Na channels

FIGURE 17.26 The o i-subuiiit of the t-tubule Ca" chainiel/DHP receptor contains six peptide segments that may associate to form the Ca" channel. This Ca" channel polypeptide is homologous with the voltage-sensitive Na channel of neuronal tissue. 

Inwardly Rectifying K+ Channels Voltage-dependent Na+ Channels... 

Prototypic inhibitor of the family of Na/H exchangers and of epithelial Na+ channels. 

The amiloride-sensitive Na+ channel (ENaC) is a cell membrane glycoprotein selective for sodium ions, which is composed of three subunits (a, (3 and y). Gating of sodium is inhibited by the diuretic amiloride. 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

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... 

Not all cells in the heart express the fast sodium channel. Thus, sinus nodal and atrioventricular nodal cells lack the fast Na+ channel and instead generate their action potentials via opening of Ca2+ channels. This is the basis for their sensitivity to Ca2+ antagonists. 

A cell may generate oscillating afterpotentials which reach the threshold for activation of the Na+ channel (triggered activity). 

Class IC antiarrhythmic drugs such as flecainide or propafenone block the Na+ channel (open state propafenone open and inactivated state) with a very long dissociation time constant so that they alter normal action potential propagation. Flecainide increased mortality of patients recovering from myocardial infarction due to its proarrhythmic effects (CAST study). Action potential is shortened in Purkinje fibres but is prolonged in the ventricles. 

Voltage-dependent Na+ Channels Voltage-dependent Ca2+ Channels (3-Adrenergic System Cardiac Glycosides... 

Antiarrhythmic drugs are antagonists of the fast Na+ channel, which slow the propagation of the cardiac action potential. Class I drugs suppress the fast upstroke of the action potential. 

Na+ channels at clinically relevant concentrations (carbamazepine, phenytoin, lamotrigine). Most of these anticonvulsant dtugs display three distinct effects on Na+ channels ... 

A pronounced slowing of Na+ channel recovery from the inactivated state. 

Quaternary ammonium salts such as carcainium chloride (RSD 931) have been shown to be antitussive whilst having much reduced local anaesthetic activity. Whilst the molecular mechanisms underlying this antitussive activity is not understood, RSD 931 appears to be A8 fibre selective and may represent a novel class of antitussive drug. More recently JMF2-1 a lidocaine derivative that blocks Na+ channels has had beneficial effects in the airways without significant local anaesthetic activity. 

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