Sodium inward currents

As just outlined, both impulse initiation (automaticity) and conduction result from changes in the permeability of the external membrane of cardiac cells to various ions. Normally, impulse propagation in most cardiac cells results from a rapid but brief increase in sodium permeability which permits an influx of that ion and produces rapid depolarization. As cells become partially depolarized, either as a result of the normal "fast" sodium inward current or for other reasons, other changes in membrane permeability occur leading to a more slowly developing and smaller inward ion flow composed primarily of calcium. In diseased and/or partially depolarized cells this "slow" calcium current may be the only mechanism available for impulse propagation. It may also be responsible for impulse initiation in areas not normally automatic. 

Fig. 29.4.13. Effects of DCJW (7) on the DUM neuron voltage-dependent inward sodium current. (A) Sodium inward current traces obtained by a 30-ms depolarizing pulse to —10 mV from a holding potential of —90 mV, in the absence and presence of 100 nM DCJW. (B) Effect of DCJW on the current-voltage relationship of the inward sodium current. The maximum peak current amplitude was plotted versus membrane...

Menthol inhibits sodium inward currents generated by heterologously expressing in HEK293 cells rat neuronal (rat type HA) and human skeletal muscle (hSkMl) sodium channel isoforms [21]. Also, the inhibitoiy potency of menthol on these channels increases when maintaining the holding potential in more depolarized levels. This fact, per se, indicates that menthol could have more affinity for channels in inactivated state [21]. 

The studies of Bhatnager et al. (1990) and Beresewicz and Horackova (1991) also report a significant and important increase in the inward movement of Na through the TTX-sensitive Na channel in cells exposed to oxidant stress. It is likely that this increased inward current may play a role in prolonging the action potential and in loading the cell with sodium. Both of these effects would combine to create a situation that would tend to load the cell with calcium through alteration in the activity of the Na/Ca exchange mechanism (Matsuura et al., 1991). 

Ibutilide prolongs action potential in isolated adult cardiac myocytes and increases both atrial and ventricular refractoriness in vivo. An additional action is blockade of outward potassium currents. Thus, ibutilide acts by blocking the rapid component of the delayed rectifier current (IKr) as well as by activation of a slow inward current carried predominantly by sodium. 

Mechanism of Action An antiarrhythmicthat prolongs both atrial and ventricular action potential duration and increases the atrial and ventricular refractory period. Activates slow, inward current (mostly of sodium), produces mild slowing of sinus node rate and AV conduction, and causes dose-related prolongation of QT interval. Therapeutic Effect Converts arrhythmias to sinus rhythm. 

Class I drugs have a local anaesthetic-like action, blocking the inward current in sodium channels. This depresses the fast depolarisation (phase 0) which initiates each action potential (Figure 8.5). This membrane-stabilising effect makes them valuable for the treatment of ectopic and tachycardic arrhythmias, such as atrial and ventricular fibrillation, extrasystoles, supraventricular and ventricular tachycardia. Class I drugs also decrease contractility. A sub-classification is made according to the effects on... 

Metarhodopsin 11 activates transducin, leading to an exchange of bound GDP for GTP several hundred molecules of transducin are activated by a single molecule of metarhodopsin 11 within a fraction of a second. Transducin-GTP binds to, and activates, GMP phosphodiesterase, lowering the intracellular concentration of cGMP. As cGMP falls, a cation channel in the membrane closes, thus interrupting the steady inward current of sodium and calcium ions. This leads to hyperpolarization of the membrane and reduced secretion of neurotransmitter (Baylor, 1996). 

Reducing cell membrane permeability to ions, particularly the voltage-dependent sodium channels which are responsible for the inward current that generates an action potential. Cells that are firing repetitively at high frequency are blocked preferentially, which permits discrimination between epileptic and physiological activity. 

Sparteine is a drug with antiarrhythmic properties. It has been deduced from pharmacological and electrophysiological studies that sparteine acts via a reduction of the Na inward current, e.g. during the upstroke of cardiac action potentials. This process was elucidated by the determination of sodium currents, in isolated muscle fibbers, by loose patch clamp measurements [236]. The IC50 value for half-maximal blocking of the sodium current was 168.8 )iM, which is in accordance witli the antiarrhythmic activity of sparteine. The importance of sparteine on Na channels inhibition was further analysed because of its potencial strong interference in neuronal transmission, particularly in herbivores. This emphasizes the role of sparteine as a chemical defence compound for the plants that produce it. 

Figure 3. Sodium currents recorded from the squid giant axons before (A) and after (B) internal application of 10 pM deltamethrin. External and internal sodium concentrations were 111 mM and 50 mM, respectively. A, a depolarizing pulse from the holding potential (V ) of -80 mV to -20 mV elicited the normal transient inward sodium current which decayed within 10 msec. Depolarization to a second depolarizing pulse (500 msec) to the sodium reversal potential (E a - +20 mV) yielded a negligible current. Repolarization to the holding potential (-80 mV) produced a very small inward sodium tail current. B, the same pulse protocol as that for A but in the presence of deltamethrin in another axon Note a large and prolonged tail current upon repolarization from +20 mV to -80 mV.

Figure 4. Effects of 60 pM (+)-trans tetramethrin on single sodium channels in an inside-out membrane patch excised from a neuroblastoma cell (N1E-115 line). A, sample records of sodium channel currents (inward deflections) associated with step depolarizations from -90 mV to -50 mV. B, as in A, but after application of tetramethrin to the internal surface of the membrane. C, current amplitude histogram in the control. D, as in C, but after application of tetramethrin. (Reproduced with permission from ref. 31. Copyright 1983 Elsevier.) Continued on next page.

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