The
function
of
the
smooth
muscle
cells
lining
walls
systemic
arteries
and
arterioles
is
to
regulate
diameter
vessels
control
blood
flow
pressure.
Here,
we
describe
an
in-silico
model,
which
call
"Hernandez-Hernandez
model",
electrical
Ca2+
signaling
in
arterial
myocytes
based
on
new
experimental
data
indicating
sex-specific
differences
male
female
from
resistance
arteries.
model
suggests
fundamental
ionic
mechanisms
underlying
membrane
potential
intracellular
during
development
myogenic
tone
vessels.
Although
suggest
that
KV1.5
channel
currents
have
similar
amplitudes,
kinetics,
voltage
dependencies
myocytes,
simulations
current
dominant
regulating
myocytes.
In
cells,
larger
KV2.1
expression
longer
time
constants
for
activation
than
predictions
simulated
plays
a
primary
role
potential.
Over
physiological
range
potentials,
gating
small
number
voltage-gated
K+
channels
L-type
are
predicted
drive
excitability.
We
also
show
idealized
computational
vessel,
exhibits
heightened
sensitivity
commonly
used
blockers
compared
male.
summary,
present
framework
investigate
impact
anti-hypertensive
drugs.
Research Square (Research Square),
Journal Year:
2023,
Volume and Issue:
unknown
Published: July 19, 2023
Abstract
In
arterial
myocytes,
the
canonical
function
of
voltage-gated
Ca
V
1.2
and
K
2.1
channels
is
to
induce
myocyte
contraction
relaxation
through
their
responses
membrane
depolarization,
respectively.
Paradoxically,
also
plays
a
sex-specific
role
by
promoting
clustering
activity
channels.
However,
impact
protein
organization
on
remains
poorly
understood.
We
discovered
that
forms
micro-clusters,
which
can
transform
into
large
macro-clusters
when
critical
site
(S590)
in
channel
phosphorylated
myocytes.
Notably,
female
myocytes
exhibit
greater
phosphorylation
S590,
macro-cluster
formation
compared
males.
Contrary
current
models,
seems
unrelated
density
or
macro-clustering
Disrupting
(K
S590A
)
eliminated
differences
cluster
size
activity.
propose
degree
tunes
manner
Frontiers in Physiology,
Journal Year:
2022,
Volume and Issue:
13
Published: Nov. 24, 2022
The
spontaneous
action
potential
(AP)
firing
rate
of
sinoatrial
nodal
cells
(SANC)
is
regulated
by
a
system
intracellular
Ca2+
and
membrane
ion
current
clocks
driven
Ca2+-calmodulin-activated
adenylyl
cyclase-protein
kinase-A
signaling.
mean
AP-cycle
length
(APCL)
APCL
variability
inform
on
the
effectiveness
clock
coupling.
Endogenous
ATP
metabolite
adenosine
binds
to
receptors
(A1,
A3)
that
couple
Gi
protein-coupled
receptors,
reducing
AP
via
Gβγ
signaling
activates
IKAch,Ado.
Adenosine
also
inhibits
cyclase
activity
Gαi
signaling,
impacting
cAMP-mediated
protein
kinase-A-dependent
phosphorylation.
We
hypothesize
in
addition
IKAch,Ado
activation,
impacts
Ca2+via
both
effects
reduce
To
this
end,
we
measured
characteristics
enzymatically
isolated
single
rabbit
SANC.
10
µM
substantially
increased
(on
average
43%,
n
=
10)
beat-to-beat
from
5.1
±
1.7%
7.2
2.0%
(n
5.0
2.2%
10.6
5.9%
40)
(assessed
as
coefficient
SD/mean).
These
were
mediated
hyperpolarization
maximum
diastolic
(membrane
effect)
suppression
local
Ca2+releases
(LCRs)
(Ca2+-clock
effect):
LCR
size
distributions
shifted
smaller
values,
time
occurrence
during
depolarization
(LCR
period)
became
prolonged,
ensemble
signal
reduced.
tight
linear
relationship
coupling
between
period
presence
"drifted"
upward
leftward,
i.e.
for
given
period,
was
becoming
non-linear
indicating
uncoupling.
An
extreme
case
uncoupling
occurred
at
higher
concentrations
(>100
µM):
small
stochastic
LCRs
failed
self-organize
synchronize
clock,
thus
creating
attempt
generate
an
resulting
arrhythmia
cessation
firing.
Thus,
activate
IKACh,Ado
Gαi,
suppressing
activity,
contribute
adenosine-induced
increase
fidelity
rate.
Frontiers in Physiology,
Journal Year:
2022,
Volume and Issue:
13
Published: Dec. 9, 2022
The
current
dogma
about
the
heartbeat
origin
is
based
on
“the
pacemaker
cell,”
a
specialized
cell
residing
in
sinoatrial
node
(SAN)
that
exhibits
spontaneous
diastolic
depolarization
triggering
rhythmic
action
potentials
(APs).
