Inhibition of sympathetic hypertensive responses in the guinea‐pig by prejunctional histamine H₃‐receptors

Abstract

1 The effect of (R)-a-methylhistamine, a selective H3-histamine receptor agonist, was examined on the neurogenic hypertension and tachycardia that is induced by stimulation of areas in the medulla oblongata of guinea-pigs. Electrical medullary stimulation (32 Hz, 3-5 s trains, 0.5-1.0 ms square pulse, 25-400 juA) produced intensity-dependent increases in blood pressure and a more variable tachycardia.2 (R)-ac-methylhistamine inhibited the hypertension and tachycardia due to submaximal CNS stimulation. The inhibition of hypertension by (R)-x-methylhistamine was dose-dependent (1O-300 tg kg-', i.v.) and was not seen at high intensities of stimulation. 3 (R)-o-methylhistamine (300 ptg kg-', i.v.) did not attenuate the pressor response to adrenaline (1 and 3 fLg kg-', i.v.), indicating that the effect of (R)-x-methylhistamine was not mediated by a postjunctional action on smooth muscle. 4 The inhibition of CNS-induced hypertension by (R)-x-methylhistamine (300 yg kg-', i.v.) was blocked by the H3 antagonists, thioperamide (ID50 = 0.39 mg kg-', iv.), impromidine (ID50 = 0.22 mg kg-, i.v.) and burimamide (ID50 = 6 mg kg-', i.v.). The rank order potency of these antagonists is consistent with activity at the H3B receptor subtype. Chlorpheniramine (30 ptg kg-', i.v.) and cimetidine (3 mg kg-', i.v.) did not antagonize the inhibition of CNS-hypertension by (R)-a-methylhistamine. 5 These results suggest that (R)-a-methylhistamine inhibits sympathetic hypertensive responses in guinea-pigs by activation of prejunctional H3-receptors, possibly located on postganglionic nerve terminals. Furthermore, on the basis of the rank order potency to different H3-antagonists, it appears that the H3B-receptor subtype is involved with H3-receptor responses on vascular sympathetic nerves.

Coordination of Histamine H₃ Receptor Antagonists with Human Adrenal Cytochrome P450 Enzymes

“…In contrast, these compounds exhibit in vitro H 3 receptor antagonist pK i and pA 2 in the sub-to low-nanomolar range [3,9,11], suggesting 2-3 orders of magnitude selectivity for H 3 receptors over adrenal P450 enzymes. However, the intravenous and oral thioperamide, clobenpropit and ciproxifan doses used to inhibit H 3 receptor activation in vivo are reported in the range of 0.2-3 mg/kg [5,8,[27][28][29] indicating that the in vivo safety margin relative to adrenal steroidogenesis is closer to one order of magnitude. Taken together, these data strongly suggest that imidazolecontaining H 3 antagonists have the potential to interfere with adrenal steroidogenesis and that, under multipledosing conditions likely to be encountered during drug development (e.g.…”

“…The histamine H 3 receptor inhibits histaminergic [1], parasympathetic [2,3] and sympathetic [4][5][6][7][8][9] neuron function in a variety of species. This activity has stimulated discovery efforts to develop potent and selective histamine H 3 receptor ligands that may have therapeutic utility.…”

Histamine H3 activation depresses cardiac function in experimental sepsis

“…In the heart, the predominant histamine receptor is the Hz-receptor. H3-receptors were first found on presynaptic nerve endings of histaminergic neurones in the brain where they function as autoreceptors to regulate the synthesis and release of histamine (Arrang et al, 1983 Hey et al, 1992;Mcleod et al, 1993).…”

Cardiovascular and autonomic effects of ω‐conotoxins MVIIA and CVID in conscious rabbits and isolated tissue assays

“…Three control sets of four ®eld pulse stimuli (100 V, 2 ms duration, 2 Hz) were delivered via a Grass S88C dual stimulator and a pair of platinum wire ®eld electrodes that were arranged parallel to the atrium. The control stimuli were followed by addition of (Ishikawa & Sperelakis, 1987;Hey et al, 1992).…”