Calcium channel blockade in vascular smooth muscle cells: major hypotensive mechanism of S-petasin, a hypotensive sesquiterpene from Petasites formosanus.
In vivo and in vitro studies were carried out to examine the putative hypotensive actions of S-petasin, a sesquiterpene extracted from the medicinal plant Petasites formosanus. Intravenous S-petasin (0.1-1.5 mg/kg) in anesthetized rats produced a dose-dependent hypotensive effect. In isolated aortic ring, isometric contraction elicited by KCl or the L-type Ca2+ channel agonist Bay K 8644 was reduced by S-petasin (0.1-100 microM), an action not affected by the cyclooxygenase inhibitor indomethacin, nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine, guanylyl cyclase inhibitor methylene blue, or removal of vascular endothelium. Pretreatment with S-petasin for 10 min shifted the concentration-response curve for KCl (15-90 mM)-induced contraction to the right and reduced the maximal response. In Ca2+-depleted and high K+-depolarized aortic rings preincubation with S-petasin attenuated the Ca2+-induced contraction in a concentration-dependent manner, suggesting that S-petasin reduced Ca2+ influx into vascular smooth muscle cells (VSMCs). Moreover, in cultured VSMCs, whole-cell patch-clamp recording indicated that S-petasin (1-50 microM) inhibited the L-type voltage-dependent Ca2+ channel (VDCC) activities. Intracellular Ca2+ concentration ([Ca2+[(i)) estimation using the fluorescent probe 1-[2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2'-amino-5'-methylphenoxy)-ethane-N,N,N,N-tetraacetic acid pentaacetoxymethyl ester indicated that S-petasin (10, 100 microM) suppressed the KCl-stimulated increase in ([Ca2+[(i)). Taken together, the results suggested that a direct Ca2+ antagonism of L-type VDCC in vascular smooth muscle may account, at least in part, for the hypotensive action of S-petasin.
National Research Institute of Chinese Medicine, Rm. 355, 155-1, Sec. 2, Li-Nong St. Pei-Tou Dist. (112), Taipei, Taiwan, Republic of China. jennyw@cma23.nricm.edu.tw
G J
GJ
Wang
A Y
AY
Shum
Y L
YL
Lin
J F
JF
Liao
X C
XC
Wu
J
J
Ren
C F
CF
Chen
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D012717:Sesquiterpenes; D011189:Potassium Chloride; C418727:petasin; D002118:Calcium