Page 12 - CBAC Newsletter 2016

a selective L-type calcium channel blocker. This result
suggest that inhibition of KCNQ channels may cause
constriction of IPA via voltage-sensitive L-type calcium
channels, possibly by increasing membrane
depolarization and activating calcium channels (173).
IV administration of linopirdine to anesthetized rats
produced increase in mesenteric vascular and
systematic blood pressure, which was reversed by
flupirtine. This study found a link between the
modulation of vascular KCNQ channels and the control
of systematic blood pressure and local blood flow,
without affecting the heart rate (170).
KCNQ channel modulators such as linopirdine influence
membrane potential, affecting the release of
neurotransmitter (179).
Linopirdine raised epileptiform activity in brain slices
from neonatal rats, whereas in slices from adult rats, it
provoked erratic interictal-like activity. While linopirdine
inhibits M-current in vitro, it can increase epileptiform
activity in a pattern similar to BNFCs (benign neonatal
familial convulsions). This inhibition effect of linopirdine
may help to develop in vitro model to study the
mechanism of epileptogenesis, and the developmental
characteristics of BFCNs (180).
3. Chromanol 293B
ImksosreeleecffteivcetiivnehicblaitsosrsIIhI aavnetiabrerhenythstmuidcieddrutgosd(i1s8co1v-1e8r 3). and rapidly activating
Chromanol 293B (Fig 3), a promising ligand in a new
class of antiarrhythmics, works by inhibiting
potassium channels (181,184,185).
In a two-electrode voltage clamp experiment using
Xenopus oocytes, chromanol 293B inhibited KCNQ1
channels wKiCthNEa1mcohdaenrnaetelsIwC5er0e(fIoCu50rf=ol2d6m.9oµreMs),ewnshiitlieve
KCNQ1 +
c(IhCr5o0m= a6n.9olµmMa)y(Tpalabylefu2n).cTtihoensael results suggested that
pharmacological roles as
drug or a research tool in cardiac tissues because of its
sneellescwtievreebinlohcikbiintegdobf yIkschchroamnnaenlosl. KCNQ1 + KCNE3 chan-
the human colon, chromanol 293B inhibited cAMP-stim-
ulated secretion of chloride at similar concentrations
(10μmol/l) (186). Chromanol can block KCNQ1 channels
which are expressed in the pancreas, leading to
increased insulin secretion by glucose stimulation, and
can raise the glucagon-like peptide-1 level in mice (187).
KCNQ1 channel homologues from Caenorhabditis
elegans were found sensitive to chromanol with a
moderate potency (IC50 = 28 µM) (Table 2) (188).
8 | CBAC Center Heartbeat
Chromanol also inhibits KCNQ5 currents moderately
(40% inhibited at 100 µM chromanol 293B); on the
other hand, it only slightly inhibits KCNQ2, KCNQ3,
KCNQ4, and KCNQ2/KCNQ3 heteromeric channels at
100 µM concentration (5%, 5%, and 10% inhibition of
KCNQ2, KCNQ3, and KCNQ4, respectively) (Table 2)
(184).
Mutations in KCNQ1, such as T312S, I337V, and F340Y,
significantly reduced the blocking effect of chromanol. It
has been suggested that hydrophobic interactions with
residues I337 and F340 located in the S6
transmembrane segment, as well as electrostatic
interactions with the innermost potassium ion in the
selectivity filter (184) stabilize chromanol 293B to block
the ion permeation pathway. This mechanism was
consistent with the state-dependent binding study, in
which chromanol blocked channels after opening, but
not while the channel was closed (189). Chromanol
cfaasnhfiounllywbitlohcokutIkss icghnaifnicnaenlstlyinaaffevcotlitnaggec-hinadnenpeel nkdineenttics
(183,189).
4. Azimilide (NE-10064)
Azimilide is a unique antiarrhythmic agent which was
used in human to prolong the time between recurrence
of atrial fibrillation, paroxysmal supraventricular, and
atrial flutter (Fig.3) (190). Azimilide is believed to have a
novel mechanism that blocks both slowly activating (IKs)
v(IiKtrr)octhoamnnaeinlsta(1in9r1a-1te9-i3n)d. eApzeimndileidnet
has been reported in
effects in ischemic or hypoxic conditions (e.g. in
cardiac IKs infarcted dogs, azimilide has similar effects at slower
and faster pacing rates) (190,194).
Studies in animal cells have suggested that azimilide
can be a potential ligand in a class of molecules with
new mechanism of action, because it has effects on
bAozitmhitlihdee’ssloinwvIiKtsroanedfferacptsidpIrKor ploontgasthsieumducrautriroenntosf (195).
the
action potential makes it a candidate for a new class of
in vivo antiarrhythmic agents (196-199). Many
studies have reported the effect of azimilide on different
293B at 10μmol/l. In potassium channels, for instance, it has displayed full
icnhhaibnintieolncuorfrIeksncths,aantn1e0l c0uµrrMen(t2s0, 0b)u.t MnoatnIyto1stourdIiKeurs have
reported that azimilide inhibits pIkirgasn.dThIkes csheasntnuedlisesinhave
ventricular myocytes of guinea
ttrhhepeanosrlItokeswdchcthoamantnpaeolzsnime(Tnilatidboelfeit2sh)ea(2dm0eo0lar-e2ye0pd2o)pt.eonAttazsbimsloiiulcimdkeecriunorhfrieIbknritts
g(Iuksi)nienavpenigtr(i1c9u3la)r. and SAN (sinuatrial node) cells of the
Azimilide may allosterically interact