Recent
high-resolution
imaging,
however,
demonstrated
Ca
signals
and
APs
SAN
are
heterogeneous,
with
many
cells
generating
of
different
rates
rhythms
or
even
remaining
non-firing
(dormant
cells),
i.e.,
only
subthreshold
signals.
Here
we
numerically
tested
hypothesis
community
dormant
can
generate
normal
automaticity,
cell”
not
required
to
initiate
cardiac
impulses.
Our
model
includes
1)
non-excitable
oscillatory
local
releases
2)
an
excitable
lacking
automaticity.
While
each
isolation
was
cell”,
system
generated
APs:
were
transformed
into
respective
membrane
potential
oscillations
via
electrogenic
Na/Ca
exchange
further
transferred
integrated
(computed)
by
reach
its
AP
threshold,
pacemaking.
Cardiac
impulse
emergent
property
cellular
network
be
initiated
intrinsic
Cell
heterogeneity,
weak
coupling,
signals,
their
summation
critical
properties
new
mechanism,
operate
signaling
process
basically
similar
“temporal
summation”
happening
neuron
input
from
multiple
presynaptic
cells.
does
refute
classical
cell-based
mechanism:
both
mechanisms
co-exist
interact
within
tissue.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2023,
Volume and Issue:
unknown
Published: June 26, 2023
Abstract
The
function
of
the
smooth
muscle
cells
lining
walls
mammalian
systemic
arteries
and
arterioles
is
to
regulate
diameter
vessels
control
blood
flow
pressure.
Here,
we
describe
an
in-silico
model,
which
call
“Hernandez-Hernandez
model”,
electrical
Ca
2+
signaling
in
arterial
myocytes
based
on
new
experimental
data
indicating
sex-specific
differences
male
female
from
murine
resistance
arteries.
model
suggests
fundamental
ionic
mechanisms
underlying
membrane
potential
intracellular
during
development
myogenic
tone
vessels.
Although
suggest
that
K
V
1.5
channel
currents
have
similar
amplitudes,
kinetics,
voltage
dependencies
myocytes,
simulations
current
dominant
regulating
myocytes.
In
cells,
larger
2.1
expression
longer
time
constants
for
activation
than
predictions
simulated
plays
a
primary
role
potential.
Over
physiological
range
potentials,
gating
small
number
voltage-gated
+
channels
L-type
are
predicted
drive
excitability.
We
also
show
idealized
computational
vessel,
exhibits
heightened
sensitivity
commonly
used
blockers
compared
male.
summary,
present
framework
investigate
impact
anti-hypertensive
drugs.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 20, 2024
ABSTRACT
BACKGROUND
The
sinoatrial
node
(SAN)
is
primary
pacemaker
of
the
heart.
Recent
high-resolution
imaging
showed
that
synchronized
action
potentials
(APs)
exit
SAN
emerge
from
heterogeneous
signals,
including
subthreshold
signals
in
non-firing
(dormant)
cells.
This
sets
up
a
new
problem
cardiac
biology
how
these
contribute
to
heartbeat
generation.
Here
we
tested
hypothesis
cells
harness
stochastic
resonance
ensure
their
fail-safe
operation,
especially
at
low
rates
bordering
on
sinus
arrest.
METHODS
We
measured
membrane
potential
and
Ca
isolated
rabbit
hearts
response
external
currents
form
sine
waves
or
white
noise.
Protocols
were
applied
via
perforated
patch
while
either
basal
state
presence
cholinergic
receptor
stimulation.
Additionally,
performed
multiscale
model
simulations
respective
sub-cellular,
cellular,
tissue
levels.
RESULTS
Noise
awakened
dormant
fire
APs
substantially
improved
rate
rhythm
firing
infrequent,
dysrhythmic
APs.
Rhythmic
AP
generation
applications
wave
different
frequencies
outlined
spectrum
cells:
capability
responding,
resonance,
specific
frequency
components
embedded
Cholinergic
stimulation
shifted
towards
lower
frequencies,
i.e.
responded
but
could
not
process
higher
signals.
added
single
cell–
tissue-models
expanded
parametric
space
beyond
bifurcation
line
where
failed
operate
without
Both
numerical
models
our
simultaneous
recordings
dynamics
also
demonstrated
amplified
by
coupled
electrical
signaling,
enhancing
noise
CONCLUSIONS
membrane-Ca
signaling
rhythmic
initiation
rates,
providing
last-resort
mechanism
avoid
arrest
when
signal
synchronization
decreases
increases,
such
as
during
strong
parasympathetic
stimulation,
disease
aging
heart
slows
high-frequency
wanes.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 20, 2024
Abstract
Spontaneous,
stochastic,
local
Ca
2+
oscillations
(LCOs)
that
are
heterogeneous
in
phase,
frequency,
and
amplitude
incessantly
occur
throughout
the
neuronal-like
cytoarchitecture
of
heart’s
pacemaker,
sinoatrial
node
(SAN).
