The SA node cell's transmembrane action potential, shown in Figure 16.10B, differs from that of a ventricular myocardial cell (refer to Figure 16.10A) in several ways. The resting potential of the SA node cell is typically less negative, the upstroke of the action potential (phase 0) is less steep, the plateau is not sustained, and repolarization (phase 3) occurs more gradually. These characteristics are indicative of the slow response. Tetrodotoxin, which blocks the fast Na+ current, does not affect the SA nodal action potential because the upstroke of the action potential is not mediated by an inward Na+ current through fast channels. Therefore, tetrodotoxin has no impact on cells that exhibit the slow response.

The frequency of pacemaker firing is ordinarily controlled by the system. Increased sympathetic nervous activity, through the release of norepinephrine, primarily raises the heart rate by increasing the slope of the slow diastolic depolarization. This mechanism is active during physical exertion, anxiety, or certain diseases such as febrile infectious diseases. On the other hand, increased vagal activity, through the release of acetylcholine, decreases the heart rate by hyperpolarizing the pacemaker cell membrane and reducing the slope of the slow diastolic depolarization. These mechanisms generally prevail over sympathetic activity. An extreme example is vasovagal syncope, a brief period of lightheadedness or loss of consciousness caused by an intense burst of vagal activity. This type of syncope is a reflex response to pain or certain psychological stimuli.

Figure 16.18 illustrates the mechanisms involved in the changes in the frequency of pacemaker firing. A reduction in the slope of the slow diastolic depolarization decreases the firing frequency, as indicated by the decrease from wave a to wave b. The threshold potential (TP) is shown in the figure. Conversely, an increase in the threshold potential (from TP-1 to TP-2) or an increase in the magnitude of the maximum diastolic potential (from wave segment at o to d) also diminishes the firing frequency. This information is derived from Hoffman and Cranefield's work on the electrophysiology of the heart in 1960.

During phase 4, the transmembrane potential in SA (and AV) nodal automatic cells is much less negative compared to atrial or ventricular myocytes. This is due to the absence of the inward rectifying potassium channel (iK1) in nodal cells. Consequently, the ratio of gK to gNa during phase 4 is much lower in nodal cells than in myocytes. As a result, the deviation of Vm from the K+ Nernst equilibrium potential (EK) is much greater in nodal cells during phase 4 than in myocytes.

The main distinguishing feature of a pacemaker cell, which sets it apart from other cells, is evident in phase 4. While the potential remains constant in nonautomatic cells during this phase, a pacemaker fiber experiences slow diastolic depolarization throughout phase 4. Depolarization occurs at a steady rate until it reaches a threshold, triggering an action potential.

The frequency of pacemaker cell activity can be altered by changes in (1) the rate of depolarization during phase 4, (2) the maximal negativity during phase 4, or (3) the threshold potential (Figure 16.18). An increase in the rate of slow diastolic depolarization leads to an earlier attainment of the threshold potential, resulting in an increased heart rate. Conversely, a rise in the threshold potential delays the onset of phase 0, thereby reducing the heart rate. Similarly, when the maximal negative potential is increased, more time is required to reach the threshold potential, resulting in a diminished heart rate, provided the slope of phase 4 remains unchanged.

The automaticity of pacemaker cells is based on several ionic currents that contribute to the characteristic slow diastolic depolarization.
A typical transmembrane action potential recorded from an SA node cell is depicted in
Fig. 16.10B.
In comparison with the transmembrane potential recorded from a ventricular myocardial cell (see
Fig. 16.10A ), the resting potential of the SA node cell is usually less negative, the upstroke of the action potential (phase 0) is less steep, the plateau is not sustained, and repolarization (phase 3) is more gradual. These are characteristic attributes of the slow response. Tetrodotoxin (which blocks the fast Na+ current) has no influence on the SA nodal action potential because the action potential upstroke is not produced by an inward Na+ current through fast channels. Thus tetrodotoxin has no effect on cells that exhibit the slow response.
Ordinarily,thefrequencyofpacemakerfiringiscontrolled system.Increasedsympatheticnervousactivity,throughthe releaseofnorepinephrine,raisestheheartrateprincipallyby increasingtheslopeoftheslowdiastolicdepolarization.Thismechanismofincreasingheartratefunctionsduringphysical exertion,anxiety,orcertainillnessessuchasfebrileinfectiousA diseases.Increasedvagalactivity,throughthereleaseof acetylcholine,diminishestheheartratebyhyperpolarizingthepacemakercellmembraneandreducingtheslope oftheslowdiastolicdepolarization.Thesemechanisms predominantoversympatheticactivity.Anextremeexample isvasovagalsyncope,abriefperiodoflightheadednessorlossofconsciousnesscausedbyanintenseburstofvagal activity.Thistypeofsyncopeisareflexresponsetopainor tocertainpsychologicalstimuli.
•Fig. 16.18 Mechanisms Involved in the Changes in Frequency of Pacemaker Firing. A, Areductionintheslope(fromwaveatowave b)ofslowdiastolicdepolarizationdiminishesthefiringfrequency.TP,thresholdpotential.B, Anincreaseinthethresholdpotential(fromTP-1toTP-2)oranincreaseinthemagnitudeofthemaximumdiastolicpotential(fromwavesegmentsatod)alsodiminishesthefiringfrequency.(FromHoffmanBF,CranefieldPF.Electrophysiology of the Heart. NewYork:McGraw-Hill;1960.)
The transmembrane potential during phase 4 is much less negative in SA (and AV) nodal automatic cells than in atrial or ventricular myocytes because nodal cells lack the iK1 (inward rectifying) type of potassium channel. Thus the ratio of gK to gNa during phase 4 is much less in nodal cells than in myocytes. Hence, during phase 4, Vm deviates much more from the K+ Nernst equilibrium potential (EK) in nodal cells than it does in myocytes.
The principal feature of a pacemaker cell that distinguishes it from the other cells manifests in phase 4. In nonautomatic cells, the potential remains constant during this phase, whereas a pacemaker fiber is characterized by slow diastolic depolarization throughout phase 4. Depolarization proceeds at a steady rate until a threshold is attained, and an action potential is then triggered.
Pacemaker cell frequency may be varied by a change in (1) the rate of depolarization during phase 4, (2) the maximal negativity during phase 4, or (3) the threshold potential (
Fig. 16.18). When the rate of slow diastolic depolarization is increased, the threshold potential is attained earlier, and the heart rate increases. A rise in the threshold potential delays the onset of phase 0, and the heart rate is reduced. Similarly, when the maximal negative potential is increased, more time is required to reach the threshold potential, when the slope of phase 4 remains unchanged, and the heart rate therefore diminishes.
Ionic Basis of Automaticity
Several ionic currents contribute to the slow diastolic depolarization that characteristically occurs in the automatic