Sperlagh_2001_Brain.Res_889_63

In this study the role of ATP-sensitive K(+) channels (K(ATP) channels) in the A(1) receptor mediated presynaptic inhibitory modulation of acetylcholine release was investigated in the rat hippocampus. N(6)-Cyclohexyladenosine (CHA), the selective A(1)-adenosine receptor agonist, reduced concentration-dependently the stimulation-evoked (2 Hz, 1 ms, 240 shocks) [3H]acetylcholine ([3H]ACh) release, from in vitro superfused hippocampal slices preloaded with [3H]choline, an effect prevented by the selective A(1) receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). By themselves, neither K(ATP) channel openers, i.e. diazoxide, pinacidil and cromakalim, nor glibenclamide and glipizide, the inhibitors of K(ATP) channels, exerted a significant effect on the resting and evoked release of [3H]ACh. Glibenclamide and glipizide (10-100 microM) completely prevented the inhibitory effect of 0.1 microM CHA and shifted the concentration response curve of CHA to the right. 4-Aminopyridine (10-100 microM), the non-selective potassium channel blocker, increased the evoked release of [3H]ACh, but in the presence of 4-aminopyridine, the inhibitory effect of CHA (0.1 microM) still persisted. Oxotremorine, the M(2) muscarinic receptor agonist, decreased the stimulation-evoked release of [3H]ACh, but its effect was not reversed by glibenclamide. 1,3-Diethyl-8-phenylxanthine (DPX), the selective A(1)-antagonist, effectively displaced [3H]DPCPX in binding experiments, while in the case of glibenclamide and glipizide, only slight displacement was observed. In summary, our results suggest that K(ATP) channels are functionally coupled to A(1) receptors present on cholinergic terminals of the hippocampus, and glibenclamide and glipizide, by interacting with K(ATP) channels, relieve this inhibitory neuromodulation.