Mesaconitine-induced relaxation in rat aorta: role of Na+/Ca2+ exchangers in endothelial cells.
Previously, we reported that mesaconitine, an aconite alkaloid, increased intracellular Ca(2+) concentration ([Ca(2+)](i)) level in endothelium and caused relaxation in rat aorta via nitric oxide production. In the present study, we investigated the mechanisms of increase in the [Ca(2+)](i) level induced by mesaconitine in rat aorta and in human umbilical vein endothelial cells (HUVECs). Treatment with the low Na(+) buffer delayed the 30 microM mesaconitine-, but not 10 microM acetylcholine-, induced relaxation in rat aorta. Treatments with an inhibitor of Na(+)/Ca(2+) exchangers (20 microM 3',4'-dichlorobenzamil) and a reversed mode (Ca(2+) influx) inhibitor of the exchangers (30 microM 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate, KBR7943) showed similar effects. In HUVECs, 30 microM mesaconitine increased the [Ca(2+)](i) level in the presence of extracellular CaCl(2) and NaCl, and the response was inhibited by KBR7943. Mesaconitine increased intracellular Na(+) concentration level in HUVECs. The [Ca(2+)](i) response by mesaconitine was inhibited by 100 microM D-tubocurarine (an inhibitor of nicotinic acetylcholine receptors), but was not inhibited in the glucose-free buffer and by inhibitors of Na(+)/H(+) exchangers. These findings suggest that mesaconitine stimulated Ca(2+) influx via the Na(+)/Ca(2+) exchangers in endothelial cells and caused relaxation in the aorta. The possibility of D-tubocurarine-sensitive Na(+) channels as target(s) of mesaconitine is discussed.
Ogura
Junko
J
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.
Mitamura
Mana
M
Someya
Akiyoshi
A
Shimamura
Ken
K
Takayama
Hiromitsu
H
Aimi
Norio
N
Horie
Syunji
S
Murayama
Toshihiko
T
D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D019831:Sodium-Calcium Exchanger / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D019831:Sodium-Calcium Exchanger; C019470:mesaconitine; D000157:Aconitine