How
information
encoded
within
ensembles
these
LCOs
is
linked
to
incessant
emergence
formation
rhythmic
SAN
impulses,
however,
an
unsolved
problem.
We
applied
a
wide
range
analytical
techniques
adapted
from
dynamical
systems
neuroscience
map
fine
details
spatiotemporal
distributions
dynamics
time-series
high-speed
acquisition
panoramic
images
mouse
SANs
ex
vivo.
Phase
analysis
delineated
network
functional
pacemaker
cell
clusters,
which
dynamic
amplitudes,
kinetics,
phases
were
similar,
but
still
differed
each
other,
those
other
clusters.
Local
clusters
formed
global
with
mean
rate
identical
recorded
by
reference
sharp
electrode
right
atria.
Initial
conditions
impulse
initiation
due
mostly
stochastic
nature
small
cluster
located
near
crista
terminalis,
having
highest
intrinsic
power,
earliest
rotor-like
energy
transfer,
most
frequent
point-to-point
instability,
acrophase,
greatest
impulse-to-impulse
variability
A
spontaneous,
slowly
increasing
ensemble
signal
this
forms
foot
CaT.
Following
foot,
CaT
increased
rapidly,
rapid
increases
kinetics
amplitudes
some
adjacent
In
inter-atrial
septum,
delayed,
increase
occurred
when
relaxation
phase
had
already
begun.
Orbit
plots
Lyapunov
exponent
analyses
detected
both
deterministic
features
Ca2+
dynamics.
Correlation
cross-talk
among
different
varied,
not
only
impulse,
also
one
next,
forming
unique
small-world
networks,
assessed
as
ratios
correlation
coefficientsand
shortest
path
lengths,
ultimately
creating
synchronization
solution
for
Thus,
individual
during
cycle
underlies
length
SAN,
recapitulating
spontaneous
CaTs
isolated,
single,
cells.
Bulletin of the National Technical University KhPI Series Mathematical modeling in engineering and technologies,
Journal Year:
2023,
Volume and Issue:
1, P. 67 - 74
Published: Aug. 1, 2023
The
results
of
experimental
researches
hydrodynamic
noise
generated
by
a
jet
flow
through
the
mechanical
bileaflet
mitral
valve
prosthesis
Italian
company
Sorin
are
given.
Physical
simulation
was
carried
out
in
laboratory
conditions
on
model
left
atrial
chamber
and
ventricular
heart.
artificial
increased
with
increasing
water
flow.
It
found
that
greatest
intensity
its
spectral
components
observed
near
central
valve.
obtained
average
pressure
values
wake
open
side
(10
–
20)
%
higher
than
jet.
determined
power
densities
fluctuations
jet,
especially
frequency
range
100)
Hz.
established
small-scale
vortex
structures,
which
broke
away
from
leaflets
(20
70)
Hz,
degenerated
starting
distance
2.5
diameters
downstream.
Increased
levels
were
more
(12
13)
dB
relative
to
inside
(5
7)
15)
With
an
increase
valve,
(60
80)
Hz
observed.
At
below
noises
jets
became
approximately
equal
entire
under
consideration.
research
showed
hydroacoustic
diagnostics
operation
heart
can
be
effective
means
diagnosing
thrombus
formation
leaflets.
The
function
of
the
smooth
muscle
cells
lining
walls
systemic
arteries
and
arterioles
is
to
regulate
diameter
vessels
control
blood
flow
pressure.
Here,
we
describe
an
in
silico
model,
which
call
“Hernandez-Hernandez
model”,
electrical
Ca2+
signaling
arterial
myocytes
based
on
new
experimental
data
indicating
sex-specific
differences
male
female
from
resistance
arteries.
model
suggests
fundamental
ionic
mechanisms
underlying
membrane
potential
intracellular
during
development
myogenic
tone
vessels.
Although
suggest
that
KV1.5
channel
currents
have
similar
amplitudes,
kinetics,
voltage
dependencies
myocytes,
simulations
current
dominant
regulating
myocytes.
In
cells,
larger
KV2.1
expression
longer
time
constants
for
activation
than
predictions
simulated
plays
a
primary
role
potential.
Over
physiological
range
potentials,
gating
small
number
voltage-gated
K+
channels
L-type
are
predicted
drive
excitability.
We
also
show
idealized
computational
vessel,
exhibits
heightened
sensitivity
commonly
used
blockers
compared
male.
summary,
present
framework
investigate
impact
anti-hypertensive
drugs.