H-3 RECEPTOR-MEDIATED INHIBITION OF NORADRENALINE RELEASE - AN INVESTIGATION INTO THE INVOLVEMENT OF CA2-PROTEIN AND ADENYLATE-CYCLASE( ANDK+ IONS, G)

The present study was aimed at the identification of mechanisms follow ing the activation of histamine H-3 receptors. Mouse brain cortex slic es preincubated with H-3-noradrenaline were superfused and the (H-3 re ceptor-mediated) effect of histamine on the electrically evoked tritiu m overflow was studied under a variety of conditions. The extent of in hibition produced by histamine was inversely related to the frequency of stimulation used to evoke tritium overflow and to the Ca2+ concentr ation in the superfusion medium. An activator (levcromakalim) and bloc ker (glibenclamide) of ATP-dependent K+ channels did not affect the el ectrically evoked tritium overflow and its inhibition by histamine. A blocker of voltage-sensitive K+ channels, tetraethylammonium (TEA), in creased the evoked overflow and attenuated the inhibitory effect of hi stamine. TEA also reduced the inhibitory effect of noradrenaline and p rostaglandin E(2) On the evoked overflow. When the facilitatory effect of TEA on the evoked overflow was compensated for by reducing the Ca2 + concentration in the superfusion medium, TEA did no longer attenuate the effect of histamine. Exposure of the slices to the SH group-alkyl ating agent N-ethylmaleimide increased the evoked overflow and attenua ted the inhibitory effect of histamine; both effects were counteracted by the SH group-protecting agent dithiothreitol, which, by itself, di d not affect the evoked overflow and its inhibition by histamine. Mous e brain cortex membranes were used to study the effect of the H-3 rece ptor agonist R-(-)alpha-methylhistamine on the basal cAMP accumulation and on the accumulation stimulated by forskolin or noradrenaline. R-( -)-alpha-Methylhistamine did not affect basal cAMP accumulation but, a t high concentrations, inhibited the forskolin- and noradrenaline-stim ulated cAMP accumulation. S-(+)-alpha-Methylhistamine (which is 100 ti mes less potent than R-(-)-alpha-methyihistamine at H-3 receptors) was equipotent with the R-(-)-enantiomer in inhibiting the forskolin-stim ulated cAMP accumulation. The inhibition by R-(-)-alpha-methylhistamin e was not affected by the H-3 receptor antagonist clobenpropit but was counteracted by the alpha(2)-adrenoceptor antagonist rauwolscine. The present results suggest that the histamine-induced inhibition of nora drenaline release depends on the availability of extracellular Ca2+ io ns for stimulus-release coupling; in particular, a decrease in Ca2+ in flux into the varicosities may contribute to this inhibition. The H-3 receptors (which may be coupled to a G protein) do not appear to be co upled to adenylate cyclase, to ATP-dependent K+ channels or to (TEA-se nsitive) voltage-regulated K+ channels. alpha-Methylhistamine, in addi tion to its main action as a stereoselective H-3 receptor agonist, pro ved to be weakly potent as an alpha(2)-adrenoceptor agonist.