Involvement of protein kinase C in the mechanism of in vitro effects of imipramine on generation of second messengers by noradrenaline in cerebral cortical slices of the rat.

Imipramine did not significantly inhibit the noradrenaline or isoproterenol-induced cyclic AMP accumulation in rat cerebral cortical slices, but inhibited the potentiation of this response by protein kinase C activator, a phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate. In low concentrations (0.1-1 microM) it prevented the inhibitory effect of the phorbol ester on accumulation of inositol phosphate induced by noradrenaline, while in higher concentrations it inhibited the response by itself. Imipramine did not bind to beta-adrenoceptors but was an effective blocking agent of alpha 1-adrenoceptors (Ki = 38.1 nM). The data suggest that imipramine acts within the noradrenergic cyclic AMP generating system on two targets: inhibiting protein kinase C and blocking the alpha 1-adrenoceptor; both actions may reduce the alpha-adrenoceptor potentiation of beta-adrenoceptor-mediated cyclic AMP generation.