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Figure Legends
Figure 1
The effect of dexmedetomidine (DEX) on the firing rate of spontaneous action potentials in
guinea pig SA node cells. A, Continuous recording of spontaneous action potentials during
the administration of DEX at concentrations of 5 nM, 10 nM, 100 nM and 1 µM (upper
panel). The simultaneous measurement of the spontaneous firing rate plotted on the same
time scale (lower panel). B, Spontaneous action potentials on an expanded time scale
recorded at the time points indicated by the characters (a-f) in panel A. C and D, The
spontaneous firing rate (C) and diastolic depolarization rate (DDR) (D) before (control) and
during the administration of DEX at each concentration (n = 10-18, N = 9). These data were
analyzed by a one-way ANOVA followed by Dunnett’s test. *P < 0.05 in comparison to
control.
Figure 2
Dexmedetomidine (DEX) induced a decrease in the conductance of If and a hyperpolarizing
shift of channel activation. A, Superimposed current traces of If activated during 2-s
hyperpolarizing steps from a holding potential of -40 mV to test potentials of -50 mV to -140
41
mV, before (control) and during the administration of 100 nM DEX for 5 min. B, The
conductance (gf)-voltage relationship for If constructed using the reversal potential of -31 mV
in the absence (control) and presence of DEX at each concentration (10 nM, 100 nM and 1
µM, fitted with the Boltzmann equation (n = 7-9, N = 8). C, Maximal conductance of If
(gf,max) obtained from fitting with the Boltzmann equation (n = 7-9, N = 8). D, The voltage at
half-maximal activation (Vh) obtained by fitting the conductance-voltage relationship to the
Boltzmann equation in the absence and presence of DEX (n = 7-9, N = 8). E, If current at a
test potential -70 mV before and during the administration of 1 µM DEX or 30 µM
ivabradine. F, The percent inhibition of If at -70 mV induced by DEX at concentrations of 10
nM, 100 nM and 1 µM (n = 7-9, N = 8). These data were analyzed by a paired t test. *P <
0.05 in comparison to control.
Figure 3
The effect of dexmedetomidine (DEX) on the activation rate of If current. A, If activated
during 2-s hyperpolarizing steps to -140 mV from a holding potential of -40 mV, before
(control) and during the administration of 1 µM DEX, which was fitted with two exponential
functions. The right traces show superimposed If, where the peak amplitude of If in the
42
presence of DEX was normalized to that of control to define the slowing of If activation. B, C,
The activation time constants for
fast,
B) and the
slow,
C) components at
-140 mV in the absence and presence of different concentrations of DEX (10 nM, 100 nM
and 1 µM, n = 7-9, N = 8). D, The relative amplitude of the fast component of If activation at
-140 mV in the absence and presence of DEX (n = 7-9, N = 8). These data were analyzed by
a paired t test. *P < 0.05 in comparison to control.
Figure 4
The attenuation of dexmedetomidine (DEX)-induced inhibition of spontaneous action
potentials in SA node cells by the α2-AR and I1R antagonists (efaroxan and idazoxan). A,
Continuous recording of action potentials during the administration of DEX at concentrations
of 10, 100 nM, and 1 µM in the presence of yohimbine (YOH, 1 µM), an α2-AR antagonist
(upper panel). The simultaneous measurement of the spontaneous firing rate plotted on the
same time scale (lower panel). B, The continuous recording of action potentials during the
administration of DEX at concentrations of 10, 100 nM, and 1 µM, in the presence of 10 µM
efaroxan (EFA, 10 µM, upper panel). The simultaneous measurement of the spontaneous
firing rate plotted on the same time scale (lower panel). C, The percent reduction in the firing
43
rate induced by DEX in the absence and presence of YOH (n = 8-9, N = 6). D, The percent
reduction in the firing rate induced by DEX in the absence and presence of EFA (n = 10, N =
5). E, The percent reduction in the firing rate induced by DEX in the absence and presence of
idazoxan (IDA, 10 µM) (n = 7, N =3). Note that the data in the absence of YOH and EFA
shown in panels C, D and E were obtained from the same data shown in Figure 1. These data
were analyzed by an unpaired t test. *P < 0.05 in comparison to control.
Figure 5
Protein kinase C (PKC) failed to suppress the effect of dexmedetomidine (DEX) on
spontaneous action potentials in SA node cells. A, The percent reduction in firing rate
induced by DEX in the absence and presence of a PKC inhibitor, bisindolylmaleimide I
(BIS-I, 200 nM) (n = 6, N = 4). Note that the data in the absence of BIS-I were obtained
from the control data shown in Figure 1. The data were analyzed by an unpaired t test. B,
The firing rate before and during the administration of phorbol 12-myristate 13-acetate
(PMA, 100 nM), a PKC activator, for more than 5 min (n = 7, N = 4). The data were
analyzed by a paired t test.
