COMPARISON OF THE EFFECTS OF 4 DENDROTOXIN PEPTIDES, 4-AMINOPYRIDINE AND TETRAETHYLAMMONIUM ON THE ELECTRICALLY EVOKED [H-3] NORADRENALINE RELEASE FROM RAT HIPPOCAMPUS

We have examined the effects of four dendrotoxin (DaTX) peptides, alpha-, beta-, gamma- and delta-DaTX, separated from the venom of the green mamba (Dendroaspis angusticeps), on field stimulation-evoked [H-3]noradrenaline (NA) release from rat hippocampus and compared their effects with those of two other inhibitors of K+ channels, 4-aminopyridine (4-AP) and tetraethylammonium (TEA). 4-AP (10-300-mu-M) and TEA (0.1-5 mM) facilitated the evoked [H-3]NA release in a concentration-dependent manner. The evoked [H-3]NA release was reduced to about half by alpha(2)-adrenoceptor stimulation (UK 14,304; 100 nM) and this reduction was antagonized by 4-AP (10-100-mu-M), whereas TEA even at 5 mM was a poor inhibitor of alpha(2)-effects. Alpha-DaTX (10-200 nM) mimicked 4-AP in increasing the electrically evoked [H-3]NA release and diminishing the inhibitory effects of UK 14,304 in a concentration-dependent manner. Delta-DaTX did not itself alter the electrically evoked [H-3]NA release, but at 200 nM, it reduced the effects of alpha(2)-receptor stimulation. Beta- and gamma-DaTX (up to 200 nM) had no significant effects. 4-AP, 3,4-diaminopyridine (3,4-DAP), TEA and the four dendrotoxins displaced the binding of [H-3]p-aminoclonidine ([H-3]PAC) from alpha(2)-receptors. The IC50 values were 6.6 x 10(-4), 1.42 x 10(-3), 5.6 x 10(-2) for 4-AP, 3,4-DAP and TEA, respectively, and 3.19 x 10(-6) M for alpha-DaTX. Thus, their potency as inhibitors of alpha(2)-receptors is apparently too low to account alone for the antagonism by K+ channel inhibitors of alpha(2)-effects on NA release. In conclusion, K+ channels that can be inhibited by both 4-AP and alpha-DaTX appear to be important in the regulation of [H-3]NA release evoked by electrical field stimulation. The antagonism of presynaptic alpha(2)-adrenoceptor agonists by K+ channel inhibitors can be caused by a combination of direct receptor actions, increased amounts of endogenous agonist in the biophase and functional antagonism.