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

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Abstract
The effect of (R)‐α‐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 μA) produced intensity‐dependent increases in blood pressure and a more variable tachycardia. (R)‐α‐methylhistamine inhibited the hypertension and tachycardia due to submaximal CNS stimulation. The inhibition of hypertension by (R)‐α‐methylhistamine was dose‐dependent (10–300 μg kg−1, i.v.) and was not seen at high intensities of stimulation. (R)‐α‐methylhistamine (300 μg kg−1, i.v.) did not attenuate the pressor response to adrenaline (1 and 3 μg kg−1, i.v.), indicating that the effect of (R)‐α‐methylhistamine was not mediated by a postjunctional action on smooth muscle. The inhibition of CNS‐induced hypertension by (R)‐α‐methylhistamine (300 μg kg−1, i.v.) was blocked by the H3 antagonists, thioperamide (ID50 = 0.39 mg kg−1, i.v.), impromidine (ID50 = 0.22 mg kg−1, i.v.) and burimamide (ID50 = 6 mg kg−1, i.v.). The rank order potency of these antagonists is consistent with activity at the H3B receptor subtype. Chlorpheniramine (30 μg kg−1, i.v.) and cimetidine (3 mg kg−1, i.v.) did not antagonize the inhibition of CNS‐hypertension by (R)‐α‐methylhistamine. These results suggest that (R)‐α‐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.