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Mouse brain cortex slices preincubated with3H-noradrenaline were superfused and the effect of histamine on the electrically (0.3 or 3 Hz) evoked tritium overflow was examined. The evoked overflow was inhibited by histamine and R-(−)-α-methylhistamine but not by 2-(2-thiazolyl)ethylamine and dimaprit. The effect of histamine was antagonized by thioperamide but not by dimethindene and ranitidine. The degree of inhibition produced by histamine was more marked at 0.3 than at 3 Hz and was attenuated by the α2-adrenoceptor agonist talipexole (the former B-HT 920) but increased by phentolamine and the α2-adrenoceptor antagonist rauwolscine. Pre-exposure of slices toN-ethylmaleimide attenuated the inhibitory effect of histamine. The results suggest that histamine inhibits nordrenaline release in the mouse brain cortex via H3 receptors which interact with presynaptic α2-adrenoceptor and may be coupled to a G (e.g. Gi or Go) protein. The extent of H3 receptor-mediated inhibition of nordrenaline release in the mouse brain is more marked than that in the rat brain.

The effect of the newly synthetized H1 agonists 2-(3-trifluoromethylphenyl)histamine (2-TFMPH) and 2-(3-bromophenyl)histamine (2-BPH) and of the reference compound 2-(2-thiazolyl)ethylamine (2-TEA) on diastolic blood pressure and heart rate was studied in pithed and vagotomized rats. 2-TFMPH and 2-BPH were at least equipotent with 2-TEA in producinga dimethindene-sensitive, short-lasting vasodepressor response. At the highest dose, 2-TFMPH and 2-BPH produced an additional small vasopressor response, which was followed by a long-lasting vasodepressor effect not counteracted by dimethindene and ranitidine 2-TEA, at the highest dose, induced an additional vasopressor response abolished by prazosin plus rauwolscine. Basal heart rate was increased by 2-TEA (in a desipramine-sensitive manner) but not affected by 2-TFMPH or 2-BPH. In conclusion, 2-TFMPH and 2-BPH are potent H1 agonists, devoid of an indirect sympathomimetic effect; at high doses, they produce a vasodepressor response not mediated via histamine receptors.

In pithed and vagotomized rats, the electrically induced vasopressor response was not affected by 2-(2-thiazolyl)ethylamine and dimaprit but was inhibited by Nα-methylhistamine (NαMH) in a thioperamidesensitive manner. NαMH did not affect the vasopressor response to exogenously added noradrenaline. NαMH produced a biphasic effect on basal diastolic blood pressure, i.e. a vasodepressor response (abolished by dimethindene plus ranitidine) and a subsequent vasopressor effect (counteracted by dimethindene or adrenalectomy). Basal heart rate was increased by NαMH (effect abolished by propranolol, dimethindene or adrenalectomy). In conclusion, presynaptic H3, but not H1 or H2, receptors are detectable in the resistance vessels of the rat. NαMH allows the characterization of another four histamine receptor-mediated effects, i.e vasodepressor effects mediated via H1 and H2 receptors and an increase in blood pressure and heart rate mediated via catecholamine-releasing H1, receptors in the adrenal medulla.

The effects of histamine, thioperamide and EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) at the noradrenaline release-modulating H3 receptor in the mouse brain were examined. In superfused mouse brain cortex slices preincubated with 3H-noradrenaline, the inhibitory effect of histamine on the electrically (0.3 Hz) evoked tritium overflow was virtually identical when the time of exposure was 30, 80 or 130 min; after withdrawal of histamine, the evoked overflow recovered within 80 min. The attenuation of the effect of histamine by thioperamide was reversible within 50 min after withdrawal of the antagonist, whereas the attenuation produced by EEDQ remained constant for at least 80 min. In conclusion, the effects of histamine and thioperamide at the H3 receptor are readily reversible, whereas EEDQ appears to be an irreversible antagonist; desensitization of the H3 receptor does not occur.