Halichlorine is a novel L-type Ca(2+) channel inhibitor isolated from the marine sponge Halichondria okadai Kadota.
Halichlorine, isolated from a marine sponge Halichondria okadai Kadota, has a unique structure and its physiological activity is virtually unknown. In the present study, we investigated the direct effect of halichlorine on vascular contractility. In endothelium-denuded rat aorta, while the treatment of halichlorine (0.01-10microM) did not induce vascular contraction, halichlorine (0.01-10microM) dose-dependently inhibited both the steady-state precontractions induced by high K(+) (65.4mM) and phenylephrine (1microM). The vasodilator effect of halichlorine (10microM) on high K(+) (65.4mM)-induced contraction was more potent than that on phenylephrine (1microM)-induced contraction (65.4mM high K(+): 72.7+/-3.4%; 1microM phenylephrine: 34.7+/-2.3%). To investigate the mechanism underlying the suppressive effect of halichlorine on vascular contractility, we examined the effect of halichlorine on intracellular Ca(2+) concentration in vascular smooth muscle with a fluorescent Ca(2+) indicator, fura-2. Treatment of halichlorine (10microM) significantly inhibited the sustained [Ca(2+)](i) elevation induced by high K(+) (65.4mM) (45.3+/-5.5%). Furthermore, current measurements by whole-cell mode patch-clamp recording in rat aortic smooth muscle cells (A7r5 cells) demonstrated that halichlorine (10microM) decreased the current density of the L-type Ca(2+) channel (peak Ca(2+)-channel current densities: -2.09+/-0.27pA/pF for control; -0.58+/-0.07pA/pF for halichlorine). These results suggest that halichlorine inhibits L-type Ca(2+) channels in vascular smooth muscle cells, which inhibit intracellular Ca(2+) influx, and then reduce vascular contractions.
Tsubosaka
Yoshiki
Y
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Murata
Takahisa
T
Kinoshita
Kazuya
K
Yamada
Kaoru
K
Uemura
Daisuke
D
Hori
Masatoshi
M
Ozaki
Hiroshi
H
D000470:Alkaloids / Q000302:isolation & purification* / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000302:isolation & purification* / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004553:Electric Conductivity; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D011161:Porifera / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000302:isolation & purification* / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D000470:Alkaloids; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D013141:Spiro Compounds; C412666:halichlorine; D002118:Calcium