Mechanisms of the vasorelaxant effect of 1-hydroxy-2, 3, 5-trimethoxy-xanthone, isolated from a Tibetan herb, Halenia elliptica, on rat coronary artery

1-Hydroxy-2, 3, 5-trimethoxyxanthone (HM-1) is a xanthone isolated from Halenia elliptica, a Tibetan medicinal herb. HM-1 (0.33–42.1 μM) produced a concentration-dependent relaxation in rat coronary artery rings pre-contracted with 1 μM 5-hydroxytryptamine (5-HT), with an EC50 of 1.67 ± 0.27 μM. Removal of the endothelium significantly affected the vasodilator potency of HM-1, resulting in 46% decrease in Emax value. The endothelium-dependent effects of HM-1 was confirmed when its vasorelaxant effect was inhibited after addition of nitric oxide synthase (NOS) inhibitor Nω-nitro-l-arginine methyl ester (100 μM) or the soluble guanylate cyclase inhibitor 1H-[1, 2, 4] oxadiazolo [4,3-α] quinoxalin-1-one (ODQ, 10 μM). Atropine (100 nM), flurbiprofen (10 μM), propranolol (100 μM), pyrilamine (10 μM), cimetidine (10 μM) and SQ22536 (100 μM) had no effect on the vasorelaxant activity of HM-1 indicated the non-involvement of other receptor/enzyme systems. In endothelium-denuded coronary artery rings, the vasorelaxant effect of HM-1 was unaffected by potassium channel blockers such as tetraethylammonium (10 mM), iberiotoxin (100 nM), barium chloride (100 μM) and 4-aminopyridine (1 mM). The involvement of Ca2+ channel in 5-HT-primed artery ring preparations incubated with Ca2+-free buffer was confirmed when HM-1 (9.93 μM) partially abolished the CaCl2-induced vasoconstriction (87% inhibition in intact-endothelium artery rings; 50% inhibition in endothelium-denuded rings). In the KCl-primed preparations incubated with Ca2+-free buffer, HM-1 (9.93 μM) produced a 27.3% inhibition in endothelium-denuded rings. HM-1 (3.31–33.1 μM) had minimal relaxant effects (14.4%–20.3%) on the contractile response generated by 10 μM phorbol 12,13-diacetate (PDA) in Ca2+-free solutions, suggesting minimal effects on intracellular Ca2+ mechanisms. These findings suggest the vasodilator action of HM-1 involved both an endothelium-dependent mechanism involving NO and an endothelium-independent mechanism by inhibiting Ca2+ influx through L-type voltage-operated Ca2+ channels; a minor contribution to the effects of HM-1 may be related to inhibition of the protein kinase C-mediated release of intracellular Ca2+ stores.