44
Figure 6
The attenuation of dexmedetomidine (DEX)-induced impairment of If current by efaroxan
(EFA). A, Superimposed current traces of If activated during 2-s hyperpolarizing steps from
a holding potential of -40 mV to test potentials of -50 mV to -140 mV, before (control) and
during the administration of 1 µM DEX for 5 min (upper panel). The lower panel shows
superimposed current traces of If activated during the same hyperpolarizing steps, before
and during the administration of 10 µM EFA and EFA plus 1 µM DEX for 5 min,
respectively. B, Comparison of the maximal conductance of If (gf,max) by fitting the
conductance-voltage relationship to a Boltzmann equation in the absence (control) and
presence of EFA and EFA plus DEX (n = 5, N =3). C, The percent inhibition of If induced
by DEX at -70 mV in the absence and presence of EFA (n = 5-9, N = 3). Note that the data
in the absence of EFA were obtained from the same data shown in Figure 2. D, The voltage
at half-maximal activation (Vh) obtained by a Boltzmann fitting in the absence (control) and
presence of EFA and EFA plus DEX (n = 5, N = 3). E, The
slow,
fast,
middle panel) components of If activation at -140 mV obtained
by fitting with two exponential functions before (control) and during the administration of
EFA and EFA plus DEX. The right panel shows the relative amplitude of the fast component
45
(n = 5, N = 3). The data concerning the gf,max, Vh and time constants were analyzed by a
paired t test, control vs. EFA and EFA vs. EFA+DEX, respectively. The data concerning the
percent inhibition were analyzed by an unpaired t test.
Figure 7
The effect of moxonidine on the firing rate of spontaneous action potentials and If current. A,
Continuous recording of the spontaneous action potentials during administration of
moxonidine (MOX) at concentrations of 100 nM and 1 µM (upper panel). The simultaneous
measurement of the spontaneous firing rate plotted on the same time scale (lower panel). B,
The spontaneous firing rate before (control) and during the administration of MOX at each
concentration (n = 6-9, N = 4). The data were analyzed by a one-way ANOVA followed by
Dunnett’s test. C, Superimposed current traces of If activated during 2-s hyperpolarizing
steps from a holding potential of -40 mV to test potentials of -50 to -140 mV before
(control) and during the administration of 1 µM MOX for 5 min. D, Superimposed current
traces of If activated by the same protocol, before (control) and during the administration of
1 µM rilmenidine (RIL) for 5 min. E, The conductance (gf)-voltage relationship for If
constructed using the reversal potential of -31 mV in the absence (control) and presence of
46
1 µM MOX (n = 8, N = 3) and 1 µM RIL (n = 8, N = 3), fitted with the Boltzmann equation.
F, Comparison of the maximal conductance of If (gf,max) by fitting the conductance-voltage
relationship to a Boltzmann equation in the absence (control) and presence of MOX (n = 8,
N = 3) and RIL (n = 8, N = 3). G, The voltage at half-maximal activation (Vh) obtained by a
Boltzmann fitting in the absence (control) and presence of MOX (n = 8, N = 3) and RIL (n
= 8, N = 3). The data of gf,max and Vh were analyzed by a paired t test. *P < 0.05 in
comparison to control.
Figure 1
Click here to access/download;Figure;Mariko Ishihara et alFigure1.tif
Figure 2
Click here to access/download;Figure;Mariko Ishihara et alFigure2.tif
Figure 3
Click here to access/download;Figure;Mariko Ishihara et al-Figure3.tif
Figure 4
Click here to access/download;Figure;Mariko Ishihara et alFigure4.tif
Figure 5
Click here to access/download;Figure;Mariko Ishihara et al-Figure 5.tif
Figure 6
Click here to access/download;Figure;Mariko Ishihara et alFigure6.tif
Figure 7
Click here to access/download;Figure;Mariko Ishihara et alFigure7.tif
Table 1
Table 1
Parameters of spontaneous action potentials of SA node cells in the absence and presence of
DEX
Control
DEX
100 nM
1 M
5 nM
10 nM
(n = 18, N = 9)
(n =10, N = 4)
(n = 13, N =7)
(n = 14, N = 8)
APA (mV)
83.5 ± 8.3
84.6 ± 8.4
86.6 ± 7.9
86.3 ± 8.1
86.4 ± 6.2
APD50 (ms)
82.5 ± 13.5
92.3 ± 14.9
81.8 ± 16.8
85.5 ± 20.0
81.6 ± 19.9
APD90 (ms)
136.4 ± 16.8
145.5 ± 19.0
133.1 ± 23.8 133.3 ± 26.8
133.1 ± 27.2
MDP (mV)
-56.7 ± 6.3
-60.1 ± 7.4
-60.1 ± 6.3
-61.43 ± 6.9
-62.9 ± 6.3
max dV/dt (V/s)
11.7 ± 6.0
10.3 ± 4.3
13.7 ± 7.0
12.9 ± 6.4
13.9 ± 4.6
(n = 11, N = 6)
Data are presented as the mean ± SD and were obtained from the experiments shown in Figure 1.
