Mitsutoshi Munakata1, Kazuo Noguchi1,2,*, Hiroaki
Araki3 and Norio Akaike1
1Department of Cellular and System Physiology, Graduate School
of Medical Sciences, Kyushu University, 1-2-2 Maidashi, Higashi-ku, Fukuoka
812-8582, Japan
2Pharmacology Laboratory, Pharmaceutical Research Laboratories,
Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Ohmiya, Saitama 330-8530,
Japan
3Department of Hospital Pharmacy, Okayama University Medical
School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan
*Corresponding author (affiliation #2). FAX: +81-48-654-6650
E-mail: s15922@ccm.taisho.co.jp
Abstract: The effects of nitrooxy alkyl apovincaminate VA-045 (+)-eburunamenine-14-carboxylic
acid(2-nitroxy-ethyl ester), VA) were investigated in acutely dissociated
rat neocortical neurons by using a nystatin-perforated patch recording configuration.
VA activated a steady-state outward current in a concentration-dependent
manner, with an EC50 of 0.65 mM. The
reversal potential for the current shifted 56.5 mV with tenfold changes
in the extracellular K+ concentration, suggesting that the current
was carried by K+. The VA-induced current was not suppressed
by apamin (1 mM), charybdotoxin (1 mM),
Cs + (3 mM), Ba2+ (3 mM), 4-aminopyridine (10 mM)
or glibenclamide (10 mM), whereas tetraethylammonium
suppressed the current with an IC50 of 1.4 mM. These pharmacological
properties of the VA-induced current were compatible with a slowly inactivating
delayed rectifier current (IK). It was suggested that the current
activated by VA was IK. The VA-induced current was not affected
by Ca2+ depletion or by staurosporine (0.1 mM),
quinacrine (10 mM), wortmanin (1 mM)
or genistein (1 mM). The intracellular perfusion
of GDPbS (0.4 mM) also had no significant effect.
Thus, VA may directly activate the K+ channels.
Keywords: VA-045, Nitrooxy alkyl apovincaminate, K+ channel,
Delayed rectifier, Neocortical neuron (rat)
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