Page 246 - Basic _ Clinical Pharmacology ( PDFDrive )

232 SECTION III Cardiovascular-Renal Drugs

potassium permeability due to the activity of channels generating relatively slow. Repolarization occurs when the calcium channels
transient outward currents. subsequently close due to inactivation and delayed rectifier-type
Although a small fraction of the sodium channels activated potassium channels open.
during the upstroke may actually remain open well into the later A similar process is involved in generating action potentials in
phases of the action potential, sustained depolarization during the AV node. Although the intrinsic rate of spontaneous diastolic
the plateau (phase 2) is due primarily to the activity of calcium depolarization in the AV node is typically faster than that of
channels. Because the equilibrium potential for calcium, like Purkinje cells, it is still slower than the rate of depolarization in
sodium, is very positive, these channels generate a depolarizing the SA node. Therefore, action potentials in the AV node are
inward current. Cardiac calcium channels activate and inactivate normally triggered by impulses that originate in the SA node and
in what appears to be a manner similar to sodium channels, but are conducted to the AV node through the atria. It is important to
in the case of the most common type of calcium channel (the recognize that action potential upstroke velocity is a key determi-
“L” type), the transitions occur more slowly and at more positive nant of impulse conduction velocity. Because the action potential
potentials. After activation, these channels eventually inactivate upstroke in AV node cells is mediated by calcium channels, which
and the permeability to potassium begins to increase, leading to open or activate relatively slowly, impulse conduction through the
final repolarization (phase 3) of the action potential. Two types of AV node is slow. This contributes to the delay between atrial and
potassium channels are particularly important in phase 3 repolar- ventricular contraction.
ization. They generate what are referred to as the rapidly activat- Electrical activity in the SA node and AV node is significantly
ing (I ) and slowly activating (I ) delayed rectifier potassium influenced by the autonomic nervous system (see Chapter 6).
Ks
Kr
currents. Repolarization, especially late in phase 3, is also aided by Sympathetic activation of β adrenoceptors speeds pacemaker
the inward rectifying potassium channels that are responsible for activity in the SA node and impulse propagation through the
the resting membrane potential. AV node by enhancing pacemaker and calcium channel activity,
It is noteworthy that other delayed rectifier-type potassium respectively. Conversely, parasympathetic activation of muscarinic
currents also play important roles in repolarization of certain car- receptors slows pacemaker activity and conduction velocity by
diac cell types. For example, the ultra-rapidly activating delayed inhibiting the activity of these channels, as well as by increasing
rectifier potassium current (I ) is particularly important in the potassium conductance by turning on acetylcholine-activated
Kur
repolarizing the atrial action potential. The resting membrane potassium channels.
potential and repolarization of atrial myocytes are also affected
by potassium channels that are gated by the parasympathetic The Effect of Membrane Potential on
neurotransmitter acetylcholine. Excitability
Purkinje cells are similar to atrial and ventricular cells in that
they generate an action potential with a fast upstroke due to the A key factor in the pathophysiology of arrhythmias and the
activity of sodium channels. However, unlike atrial and ventricular actions of antiarrhythmic agents is the relationship between the
cells, the membrane potential during phase 4 exhibits spontaneous membrane potential and the effect it has on the ion channels
depolarization. This is due to the presence of pacemaker channels responsible for excitability of the cell. During the plateau of
that generate an inward depolarizing pacemaker current. This atrial, ventricular, or Purkinje cell action potentials, most sodium
is sometimes referred to as the “funny” current (I ), because the channels are inactivated, rendering the cell refractory or inexcit-
f
channels involved have the unusual property of being activated able. Upon repolarization, recovery from inactivation takes place
by membrane hyperpolarization. Under some circumstances, (in the terminology of Figure 14–3, the h gates reopen), making
Purkinje cells can act as pacemakers for the heart by spontane- the channels available again for excitation. This is a time- and
ously depolarizing and initiating an action potential that is then voltage-dependent process. The actual time required for enough
propagated throughout the ventricular myocardium. However, sodium channels to recover from inactivation in order that a new
under normal conditions, the action potential in Purkinje cells propagated response can be generated is called the refractory
is triggered by impulses that originate in the SA node and are period. Full recovery of excitability typically does not occur until
conducted to these cells through the AV node. action potential repolarization is complete. Thus, refractoriness
Pacemaking activity in the SA node is due to spontaneous or excitability can be affected by factors that alter either action
depolarization during phase 4 of the action potential as well potential duration or the resting membrane potential. This rela-
(Figure 14–1). This diastolic depolarization is mediated in part tionship can also be significantly impacted by certain classes of
by the activity of pacemaker channels. It is also thought to be antiarrhythmic agents. One example is drugs that block sodium
due to the net inward current generated by the sodium-calcium channels. They can reduce the extent and rate of recovery from
exchanger, which is activated by the spontaneous release of cal- inactivation (Figure 14–4). Changes in refractoriness caused by
cium from intracellular storage sites. Unlike the action potential either altered recovery from inactivation or altered action potential
in Purkinje cells, spontaneous depolarization in the SA node duration can be important in the genesis or suppression of certain
triggers the upstroke of an action potential that is primarily due arrhythmias. A reduction in the number of available sodium chan-
to an increase in permeability to calcium, not sodium. Because nels can reduce excitability. In some cases, it may result in the cell
the calcium channels involved open or activate slowly, the maxi- being totally refractory or inexcitable. In other cases, there may
mum upstroke velocity of the action potential in SA node cells is be a reduction in peak sodium permeability. This can reduce the