Comparison of the effects of four dendrotoxin peptides, 4-aminopyridine and tetraethylammonium on the electrically evoked [3H]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 [3H]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 microM) and TEA (0.1-5 mM) facilitated the evoked [3H]NA release in a concentration-dependent manner. The evoked [3H]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 microM), 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 [3H]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 [3H]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 [3H]p-aminoclonidine ([3H]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.(ABSTRACT TRUNCATED AT 250 WORDS)
Hu
P S
PS
Department of Pharmacology, Karolinska Institute, Stockholm, Sweden.
Benishin
C
C
Fredholm
B B
BB
D015761:4-Aminopyridine / Q000378:metabolism / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000031:analogs & derivatives / Q000378:metabolism; D004546:Elapid Venoms / Q000378:metabolism / Q000494:pharmacology*; D004558:Electric Stimulation; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000378:metabolism / Q000494:pharmacology*; D014316:Tritium
D000316:Adrenergic alpha-Agonists; D004546:Elapid Venoms; D010446:Peptide Fragments; D010455:Peptides; D011810:Quinoxalines; D011942:Receptors, Adrenergic, alpha; D013757:Tetraethylammonium Compounds; D014316:Tritium; C081640:dendrotoxin, beta; C081639:dendrotoxin, gamma; D000068438:Brimonidine Tartrate; D019789:Tetraethylammonium; C020273:dendrotoxin; C016986:apraclonidine; D015761:4-Aminopyridine; D003000:Clonidine; D009638:Norepinephrine