Mesaconitine-induced relaxation in rat aorta: involvement of Ca2+ influx and nitric-oxide synthase in the endothelium.
Aconiti tuber, roots of aconite (Aconitum japonicum), is an oriental herbal medicine used for centuries in Japan and China to improve the health of persons with a weak constitution and poor metabolism. We investigated the effects of mesaconitine, one of the aconite alkaloids in Aconiti tuber, on the contraction and free intracellular Ca2+ concentration ([Ca2+]i) level in isolated rat thoracic aorta. Mesaconitine at 30 microM inhibited 3 microM phenylephrine-induced contraction in the endothelium-intact, but not endothelium-denuded, aortic rings. The effect of mesaconitine was dependent on external Ca2+ concentrations. The relaxation induced by mesaconitine was abolished by N(omega)-nitro-L-arginine methyl ester (0.1 mM, an inhibitor of nitric-oxide synthase), as well as the relaxation induced by acetylcholine. Acetylcholine induced relaxation in two phases in our conditions; the initial phase was transient and external Ca2+ -independent, and the second phase was sustained and external Ca2+ -dependent. Treatment with 100 nM thapsigargin, which depleted intracellular Ca2+ stores, inhibited acetylcholine-induced, but not mesaconitine-induced, relaxation. Mesaconitine increased the [Ca2+]i level in endothelial cells by influx of Ca2+ from extracellular spaces. These findings suggest that mesaconitine-induced Ca2+ influx and activation of nitric-oxide synthase in endothelial cells and, thus, induced vasorelaxation in rat aorta.
Mitamura
Mana
M
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.
Horie
Syunji
S
Sakaguchi
Masaru
M
Someya
Akiyoshi
A
Tsuchiya
Shizuko
S
Van de Voorde
Johan
J
Murayama
Toshihiko
T
Watanabe
Kazuo
K
D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D001285:Atropine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002122:Calcium Chloride / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018738:Hexamethonium / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013779:Tetrodotoxin / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D018738:Hexamethonium; D013779:Tetrodotoxin; C019470:mesaconitine; D019284:Thapsigargin; D001285:Atropine; D019001:Nitric Oxide Synthase; D002122:Calcium Chloride; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester; D000157:Aconitine