The rapid opening of sodium channels, or activation, results in a sudden increase in gNa, occurring in approximately 0.1 msec. However, once open, the sodium channels enter an inactive state for a time period of about 1 to 2 msec, causing gNa to rapidly decrease (as shown in Figure 16.3). These channels remain in the inactive state until the membrane starts to repolarize. During repolarization, the channel transitions to the closed state and can be reopened by another depolarization of Vm that reaches the threshold. These characteristics of the sodium channel form the basis of the refractory period of the action potential. In the inactive state, the sodium channels cannot be reopened, preventing the generation of another action potential. This period is known as the effective refractory period. It ensures that the cardiac muscle does not undergo sustained, tetanic contraction, which would hinder ventricular relaxation and interfere with the normal pumping action of the heart. As the cell repolarizes (phase 3), the inactive channels begin transitioning to the closed state. This period, called the relative refractory period, allows for the generation of another action potential, but it requires a larger-than-normal depolarization of Vm. Only when Vm returns to the resting level (phase 4) are all the sodium channels closed and able to be reactivated by the normal depolarization of Vm.

The patch clamp technique is used to measure the flow of anionic current through a membrane channel. Individual channels open and close in a random manner, as illustrated in Figure 16.4, which depicts the current flow through sodium channels in a myocardial cell. Prior to the time indicated by the arrow, the membrane potential was clamped at -85mV. At the time indicated by the arrow, the potential was suddenly changed to -45mV and remained at this value for the duration of the recording.

Figure 16.4 shows that immediately after the membrane potential became less negative, one sodium channel opened with an amplitude of 1.5pA. Subsequently, a second sodium channel opened, resulting in a total current of 3pA from both channels, after which both channels closed (i.e., the current returned to 0). Both channels remained closed for approximately 4 to 5 msec, and then both opened simultaneously. One channel closed, followed by the rapid closure of the second channel. Finally, after several seconds, one channel opened and then closed. Thereafter, both channels remained closed for the rest of the recording, even though the membrane voltage was held constant at -45mV.

Early Repolarization Genesis (Phase 1) is observed in many cardiac cells that exhibit a prominent plateau. During phase 1, there is an early and brief period of limited repolarization. This brief repolarization creates a notch between the end of the upstroke and the beginning of the plateau, as seen in Figures 16.1 and 16.3.

The activation of a transient outward current (ito), primarily carried by K+, leads to repolarization during phase 1. Activation of potassium channels in this phase causes a brief efflux of K+ from the cell, as the intracellular environment is positively charged and intracellular [K+] greatly exceeds extracellular [K+], as depicted in Figure 16.3. The transient efflux of K+ results in a brief and partial repolarization of the cell.

The magnitude of the phase 1 notch varies among cardiac cells. It is prominent in myocytes located in the epicardial and midmyocardial regions of the left ventricular wall (Figure 16.5), as well as in ventricular Purkinje fibers. However, the notch is negligible in myocytes from the endocardial region of the left ventricle.
The sodium channels open very rapidly, or activate (in ≈0.1 msec), thereby resulting in an abrupt increase in gNa. However, once open, the sodium channels inactivate (time course ≅ 1 to 2 msec), and gNa rapidly decreases (Fig. 16.3 ). The sodium channels remain in the inactivated state until the membrane begins to repolarize. With repolarization, the channel transitions to the closed state, from which it can then be reopened by another depolarization of Vm to the threshold. These properties of the sodium channel are the basis of the refractory period of the action potential. When the sodium channels are in the inactivated state, they cannot be reopened, and another action potential cannot be generated. During this period, the cell is said to be in the effective refractory period. This prevents a sustained, tetanic contraction of cardiac muscle, which would retard ventricular relaxation and therefore interfere with the normal intermittent pumping action of the heart. As the cell repolarizes (phase 3), the inactivated channels begin to transition to the closed state. During this period, called the relative refractory period, another action potential can be generated, but it requires a larger-than-normal depolarization of Vm. Only when Vm has returned to the resting level (phase 4) are all the sodium channels closed and thus able to be reactivated by the normal depolarization of Vm.
Anioniccurrentthroughonemembranechannelcanbemeasuredwiththepatchclamptechnique.Theindividualchannelsopenandcloserepeatedlyinarandommanner.Thisprocessisillustratedin
Fig.16.4 ,whichshowsthecurrentflowthroughsodiumchannelsinamyocardialcell.Beforethetimeindicatedbythearrow,themembranepotentialwasclampedat−85mV.Atthetimeindicatedbythearrow,thepotentialwassuddenlychangedto−45mV,atwhichvalueitwasheldfortheremainderoftherecording.
Fig.16.4 indicatesthatimmediatelyafterthemembranepotentialwasmadelessnegative,onesodiumchannelopened(1.5pAinamplitude),andthenasecondsodiumchannelopened(3pAtotalcurrentfrombothchannels),whereuponbothchannelsclosed(i.e.,thecurrentreturnedto0).Bothchannelsclosedforapproximately4or5msec,andthenbothchannelsopenedatthesametime.Thereafter,onechannelclosedandthenthesecondrapidlyclosed.Finally,afterseveralseconds,onechannelopenedandthenclosed.Thereafter,bothchannelsremainedclosedfortherestoftherecording,eventhoughthemembranevoltagewasheldconstantat−45mV.
Genesis of Early Repolarization (Phase 1)
In many cardiac cells that have a prominent plateau, phase 1 is an early, brief period of limited repolarization. This brief repolarization results in the notch between the end of the upstroke and the beginning of the plateau (see
Figs. 16.1 16.3).
Repolarization is brief because of activation of a transient outward current (ito) carried mainly by K+ . Activation of potassium channels during phase 1 causes a brief efflux of K+ from the cell because the cell interior is positively charged and intracellular [K+] greatly exceeds extracellular [K+] (see
Fig. 16.3 ). The cell is briefly and partially repolarized as a result of this transient efflux of K+ .
The size of the phase 1 notch varies among cardiac cells. It is prominent in myocytes in the epicardial and midmyocardial regions of the left ventricular wall (
Fig. 16.5 ) and in ventricular Purkinje fibers. However, the notch is negligible in myocytes from the endocardial region of the left ventricle (see