Further characterization of the presynaptic alpha-1 receptor modulating [3H]ACh release from rat atria

We have reported previously that norepinephrine (NE) and epinephrine reduce acetylcholine (ACh) overflow from superfused rat atria apparently through interaction with a presynaptic alpha-1 receptor. To characterize further this novel alpha-1-mediated effect, we tested the ability of a series of alpha antagonists and agonists to modulate ACh release in this preparation. The alpha-1 selective antagonists YM 12617 and WB 4101 blocked the inhibitory action of NE with IC50 values of about 0.1 and 1 nM, respectively, whereas the alpha-2 selective antagonists Wy 26703 and rauwolscine were much less potent. These data are consistent with the involvement of an alpha-1 receptor in the response to NE. ACh release was diminished by (-)-alpha-methyl-NE but similar concentrations of the alpha-2 selective agonists B-HT 920 and UK 14304 had no effect on ACh release. A number of alpha-1 selective agonists including amidephrine, cirazoline, St 587 and SK&F 89748 failed to inhibit [3H]ACh release or had only a small effect (phenylephrine). When tested as antagonists, however, phenylephrine, cirazoline and SK&F 89748 could block the inhibitory effect of NE at concentrations consistent with their affinities at alpha-1 receptors in other systems. These compounds thus bind to but do not activate the alpha receptor regulating ACh release, apparently due to their low efficacies compared to NE. Experiments carried out after alpha receptor inactivation with phenoxybenzamine demonstrate that there is little receptor reserve for the inhibition of ACh release by NE.(ABSTRACT TRUNCATED AT 250 WORDS)