel (c.f. nicorandil and minoxidil), with little effect on veins. The t) is 36 h. 

Nicorandil is an effective vasodilator through two actions. It acts as a nitrate by activating cyclic GMP (see above) but also opens the ATP-dependent potassium channel to allow potassium efflux and h5rperpolarisation of the membrane which reduces calcium ion entry and induces muscular relaxation. It is indicated for use in angina, where it has similar efficacy to p-blockade, nitrates or calcium channel blockade. It is administered orally and is an alternative to nitrates when tolerance to these is a problem, or to the other classes when these are contraindicated by asthma or cardiac failure. Adverse effects to nicorandil are similar to those of nitrates, with headache reported in 35% of patients. It is the only antianginal drug for which at least one trial has demonstrated a beneficial influence upon outcome. ... 

Repaglinide is a very short-acting oral hypogly-caemic agent whose action, like the sulphonylureas, is mediated through blockade of ATP-dependent potassium channels. It affects only postprandial insulin profiles, and should in theory reduce risk of hypoglycaemia. 

The authors suggested that cibenzoline may have inhibited ATP-dependent potassium channels in skeletal muscle. The plasma cibenzoline concentration at the height of this patient s symptoms was very high at 1890 pg/ml (usual target range 300-600) and the authors counselled caution in patients with renal insufficiency (SEDA-15, 174). 

Gross GJ, Auchampach JA. Role of ATP dependent potassium channels in myocardial ischaemia. Cardiovasc Res 1992 26(11) 1011-16. 

Y. Liu, T. Sato, B. O Rourke and E. Marban, Mitochondrial ATP-dependent potassium channels novel effectors of cardioprotection Circulation 97,2463-2469, (1998). 

Compound 41 produces a concentration-dependent relaxation in vessels precontracted with phenylephrine, exerting significant vasodilatation starting at concentrations of 25-50 Blockers of ATP-dependent potassium channels or... 

FJ. Ortega, J. Gimeno-Bayon, J.E Espinosa-Parrilla, J.L. Carrasco, M. Batlle, M. Pugliese, N. Mahy, and M.J. Rodriguez, ATP-dependent potassium channel blockade strengthens microglial neuroprotection after hypoxia-ischemia in rats. Exp. Neurol. 235(1), 282-296 (2012). 

Riesco-Fagundo AM, Perez-Garcia MT, Gonzalez C, Lopez-Lopez JR. O2 modulates large-conductance Ca -dependent K+ channels of rat chemoreceptor cells hy a membrane-restricted and CO-sensitive mechanism. Circ Res 2001 89 430-436. Rustenheck I, Dickel C, Herrmann C, Giimmsmann T. Mitochondria present in excised patches from pancreatic B-cells may form microcompartments with ATP-dependent potassium channels. Biosci Rep 1999 19 89-98. 

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