Abstract
The present study was aimed at the identification of mechanisms following the activation of histamine H3 receptors.
Mouse brain cortex slices preincubated with 3H-noradrenaline were superfused and the (H3 receptor-mediated) effect of histamine on the electrically evoked tritium overflow was studied under a variety of conditions. The extent of inhibition produced by histamine was inversely related to the frequency of stimulation used to evoke tritium overflow and to the Ca2+ concentration in the superfusion medium. An activator (levcromakalim) and blocker (glibenclamide) of ATP-dependent K+ channels did not affect the electrically evoked tritium overflow and its inhibition by histamine. A blocker of voltage-sensitive K+ channels, tetraethylammonium (TEA), increased the evoked overflow and attenuated the inhibitory effect of histamine. TEA also reduced the inhibitory effect of noradrenaline and prostaglandin E2 on the evoked overflow. When the facilitatory effect of TEA on the evoked overflow was compensated for by reducing the Ca 2+ concentration in the superfusion medium, TEA did no longer attenuate the effect of histamine. Exposure of the slices to the SH group-alkylating agent N-ethylmaleimide increased the evoked overflow and attenuated the inhibitory effect of histamine; both effects were counteracted by the SH group-protecting agent dithiothreitol, which, by itself, did not affect the evoked overflow and its inhibition by histamine. Mouse brain cortex membranes were used to study the effect of the H3 receptor agonist R-(−)α-methylhistamine on the basal cAMP accumulation and on the accumulation stimulated by forskolin or noradrenaline. R-(−)-α-Methylhistamine did not affect basal cAMP accumulation but, at high concentrations, inhibited the forskolin- and noradrenaline-stimulated cAMP accumulation. S-(+)-α-Methylhistamine (which is 100 times less potent than R-(−)-α-methylhistamine at H3 receptors) was equipotent with the R-(−)-enantiomer in inhibiting the forskolin-stimulated CAMP accumulation.
The inhibition by R-(−)-α-methylhistamine was not affected by the H3 receptor antagonist clobenpropit but was counteracted by the α2-adrenoceptor antagonist rauwolscine.
The present results suggest that the histamine-induced inhibition of noradrenaline release depends on the availability of extracellular Ca2+ ions for stimulus-release coupling; in particular, a decrease in Ca 2+ influx into the varicosities may contribute to this inhibition. The H3 receptors (which may be coupled to a G protein) do not appear to be coupled to adenylate cyclase, to ATP-dependent K+ channels or to (TEA-sensitive) voltage-regulated K+ channels. α-Methylhistamine, in addition to its main action as a stereoselective H3 receptor agonist, proved to be weakly potent as an α2-adrenoceptor agonist.
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Correspondence to: E. Schlicker at the above address
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Schlicker, E., Kathmann, M., Detzner, M. et al. H3 receptor-mediated inhibition of noradrenaline release: an investigation into the involvement of Ca2+ and K+ ions, G protein and adenylate cyclase. Naunyn-Schmiedeberg's Arch Pharmacol 350, 34–41 (1994). https://doi.org/10.1007/BF00180008
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DOI: https://doi.org/10.1007/BF00180008