R-(-)-α-Methylhistamine, a Histamine H3 Receptor Agonist, Induces Endothelium-Dependent Vasodilation in Rat Mesenteric Resistance Arteries

A novel histamine receptor subtype, histamine H-3 receptor, mediates inhibition of peripheral autonomic neurotransmission. The present study was designed to examine vascular effects of histamine H-3 receptor by using a selective histamine H-3 receptor agonist, R-(-)-alpha methylhistamine (alpha-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 mu M methoxamine. In preparations with intact endothelium, perfusion of alpha-methylhistamine (1-100 mu M) 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-3 receptor antagonists, thioperamide and clobenpropit, but not by chlorpheniramine (histamine H-1 receptor antagonist) and cimetidine (histamine H-2 receptor antagonist). N-omega-nitro-L-arginine methyl ester (L-NAME, nitric oxide (NO) synthase inhibitor), indomethacin (cyclooxygenase inhibitor) and tetraethylammonium (nonselective K+-channel blocker) and high KCl (30 mM) significantly inhibited alpha-methylhistamine-induced endothelium-dependent vasodilation. These findings suggest that alpha-methylhistamine induces endothelium-dependent vasodilation mainly via endothelium histamine H-3 receptors. It is also suggested that activation of histamine H-3 receptors in the endothelium releases mainly NO and partially prostaglandin I-2 and endothelium-derived hyperpolarizing factors to induce endothelium-dependent vasodilation.