Ryuji Uchida1,*, Jun Yamazaki2, Satoru Ozeki1
and Kenji Kitamura2
1Department of Oral Surgery and 2Department of
Pharmacology, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka
814-0193, Japan
*Corresponding author. FAX: +81-92-801-4909
E-mail: ryu@college.fdcnet.ac.jp
Abstract: Using a whole-cell patch-clamp technique, state-dependent
inhibition of dihydropyridines (DHP)s was investigated on L-type channels
in A7r5 cells. Cilnidipine, its derivatives (D-342 and D-69) and nimodipine
inhibited the Ba2+ current. However, cilnidipine and D-342, but
not D-69 or nimodipine, accelerated current decay. The apparent rank order
for the effects on the DHP-sensitive decaying component was different from
that obtained for inhibition of the peak current. The dissociation constants
for cilnidipine in the resting and inactivated states were estimated to
be 190 and 12 nM, respectively. Cilnidipine, but not other DHP derivatives,
created a faster and voltage-independent component (t=37
ms). The linear relationship between the t-1
of the current decay and the cilnidipine concentration provided a value
of 471 nM for the dissociation constant in the open state, suggesting that
the current decay is mediated by one-to-one lower affinity binding of cilnidipine
molecules to their binding site. The present study demonstrates that structurally
related DHPs act in distinct ways to inhibit the L-type channel in the resting,
open and inactivated states. Cilnidipine and some related DHPs probably
exert their blocking action on the open channel by binding to a receptor
distinct from the known DHP-binding site.
Keywords: Dihydropyridine, Ca2+ channel, Ca2+ antagonist,
Open channel, Channel blocker
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