Biomedical Engineering Reference
In-Depth Information
cells (75%) were HEK-293 cells. With full blockade of
I
K1
current, more subtle tuning
of the remaining ensemble spontaneous beating rate resulted. Although the authors
did not emphasize this themselves, it is of particular interest that even with full
blockade of
I
K1
current, the percentage of HEK-293 cells remains important for the
final beating rate. This resembles the natural situation in which an intact, but isolated
sinus node has a higher frequency than a complete right atrium, where the sinus node
is connected to the surrounding atrial muscle [27].
6.2 Requirements of a Biological Pacemaker
I cite here a phrase from the paper by Rosen et al. [53] elsewhere in this issue: ''...we
have taken a lesson from our engineering colleagues who designed the electronic
pacemaker; that is we are working to fine-tune a structure that mimics the sinus node
functionally without recapitulating it morphologically.'' Creating a homogeneous
biological sinus node with functional responses to neurotransmitters with a prospect
to real innervation, or at least with adrenergic-and muscarinic-type responses to
humoural factors seems at first glance a desirable goal, but might probably not be
such a good idea. The reason is simple. Such a biological pacemaker would also have
the capacity of quiescence. This is exactly what we do not want. The ideal biological
pacemaker would be one that is able to cope with postural changes and exercise. The
former goal may seem far-fetched. It requires innervation, because adaptations are
needed within a single cardiac cycle. For a response to exercise it is sufficient that a
biological pacemaker can increase its rate. The biological pacemaker
in statu
nascendi
as proposed by Rosen et al. [53] in this issue fulfils this more moderate goal
and has a limitation that may constitute two advantages that can become important in
future competition with the electronic pacemaker. The biological pacemaker is based
on the pacemaker current (
I
f
) only, not on a combination of multiple membrane
currents, e.g. the acetylcholine sensitive K
+
current (
I
K-Ach
) is lacking. Therefore it
cannot easily turn quiescent. It can only accelerate, which is exactly what an
electronic pacemaker cannot. The debate on the mechanism of vagal modulation of
sinus rhythm has never been definitely settled. Either acetylcholine inhibits
I
f
current
or it increases
I
K-Ach
current or it does both (see for details Boyett et al. 2000).
Figure 9 (taken from [18]) focuses on this issue. The left panel shows the effect of
postganglionic vagal nerve stimulation (same technique as applied by Fedorov et al.
[22]; see Fig. 8 in this paper), coupled to the cardiac cycle in the isolated right atrium
of the rabbit. The top left panel shows the effect 10 stimuli per cycle leading to a
prolongation of cycle length from 456 to 531 ms. The bottom left panel shows the
same experiment in the presence of 3 µM atropine, blocking the vagally mediated
response. During this procedure a hyperpolarizing pulse was given during diastole
(right panel). This leads to an electrotonic disturbance of the membrane potential
during diastole, which can be followed at a distance from the site of current injection.
When the membrane conductance is high, much current 'escapes' over the
sarcolemma and little current is transported along the axial pathway, the conductance
of which is determined by cytoplasm and gap junctions. The right panel shows that
during vagal stimulation the electrotonic potential decreases, which by simple Ohm's
law means that the resistance of the sarcolemma has decreased by opening of a
membrane channel, not by closing. This provides a strong argument for opening of
