R-(-)-alpha-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 microM methoxamine. In preparations with intact endothelium, perfusion of alpha-methylhistamine (1-100 microM) 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.