R-(-)-α-methylhistamine, a histamine H₃ receptor agonist, induces endothelium-dependent vasodilation in rat mesenteric resistance arteries

A novel histamine receptor subtype, histamine H₃ receptor, mediates inhibition of peripheral autonomic neurotransmission. The present study was designed to examine vascular effects of histamine H₃ receptor by using a selective histamine H3 receptor agonist, R-(-)- a 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 μM methoxamine. In preparations with intact endothelium, perfusion of α-methylhistamine (1-100 μM) 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 H₃ receptor antagonists, thioperamide and clobenpropit, but not by chlorpheniramine (histamine H₁ receptor antagonist) and cimetidine (histamine H ₂ receptor antagonist). N^ω-nitro-L-arginine methyl ester (L-NAME, nitric oxide (NO) synthase inhibitor), indomethacin (cyclooxygenase inhibitor) and tetraethylammonium (nonselective K ⁺-channel blocker) and high KCl (30mM) significantly inhibited α-methylhistamine-induced endothelium-dependent vasodilation. These findings suggest that a-methylhistamine induces endothelium-dependent vasodilation mainly via endothelium histamine H₃ receptors. It is also suggested that activation of histamine H₃ receptors in the endothelium releases mainly NO and partially prostaglandin I₂ and endothelium-derived hyperpolarizing factors to induce endothelium-dependent vasodilation.