gK+ occurs, which contributes to the depolari-
zation as shown in the following equation:
Em = g'K( - 96 mV) + g'Ca( +134 mV)
Depolarization causes voltage-operated, delayed
rectifier potassium channels to open, and the
increased gK+ repolarizes the cell toward the
equilibrium potential for K+ (phase 3). At the
same time, the slow inward Ca++ channels that
opened during phase 0 become inactivated,
to the repolarization. Phase 3 ends when the
membrane potential reaches about -65 mV The
phase of repolarization is self-limited because
the potassium channels begin to close again as
the cell becomes repolarized.
The ionic mechanisms responsible for the
spontaneous depolarization of the pacemaker
potential (phase 4) are not entirely clear, but
probably involve multiple ionic currents. First,
early in phase 4, gK+ is still declining. This fall
in gK+ contributes to depolarization. Second, in
the repolarized state, a pacemaker current (If),
or “funny” current, has been identified (see
Fig. 2.6). This depolarizing current involves,
in part, a slow inward movement of Na+. Third,
in the second half of phase 4, there is a small
increase in gCa++ through T-type calcium chan-
nels. T-type (“transient”) calcium channels dif-
fer from L-type calcium channels in that they
open briefly only at very negative voltages
(-50 mV) and are not blocked by the classi-
cal L-type calcium channel blockers. Fourth,
as the depolarization begins to reach threshold,
the L-type calcium channels begin to open,
causing a further increase in gCa++ until thresh-
old is reached and phase 0 is initiated.
potentials found in SA nodal cells primarily
depend on changes in gCa++ and gK+ conduct-
ances, with “funny” currents (If) and changes
in gCa++ and gK+ conductances playing a role
in the spontaneous depolarization.
The SA node displays intrinsic automaticity
a rate
per minute. Heart rate, however, can vary
between low resting values of 50 to 60 beats/
min and over 200 beats/min. These changes
in rate primarily are controlled by autonomic
nerves acting on the SA node. At low resting
heart rates, vagal influences are dominant
over sympathetic influences. This is termed
vagal tone. Autonomic nerves increase SA
nodal firing rate by both decreasing vagal tone
and increasing sympathetic activity on the SA
node in a reciprocal manner. An increase in
heart rate is a positive chronotropic response
(or positive chronotropy), whereas a reduc-
tion in heart rate is a negative chronotropic
response (or negative chronotropy).
Autonomic influences alter the rate of pace-
maker firing through the following mechanisms:
changing the slope of phase 4; (2) altering the
threshold voltage for triggering phase 0; and (3)
altering the degree of hyperpolarization at the
end of phase 3. Any of these three mechanisms
will either increase or decrease the time to reach
threshold. Sympathetic activation of the SA node
increases the slope of phase 4 (Fig. 2.7) and low-
ers the threshold, thereby increasing pacemaker
frequency (positive chronotropy). In this mech-
anism, norepinephrine released by sympathetic
adrenergic nerves binds to P:-adrenoceptors
coupled to a stimulatory G-protein (Gs-protein),
which activates adenylyl cyclase and increases
cyclic adenosine monophosphate (cAMP; see
Chapter 3). This effect leads to an increase in If
and an earlier opening of L-type calcium chan-
nels, both of which increase the rate of depolari-
zation. Repolarization is also accelerated, which
shortens overall cycle length and may increase
maximal hyperpolarization.
Vagal stimulation releases acetylcholine at
the SA node, which decreases the slope of phase
4 (by inhibiting “funny” currents), hyperpolar-
izes the cell, and increases the threshold voltage
required to trigger phase 0. All of these effects
cause the pacemaker potential to take longer
to reach threshold, thereby slowing the rate
(negative chronotropy). The rate of repolariza-
tion is reduced, which contributes to increas-
ing overall cycle length. Acetylcholine acts by
binding to muscarinic receptors (M2). This
decreases cAMP via the inhibitory G-protein
(Gi-protein), the opposite effect of sympathetic
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