Inhibition of sympathetic hypertensive responses in the guinea-pig by prejunctional histamine H3-receptors.
1. The effect of (R)-alpha-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 microA) produced intensity-dependent increases in blood pressure and a more variable tachycardia. 2. (R)-alpha-methylhistamine inhibited the hypertension and tachycardia due to submaximal CNS stimulation. The inhibition of hypertension by (R)-alpha-methylhistamine was dose-dependent (10-300 micrograms kg-1, i.v.) and was not seen at high intensities of stimulation. 3. (R)-alpha-methylhistamine (300 micrograms kg-1, i.v.) did not attenuate the pressor response to adrenaline (1 and 3 micrograms kg-1, i.v.), indicating that the effect of (R)-alpha-methylhistamine was not mediated by a postjunctional action on smooth muscle. 4. The inhibition of CNS-induced hypertension by (R)-alpha-methylhistamine (300 micrograms 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 micrograms kg-1, i.v.) and cimetidine (3 mg kg-1, i.v.) did not antagonize the inhibition of CNS-hypertension by (R)-alpha-methylhistamine. 5. These results suggest that (R)-alpha-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.
Hey
J A
JA
Schering-Plough Research Institute, Bloomfield, NJ 07003.
del Prado
M
M
Egan
R W
RW
Kreutner
W
W
Chapman
R W
RW
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002049:Burimamide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004837:Epinephrine / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D017442:Histamine Agonists / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology; D017446:Impromidine / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000502:physiology*; D008761:Methylhistamines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011968:Receptors, Histamine / Q000502:physiology*; D018100:Receptors, Histamine H3; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*
D017442:Histamine Agonists; D006633:Histamine Antagonists; D008761:Methylhistamines; D010880:Piperidines; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; C069357:alpha-methylhistamine; D017446:Impromidine; C052075:thioperamide; D002049:Burimamide; D004837:Epinephrine