264
J. C. B. Jacobsen and C. Aalkjær
the Ca
2+ concentration of all the smooth muscle cells in the wall can oscillate and
it is the entrainment of these oscillations which sets up vasomotion. It is also likely
that it is electrical current running between the cells via gap-junctions which is key
to understanding the entrainment. This is supported by the finding that in all cases,
where the membrane potential of the smooth muscle has been measured during
vasomotion, the membrane potential is oscillating [9, 13, 19, 21–23, 39, 41, 53].
These oscillations occur with the same frequency as the contractions (between 2 and
20 Hz) and only slightly phase shifted relative to the latter, so the depolarizing phase
of the oscillation precedes the contractile phase of the vasomotion with 1–2 s [1].
Also Ca
2+ is oscillating synchronized in all cells when vasomotion occurs and is
phase shifted less than 1 s relatively to the contraction [1]. There is thus little doubt
that vasomotion in all instances is caused by oscillation of the membrane potential
which sets up the oscillation of Ca
2+ in the smooth muscle cells in turn leading to
vasomotion.
There is evidence for the existence of two types of oscillators in smooth muscle
cells. One where interactions between potential sensitive and/or Ca
2+ sensitive ion
channels in the membrane leads to oscillations of the membrane potential—the
membrane oscillator, and one where release of Ca
2+ from intracellular stores and
slow reuptake of Ca
2+ into these stores, sets up and oscillation of Ca
2+ —a cytosolic
oscillator. A combination of the two is also a possibility and in the following, we will
provide an example of a model for vasomotion in small arteries from the rat intestine
where the oscillator is based on an interaction between an intracellular oscillator
and a cytosolic oscillator. This mechanism for initiation of vasomotion has been
modelled in silico [29, 30].
In the smooth muscle cells of small muscular arteries, when exposed to a low
concentration of noradrenaline, Ca
2+ waves run along the cell length axis in an uncoordinated fashion [43]. After a few minutes these Ca
2+ oscillations synchronize and
become global oscillations (i.e. not waves) in cell Ca
2+ ; at this point vasomotion starts.
The initial Ca
2+ waves are caused by release of Ca
2+ from the intracellular Ca
2+ store,
while the synchronized oscillations of global Ca
2+ are dependent on Ca
2+ influx from
the extracellular space consequent to oscillations of the membrane potential [43]. The
synchronizing step is prevented by removing the endothelial cells from the arteries
[43] and it was shown that adding a constant concentration of the a membrane permeable variant of the messenger molecule cGMP to an artery where the endothelium is
removed induces vasomotion [18] and synchronization of the Ca
2+ transients [43].
Since membrane potential oscillations are critical for vasomotion, it is of interest
to understand how the oscillatory Ca
2+ transients in a cGMP dependent manner
lead to oscillations of the membrane potential. Pharmacologically induced release
of Ca
2+ from the intracellular stores could induce depolarization of the membrane
potential in an endothelium- and cGMP dependent manner. This would mean that a
Ca
2+ -activated and cGMP-dependent ion conductance, which provides a depolarizing
current is most likely of importance. We showed that a Cl
− conductance with these
characteristics is present in rat small arteries [38] and suggested that this Cl
− conductance would be important for vasomotion in these arteries [43]. This is consistent
with the idea that a Cl
− conductance is also important for the rhythmic contraction
J. C. B. Jacobsen and C. Aalkjær
the Ca
2+ concentration of all the smooth muscle cells in the wall can oscillate and
it is the entrainment of these oscillations which sets up vasomotion. It is also likely
that it is electrical current running between the cells via gap-junctions which is key
to understanding the entrainment. This is supported by the finding that in all cases,
where the membrane potential of the smooth muscle has been measured during
vasomotion, the membrane potential is oscillating [9, 13, 19, 21–23, 39, 41, 53].
These oscillations occur with the same frequency as the contractions (between 2 and
20 Hz) and only slightly phase shifted relative to the latter, so the depolarizing phase
of the oscillation precedes the contractile phase of the vasomotion with 1–2 s [1].
Also Ca
2+ is oscillating synchronized in all cells when vasomotion occurs and is
phase shifted less than 1 s relatively to the contraction [1]. There is thus little doubt
that vasomotion in all instances is caused by oscillation of the membrane potential
which sets up the oscillation of Ca
2+ in the smooth muscle cells in turn leading to
vasomotion.
There is evidence for the existence of two types of oscillators in smooth muscle
cells. One where interactions between potential sensitive and/or Ca
2+ sensitive ion
channels in the membrane leads to oscillations of the membrane potential—the
membrane oscillator, and one where release of Ca
2+ from intracellular stores and
slow reuptake of Ca
2+ into these stores, sets up and oscillation of Ca
2+ —a cytosolic
oscillator. A combination of the two is also a possibility and in the following, we will
provide an example of a model for vasomotion in small arteries from the rat intestine
where the oscillator is based on an interaction between an intracellular oscillator
and a cytosolic oscillator. This mechanism for initiation of vasomotion has been
modelled in silico [29, 30].
In the smooth muscle cells of small muscular arteries, when exposed to a low
concentration of noradrenaline, Ca
2+ waves run along the cell length axis in an uncoordinated fashion [43]. After a few minutes these Ca
2+ oscillations synchronize and
become global oscillations (i.e. not waves) in cell Ca
2+ ; at this point vasomotion starts.
The initial Ca
2+ waves are caused by release of Ca
2+ from the intracellular Ca
2+ store,
while the synchronized oscillations of global Ca
2+ are dependent on Ca
2+ influx from
the extracellular space consequent to oscillations of the membrane potential [43]. The
synchronizing step is prevented by removing the endothelial cells from the arteries
[43] and it was shown that adding a constant concentration of the a membrane permeable variant of the messenger molecule cGMP to an artery where the endothelium is
removed induces vasomotion [18] and synchronization of the Ca
2+ transients [43].
Since membrane potential oscillations are critical for vasomotion, it is of interest
to understand how the oscillatory Ca
2+ transients in a cGMP dependent manner
lead to oscillations of the membrane potential. Pharmacologically induced release
of Ca
2+ from the intracellular stores could induce depolarization of the membrane
potential in an endothelium- and cGMP dependent manner. This would mean that a
Ca
2+ -activated and cGMP-dependent ion conductance, which provides a depolarizing
current is most likely of importance. We showed that a Cl
− conductance with these
characteristics is present in rat small arteries [38] and suggested that this Cl
− conductance would be important for vasomotion in these arteries [43]. This is consistent
with the idea that a Cl
− conductance is also important for the rhythmic contraction