Biomedical Engineering Reference
In-Depth Information
junctions, it remains unclear whether the principal coupling mechanism is electrical
or chemical in nature [
19
].
Background to the Model
The excitation-contraction coupling, or electrochemical coupling, is primarily con-
trolled by movements of
Ca
2
+
that permeates from the extracellular space into
the cytoplasm. Cytosolic
Ca
2
+
concentration (
Ca
2
+
]
i
) is normally maintained at
[
100nm by the plasma membrane
Ca
2
+
−
a basal level of
∼
ATPase (PMCA), the
Na
+
−
Ca
2
+
exchanger (NCX) and the sarco endoplasmic reticulum
Ca
2
+
−
ATPa s e
Ca
2
+
]
i
,
(SERCA). Vasoconstricting stimuli initiate SMcontraction by increasing the
[
to reach the
M range. Extensive pharmacological probing has characterised vaso-
motion as the interplay between a 'slow, intracellular'
Ca
2
+
oscillator (period
µ
1-
5min) and a 'fast, membrane' oscillator (period 5-30 s) operating within the SMC
layer of the arterial wall [
15
,
20
]. The intracellular oscillator is identified by the
cyclic
Ca
2
+
-induced
Ca
2
+
release (CICR) from ryanodine-sensitive stores of the
sarco endoplasmic reticulum (SR/ER). Morphologically, the SR/ER of the SM is
spatially heterogeneous and possesses both
Ca
2
+
- and inositol 1,4,5-trisphosphate
(InsP
3
)-sensitive
Ca
2
+
stores. In addition to the action of CICR and InsP
3
-induced
Ca
2
+
release (IICR),
Ca
2
+
release from the stores is also due to a passive leak
from the SR. Refilling of the stores is achieved by the SERCA pump. SERCA
pump blockers, such as cyclopiazonic acid and thapsigargin, deplete the
Ca
2
+
stores
and eliminate the slow/large amplitude component of vasomotion [
17
,
20
]. After
each discharge the stores are replenished by
Ca
2
+
influx across the cell mem-
brane. These
Ca
2
+
currents are primarily conducted via voltage-operated channels
(VOCCs), nonspecific cation channels (NSCCs) and
Na
+
-
Ca
2
+
exchange via the
NCX.
Ca
2
+
released by the SR is extruded from the cytosol via the membrane
Ca
2
+
extrusion ATPase, and inhibition of the pump with vanadate produces large
constrictor response due to increased
∼
Ca
2
+
]
i
[
16
].
Ca
2
+
extrusion can also be
performed by the NCX with a stoichiometry of 3
Na
+
for 1
Ca
2
+
[
15
,
21
]. The
exchanger can act both as an efflux or an influx (forward/reverse mode respectively)
based on the membrane potential being above or below the reversal potential of NCX.
Membrane potential is a distinct dynamic variable determined by the addi-
tive contribution of a large number of ionic transport mechanisms (ion channels,
pumps, and exchangers). Suppression of
Ca
2
+
-activated
K
+
(
K
Ca
) channels (with
tetraethylammonium and charybdotoxin),
Cl
−
channels (by reducing extracellular
Cl
−
concentration and niflumic acid), the
Na
+
−
[
K
+
−
ATPase (by ouabain), or
Na
+
/
Ca
2
+
exchange (by low extracellular
Na
+
) consistently attenuate the fast
membrane component of arterial vasomotion, suggesting that these transport mech-
anisms are fundamental in the genesis of vasomotion [
22
]. The fundamental ionic
transport mechanisms involved in the homeodynamics of intracellular
Ca
2
+
are pre-
sented in Fig.
1
.