DEX, dexmedetomidine; APA, action potential amplitude; APD50, action potential duration at 50
repolarization; APD90, action potential duration at 90 repolarization; MDP, maximal diastolic
potential; max dV/dt, maximal rate of action potential depolarization. These data were analyzed
by a one-way ANOVA followed by Dunnett’s test.
Supplemental Data File (.doc, .tif, pdf, etc.)
Click here to access/download;Supplemental Data File
(.doc, .tif, pdf, etc.);Mariko Ishihara et al-Supplemental
The effect of dexmedetomidine (DEX) on IKr channel activity. A, Superimposed current traces
during 250-ms depolarization steps from a holding potential of -50 mV to test potentials of 0 mV,
before (control) and during the administration of DEX (1 µM) for 5 min and 5 min after the
subsequent addition of 1 µM E-4031. B, Current-voltage relationships for IKr tail current, determined
as E-4301-sensitive current in the absence (control) and presence of 1 µM DEX. The smooth curves
through the data points represent the least-squares fit of the Boltzmann equation (n = 6, N = 4). C,
The maximal amplitude of IKr (IKr, tail max) in control and in the presence of DEX obtained by
Boltzmann fitting (n = 6, N = 4). The data were analyzed by a paired t test. Supplemental Figure 1
Supplemental Data File (.doc, .tif, pdf, etc.)
Click here to access/download;Supplemental Data File
(.doc, .tif, pdf, etc.);Mariko Ishihara et al-Supplemental
The effect of dexmedetomidine (DEX) on IKs channel activity. A, Superimposed current traces during
2-s depolarization steps from a holding potential of -50 mV to test potentials of -40 mV to +50 mV,
before (control) and during the administration of 1 µM DEX in a cumulative manner for 5 min. B,
Current-voltage relationships for IKs tail currents in the absence and presence of DEX. The smooth
curves through the data points represent the least-squares fit of the Boltzmann equation (n = 6, N = 3).
C, The maximal amplitude of IKs (IKs, tail max) in the absence (control) and presence of DEX obtained by
fitting with the Boltzmann equation(n = 6, N = 3). The data were analyzed by a paired t test. Supplemental Figure 2
Supplemental Data File (.doc, .tif, pdf, etc.)
Click here to access/download;Supplemental Data File
(.doc, .tif, pdf, etc.);Mariko Ishihara et al-Supplemental
The effect of dexmedetomidine (DEX) on ICa,L channel activity. A, The time course of the changes in
the amplitude of ICa,L evoked by 500-ms depolarizing steps from a holding potential of -50 mV to test
potentials of 0 mV in the absence of DEX for 15 min. B, The time course of the changes in the
amplitude of ICa,L evoked by the same protocol in the presence of 1 µM DEX, 8 min after the start of
experiment. C, The percent amplitude of ICa,L in the absence and presence of DEX at the time points
indicated by the characters (a, b in panel A; a’, b’ in panel B, n = 4-6, N = 3). The data were analyzed
by an unpaired t test. Supplemental Figure 3
Supplemental Data File (.doc, .tif, pdf, etc.)
Click here to access/download;Supplemental Data File
(.doc, .tif, pdf, etc.);Mariko Ishihara et al-Supplemental
The effect of dexmedetomidine (DEX) on the INCX activity. (A) The time course of the changes in
membrane currents measured at +40 mV and -120 mV in the voltage-ramp protocol, during the
administration of 1 µM DEX and 1 mM NiCl2, as indicated. B, The current-voltage relationship of
membrane currents at the time points indicated by the characters in panel A. C, The current-voltage
relationships for the DEX-sensitive current (a-b) and NiCl2-sensitive current (a-d) obtained by digital
subtraction of the current traces shown in panel B (n = 4, N = 2). Supplemental Figure 4
Supplemental Data File (.doc, .tif, pdf, etc.)
Click here to access/download;Supplemental Data File
(.doc, .tif, pdf, etc.);Mariko Ishihara et al-Supplemental
The effect of dexmedetomidine (DEX) on the IK,Ach channel activity. A, The time course of the
changes in membrane currents measured at +40 mV and -120 mV in the voltage-ramp protocol,
during the administration of 1 µM DEX and 1 µM acetylcholine (ACh). B, The current-voltage
relationships for membrane currents recorded at the time points indicated by the characters in
panel A. C, The current-voltage relationships for DEX-sensitive current (b-a) and ACh-sensitive
current (d-c) obtained by digital subtraction of the current traces shown in panel B (n = 6, N = 3). Supplemental Figure 5
...
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