4-Aminopyridine-induced increase in basal and stimulation-evoked [3H]-NA release in slices from rat hippocampus: Ca2+ sensitivity and presynaptic control.
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 microM). The Ca(2+)-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 microM) and omega-conotoxin (30 nM), but not by nifedipine (1 microM). 4. Transmitter release evoked by 100 microM 4-AP could be blocked by the alpha 2-adrenoceptor agonist, UK 14,304 (0.1 microM) and by the A1-receptor agonist R-N6-phenylisopropyl adenosine (R-PIA, 1 microM) and increased by the alpha 2-adrenoceptor antagonist, yohimbine (1 microM), both in 0.25 and 1.3 mM Ca(2+)-containing medium. By contrast, the effect of alpha 2-adrenoceptor agonist and antagonists on transmitter release evoked by electrical stimulation was markedly reduced in the presence of 4-AP (100 microM). 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 alpha 2-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.
Department of Pharmacology, Karolinska Institutet, Stockholm, Sweden.
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Fredholm
D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013779:Tetrodotoxin / Q000494:pharmacology; D014316:Tritium
D015221:Potassium Channels; D014316:Tritium; D013779:Tetrodotoxin; D015761:4-Aminopyridine; D002118:Calcium; D009638:Norepinephrine