R-(-)-.ALPHA.-Methylhistamine, a Histamine H3 Receptor Agonist, Induces Endothelium-Dependent Vasodilation in Rat Mesenteric Resistance Arteries
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A novel histamine receptor subtype, histamine H<sub>3</sub> receptor, mediates inhibition of peripheral autonomic neurotransmission. The present study was designed to examine vascular effects of histamine H<sub>3</sub> receptor by using a selective histamine H<sub>3</sub> receptor agonist, <i>R</i>-(−)-α methylhistamine (α-methylhistamine), in rat mesenteric resistance arteries. The isolated mesenteric vascular beds were perfused with Krebs solution and perfusion pressure was measured. Active tone was produced by perfusion of Krebs solution containing 7 μ<small>M</small> methoxamine. In preparations with intact endothelium, perfusion of α-methylhistamine (1—100 μ<small>M</small>) for 1 min produced a concentration-dependent vasodilation. The maximum vasodilation at the highest concentration was approximately 45%. This vasodilation was abolished by endothelium removal and attenuated by histamine H<sub>3</sub> receptor antagonists, thioperamide and clobenpropit, but not by chlorpheniramine (histamine H<sub>1</sub> receptor antagonist) and cimetidine (histamine H<sub>2</sub> receptor antagonist). <i>N</i><sup>ω</sup>-nitro-<small>L</small>-arginine methyl ester (<small>L</small>-NAME, nitric oxide (NO) synthase inhibitor), indomethacin (cyclooxygenase inhibitor) and tetraethylammonium (nonselective K<sup>+</sup>-channel blocker) and high KCl (30 m<small>M</small>) significantly inhibited α-methylhistamine-induced endothelium-dependent vasodilation. These findings suggest that α-methylhistamine induces endothelium-dependent vasodilation mainly <i>via</i> endothelium histamine H<sub>3</sub> receptors. It is also suggested that activation of histamine H<sub>3</sub> receptors in the endothelium releases mainly NO and partially prostaglandin I<sub>2</sub> and endothelium-derived hyperpolarizing factors to induce endothelium-dependent vasodilation.
- Biological and Pharmaceutical Bulletin
Biological and Pharmaceutical Bulletin 33(1), 58-63, 2010
The Pharmaceutical Society of Japan