Effects of Cyclic AMP Analogues and Phosphodiesterase Inhibitors on K+-Induced [3H]Noradrenaline Release from Rat Brain Slices and on Its Presynaptic α-Adrenergic Modulation

: The possible role of cyclic AMP in the presynaptic α-adrenoceptor-mediated modulation of [3H]noradrenaline (NA) release induced by 13 mM K+ from superfused rat cerebral cortex slices was investigated. Both dibutyrylcyclic AMP (db-cAMP) and 8-bromo-cyclic AMP (8-Br-cAMP) dose-dependently (10−4-10−2M) enhanced K+-induced [3H]NA release, maximally to about 160% of control. In contrast, db-cAMP had no effect on calcium-induced [3H]NA release in the presence of the calcium ionophore A 23187. Surprisingly, the phosphodiesterase (PDE) inhibitors 3-isobutyl-1-methylxanthine (IBMX), 7-benzyl-IBMX, 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62771), and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724) appeared to inhibit K+-induced [3H]NA release in a dose-dependent (10−5-10−3M) manner. At a concentration of 10−4M, ZK 62771 caused an inhibition of [3H]NA release by 30%, and this inhibitory effect was not affected by 10−6M phentolamine nor by 10−3M db-cAMP or 10−4M theophylline. Theophylline by itself enhanced [3H]NA release to about 135% of control. The inhibitory effect of the a-adrenoceptor agonist oxymetazoline (1 μM) and the enhancing effect of the antagonist phentolamine (1 μM) on [3H]NA release were significantly decreased in the presence of 10−3M db-cAMP or 8-Br-cAMP, whereas 10−4M ZK 62771 had no effect. In the presence of 10−2M NaF, a potent activator of adenylate cyclase, the inhibitory effect of oxymetazoline (1 μM) on [3H]NA release was significantly decreased. The data obtained with the cyclic AMP analogues support the hypothesis that activation of presynaptic α-receptors modulating NA release results in an inhibition of a presynaptic adenylate cyclase. Possible causes for the anomalous effects of the PDE inhibitors are discussed.