Fast depolarization

The Class I antiarrhythmic agents inactivate the fast sodium channel, thereby slowing the movement of Na" across the cell membrane (1,2). This is reflected as a decrease in the rate of development of phase 0 (upstroke) depolarization of the action potential (1,2). The Class I agents have potent local anesthetic effects. These compounds have been further subdivided into Classes lA, IB, and IC based on recovery time from blockade of sodium channels (11). Class IB agents have the shortest recovery times (t1 ) Class lA compounds have moderate recovery times (t 2 usually <9 s) and Class IC have the longest recovery times (t 2 usually >9 s). 

Verapamil. Verapamil hydrochloride (see Table 1) is a synthetic papaverine [58-74-2] C2qH2 N04, derivative that was originally studied as a smooth muscle relaxant. It was later found to have properties of a new class of dmgs that inhibited transmembrane calcium movements. It is a (+),(—) racemic mixture. The (+)-isomer has local anesthetic properties and may exert effects on the fast sodium channel and slow phase 0 depolarization of the action potential. The (—)-isomer affects the slow calcium channel. Verapamil is an effective antiarrhythmic agent for supraventricular AV nodal reentrant arrhythmias (V1-2) and for controlling the ventricular response to atrial fibrillation (1,2,71—73). 

In the following, the cardiac action potential is explained (Fig. 1) An action potential is initiated by depolarization of the plasma membrane due to the pacemaker current (If) (carried by K+ and Na+, which can be modulated by acetylcholine and by adenosine) modulated by effects of sympathetic innervation and (3-adrenergic activation of Ca2+-influx as well as by acetylcholine- or adenosine-dependent K+-channels [in sinus nodal and atrioventricular nodal cells] or to dqjolarization of the neighbouring cell. Depolarization opens the fast Na+ channel resulting in a fast depolarization (phase 0 ofthe action potential). These channels then inactivate and can only be activated if the membrane is hyperpolarized... 

In order to accomplish these diverse physiological tasks described above, nature has created at least five different types of Ca2+ channels. These are termed L-, N-, P/Q-, R-, and T-type. Although they are all structurally similar (Fig. 1) they differ with respect to their biophysical properties. Some of them need only weak depolarizations to open and inactivate fast (e.g., T-type Ca2+ channels), whereas others require strong depolarizations and inactivate more slowly (e.g. P- or L-type Ca2+ channels). Channel types also differ with respect to their sensitivity to drugs. This selectivity is exploited for pharmacotherapy. 

All these postsynaptic events last only for a few milliseconds synaptic transmission through LGICs is fast. When the postsynaptic cell membrane is sufficiently depolarized, voltage-dependent Na+ channels open and an action potential is generated. 

Figure 7. Slow inactivation of Na channels is potentiated by STX. The graph shows the time required for the recovery of Na channels to an activatable state after a long (1 sec, +50 mV) inactivating depolarization. When tested by a brief test pulse, control currents (A) recovered in a fast (r = 233 msec) phase. Addition of STX (q, 2 nM, which approximately halved the currents with no inactivating pulse) approximately doubled the fraction of currents recovering in the slow phase and also increased the time constant of slow recovery. The fast recovery rate was unaffected. (Reproduced with permission from Ref. 47. Copyright 1986 The New York Academy of Sciences).

The sinoatrial (SA) node is located in the wall of the right atrium near the entrance of the superior vena cava. The specialized cells of the SA node spontaneously depolarize to threshold and generate 70 to 75 heart beats/ min. The "resting" membrane potential, or pacemaker potential, is different from that of neurons, which were discussed in Chapter 3 (Membrane Potential). First of all, this potential is approximately -55 mV, which is less negative than that found in neurons (-70 mV see Figure 13.2, panel A). Second, pacemaker potential is unstable and slowly depolarizes toward threshold (phase 4). Two important ion currents contribute to this slow depolarization. These cells are inherently leaky to sodium. The resulting influx of Na+ ions occurs through channels that differ from the fast Na+ channels that cause rapid depolarization in other types of excitable cells. Toward the end of phase... 

Phase 0 begins when the membrane potential reaches threshold (-40 mV). Recall that the upstroke of the action potential in neurons is due to increased permeability of fast Na+ channels, resulting in a steep, rapid depolarization. 

However, in the SAnode, the action potential develops more slowly because the fast Na+ channels do not play a role. Whenever the membrane potential is less negative than -60 mV for more than a few milliseconds, these channels become inactivated. With a resting membrane potential of -55 mV, this is clearly the case in the SA node. Instead, when the membrane potential reaches threshold in this tissue, many slow Ca++ channels open, resulting in the depolarization phase of the action potential. The slope of this depolarization is less steep than that of neurons. 

Another unusual feature of CuCl and CuBr is the presence of two Mu centers with nearly identical isotropic hyperfine parameters. One of the centers, Mu7, occurs preferentially at low temperatures but is metastable as evidenced by a thermally activated transition to the second center, Mu77 (see Fig. 13). As the temperature increases, the effects of this transition first appear as an increse of the Mu7 depolarization rate (lifetime broadening). At higher temperatures the transition becomes fast enough so that... 

Very fast repolarization (1 ms) Fast repolarization (200 ms) Continuous waves of depolarization with slow repolarization... 

Phase 0 Rapid depolarization occurs after threshold potential is reached owing to fast Na+ influx. The gradient of this line should be almost vertical as shown. 

To avoid depolarization by excitation transfer, the DNA is unwound using a second intercalator, for example, chloroquine, that does not engage in excitation transfer to or from the extremely dilute FPA probe, ethidium. Equation (4.68) applies to chloroquine when it is in excess, but the simultaneous binding of trace ethidium obeys a somewhat different relation, which is expressed in terms of the ratio of amplitudes (Ab/Af) of the bound (slow) and free (fast) components in its fluorescence decay as follows<53) ... 

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