Biomedical Engineering Reference
In-Depth Information
be active, under different experimental conditions, in the spontaneously beating
mammalian SAN cells include (Fig. 1): the hyperpolarization-activated inward cur
rent
I
f
; the L-type calcium current,
I
CaL
and the closely related sustained inward
current
I
st
[65]; the T-type calcium current,
I
CaT
; the sodium-calcium exchanger,
I
Na/Ca
;
the delayed rectifier current,
I
K
[62] (in toto, or through its individual components:
slow,
I
Ks
,
fast,
I
Kr
, or ultrafast, I
Kur
) [30, 62]; the transient outward current
I
to
; and the
inward rectifying
I
K1
. Despite a considerable amount of work on the subject, by many
groups, spanning many decades, it is still controversial as to which of the above
currents, if any, dominates the pacemaking activity of the SAN under normal in vivo
conditions, or as to whether the pacemaker activity of the SAN is indeed a solely,
membranebased, phenomenon. From the vast body of knowledge adduced, to date, for
the currently prevalent theory, that of a membranary pacemaker, the most likely
candidates for the role of the still elusive, dominant, pacemaker current appear to be
I
f
and the calcium currents.
I
f
the funny current, is carried by the hyperpolarization-activated, cyclic nucleotide
gated (HCN) channel, which, through a cyclic AMP (cAMP) binding site, is sensitive
to modulation by catecholamines.
I
f
is well accepted as a component of the pacemaker
current present in the SAN, and at various levels in the AVN, Purkinje fibers, atria,
and the ventricles [81]. The magnitude to which this current participates in the
pacemaking activity of the cardiac conduction system, though, has been a subject of
intense debate [6, 16-18, 66, 79]. DiFrancesco, Brown, and their colleagues [8, 14,
15] have contributed a wealth of data suggesting a cardinal role of
I
f
in the initiation,
and the control thereafter, of the rate of diastolic depolarization. The principal
observations supporting this role are: (1) expression of
I
f
parallels the presence of
spontaneous activity of cardiomyocytes of adult mammals, (2) during patch clamping
experiments, the partially depolarized, nonbeating SAN cells start beating during
hyperpolarizing steps, and not during depolarization, and (3) the rate of SAN cells
accelerates with application of more hyperpolarizing voltages [16] (Fig. 2). Data from
other groups suggest that the role of
I
f
in the highly structured SAN may be very
important in achieving other functions. As described by Boyett et al. [7] the increased
density of
I
f
toward the periphery of the node, while regarded as insufficient to carry
the pacemaking current by itself [79], seems to protect the SAN from the
hyperpolarizing influence of the right atrium. The grounds for this theory lie on
voltage clamp data.
I
f
is activated, under experimental conditions, by pulses achieving
hyperpolarization of -70 mV or more, which is greater than the middiastolic potential
of the SAN cells, but similar to that of the right atrial myocytes. Thus, at the border of
the SAN, the hyperpolarizing atrial influence would induce increased activation of
I
f
,
which in turn opposes the hyperpolarization, thus protecting the electrical milieu
present in the more central regions of the SAN proper.
Since the discovery of the voltage-dependent calcium channels in the rabbit SAN,
and the initial thorough description by Hagiwara's group in 1988 [33, 60], ample
direct and indirect evidence has accumulated as to the contribution of these channels
to the diastolic depolarization of pacemaker cells. Identified in tissues exhibiting
