4‐Aminopyridine‐induced increase in basal and stimulation‐evoked [3H]‐NA release in slices from rat hippocampus: Ca2+ sensitivity and presynaptic control

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Abstract
1 We have examined the mechanisms by which the K+-channel blocker 4-aminopyridine (4-AP) can dose-dependently increase both basal [3H]-noradrenaline ([3H]-NA) release and the [3H]-NA release evoked by electrical stimulation, but not the release of [3H]-acetylcholine ([3H]-ACh), from slices of rat hippocampus. 2 Both the electrically evoked and the 4-AP-induced release were blocked by tetrodotoxin (TTX) (3 μm). The Ca2+-dependence of the 4-AP-induced release (EC50 0.15 mm) was, however, different from that of the electrically evoked [3H]-NA release (EC50 0.76 mm). 3 The 4-AP-induced release could be inhibited by CdCl2(10 μm) and ω-conotoxin (30 nm), but not by nifedipine (1 μm). 4 Transmitter release evoked by 100 μm 4-AP could be blocked by the α2-adrenoceptor agonist, UK 14,304 (0.1 μm) and by the A1-receptor agonist R-N6-phenylisopropyl adenosine (R-PIA, 1 μm) and increased by the α2-adrenoceptor antagonist, yohimbine (1 μm), both in 0.25 and 1.3 mm Ca2+-containing medium. By contrast, the effect of α2-adrenoceptor agonists and antagonists on transmitter release evoked by electrical stimulation was markedly reduced in the presence of 4-AP (100 μm). 5 The results suggest that 4-AP can depolarize some nerve endings in the central nervous system, leading to transmitter release that is dependent on nerve impulses and Ca2+. Furthermore, the fact that α2-receptors and adenosine A1 receptor agonists can influence the release of NA evoked by 4-AP suggests that these drugs may have actions that are independent of blockade of aminopyridine-sensitive K+-channels.