Depolarization channels

Like other voltage-gated cation channels, Ca2+ channels exist in at least three states A resting state stabilized at negative potentials (such as the resting potentials of most electrically excitable cells) that is a closed state from which the channel can open. The open state is induced by depolarization. Channels do not stay open indefinitely because they are turned off during prolonged depolarization by transition into an inactivated state. Inactivation is driven both by depolarization... 

Local anesthetics produce anesthesia by blocking nerve impulse conduction in sensory, as well as motor nerve, fibers. Nerve impulses are initiated by membrane depolarization, effected by the opening of a sodium ion channel and an influx of sodium ions. Local anesthetics act by inhibiting the channel s opening they bind to a receptor located in the channel s interior. The degree of blockage on an isolated nerve depends not only on the amount of dmg, but also on the rate of nerve stimulation (153—156). 

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... 

Big-conductance Ca2+ sensitive K+ (BKca) channels are activated by calcium surge and membrane depolarization. BKCa channels are specifically blocked by iberiotoxin and less selectively by charybdotoxin. BKCa channels are composed of pore-forming a and auxiliary (3 subunits. Both BKCa,a andBKca, 3 subunits as well as their efficient coupling in the heteromultimeiic formation of BKca channel complexes are important for the function of BKCa channels. 

Ca2+ is an important intracellular second messenger that controls cellular functions including muscle contraction in smooth and cardiac muscle. Ca2+ channel blockers inhibit depolarization-induced Ca2+ entry into muscle cells in the cardiovascular system causing a decrease in blood pressure, decreased cardiac contractility, and antiarrhythmic effects. Therefore, these drugs are used clinically to treat hypertension, myocardial ischemia, and cardiac arrhythmias. 

Voltage-gated Ca2+ channels are Ca2+-selective pores in the plasma membrane of electrically excitable cells, such as neurons, muscle cells, (neuro) endocrine cells, and sensory cells. They open in response to membrane depolarization (e.g., an action potential) and permit the influx of Ca2+ along its electrochemical gradient into the cytoplasm. 

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 three classes also inhibit depolarization-induced contraction of venous smooth muscle in vitro. However, venous relaxation does not substantially contribute to the hemodynamic actions of Ca2+ channel blockers. 

Inward Rectification refers to decreased conductance upon membrane depolarization. In classical inward rectifier K+ channels, rectification is strong and currents rapidly decline at membrane potentials positive to the reversal potential, in contrast to other Kir channels in which rectification is weak and currents decline only gradually at potentials positive to the reversal potential. 

Inward Rectifier K+ Channels. Figure 1 The role of inward rectifier (Kir) channels in cardiac action potentials. Depolarization is generated and maintained by Na and Ca currents (/Na, /Ca). Voltage-gated K currents (Kv) and Kir channels contribute to repolarization and maintenance of a negative resting potential. 

Inward Rectifier K+ Channels. Figure 2 High [K+] inside cells relative to outside results in normal rectification, whereby outward (positive by convention) potassium currents (/) when cells are depolarized (is positive relative to EK), are biggerthan inward (negative) currents at hyperpolarized (negative) voltages. Inward or anomalous rectifiers show strong or weak inward rectification whereby outward currents are smaller than inward currents. 

---