Purkinje channels

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. 

In cerebellar Purkinje cells, a TTX-sensitive inward current is elicited, when the membrane was partially repolarized after strong depolarization. This resurgent current contributes to high-frequency repetitive firing of Purkinje neurons. The resurgent current results from open channel block by the cytoplasmic tail of the (34 subunit. The med Nav 1.6 mutant mice show defective synaptic transmission in the neuromuscular junction and degeneration of cerebellar Purkinje cells. 

Procainamide (Class IA antiarrhythmic drug) is an effective agent for ventricular tachycardia. Its mechanism of action involves blockade of the fast Na+ channels responsible for phase 0 in the fast response tissue of the ventricles. Therefore, its effect is most pronounced in the Purkinje fibers. The effects of this drug s activity include a decrease in excitability of myocardial cells and in conduction velocity. Therefore, a decrease in the rate of the phase 0 upstroke and a prolonged repolarization are observed. As a result, duration of the action potential and the associated refractory period is prolonged and the heart rate is reduced. These effects are illustrated by an increase in the duration of the QRS complex. 

Dehnes, Y., Chaudhry, F. A., Ullensvang, K., Lehre, K. P, Storm-Mathisen, J., and Danbolt, N. C. (1998) The glutamate transporter EAAT4 in rat cerebellar Purkinje cells a glutamategated chloride channel concentrated near the synapse in parts of the dendritic membrane facing astroglia. J. Neurosci. 18, 3606-3619. 

Cardiac Action Potential In Vitro Purkinje Fibers. Intracellular recording of action potentials from cardiac Purkinje fibers isolated from dog or sheep ventricle. Measurement of maximum rate of depolarization and action potential duration to detect sodium and potassium channel interactions, respectively, according to recommendations in EM A CPMP Points to Consider document, CPMP 986/96 (1998). 

The potassium sparing diuretic, amiloride (43), also produces a Class III effect in cardiac tissue. In canine Purkinje fibres APD is increased by 35% after prolonged exposure to 5 /zM of the drug [121]. The authors suggest two potential mechanisms for this effect (1) delay of inactivation of Na+ channels, or (2) inhibition of Na+/Ca + exchange. In infarcted dogs which were subjected to a PES protocol to produce re-entrant ventricular arrhyth-... 

A next-level assay is usually an isolated heart/cardiac tissue preparation. The canine Purkinje fiber assay (GLP) measures several action potential parameters, like resting membrane potential, upstroke velocity, action potential duration and shape, but also if a drug acts reverse-use dependently [72]. Based on changes of the action potential shape it is possible to conclude which ion channels are modulated (e.g., L-type calcium channel block would abolish the plateau phase). The papillary muscle assay (e.g., guinea pigs) determines similar parameters [73]. 

Flecainide (Tambocor) is a fluorinated aromatic hydrocarbon examined initially for its local anesthetic action and subsequently found to have antiarrhythmic effects. Flecainide inhibits the sodium channel, leading to conduction slowing in all parts of the heart, but most notably in the His-Purkinje system and ventricular myocardium. It has relatively minor effects on repolarization. Flecainide also inhibits abnormal auto-maticity. 

These drugs inhibit Ca + mediated slow channel inward current, thus inhibiting Ca + mediated depolarization. Phase 4 depolarization in SA node and Purkinje fibres is reduced. They also prolong AV nodal effective refractory period thus AV conduction is slowed. There is also negative inotropic action. 

Lidocaine blocks activated and inactivated sodium channels with rapid kinetics (Figure 14-9) the inactivated state block ensures greater effects on cells with long action potentials such as Purkinje and ventricular cells, compared with atrial cells. The rapid kinetics at normal resting potentials result in recovery from block between action potentials and no effect on conduction. The increased inactivation and slower unbinding kinetics result in the selective depression of conduction in depolarized cells. 

Staggerer Purkinje cell defect Vibrator Phosphatidylinositol transfer protein gene Tottering Mutation in voltage-gated Ca2+ channel Lurcher Abnormality in cerebellum Weaver Gly —> Ser mutation in K+ channel... 

Barclay J, Balaguero N, Mione M, Ackerman SL, Letts VA, Brodbeck J, Canti C, Meir A, Page KM, Kusumi K, Perez-Reyes E, Lander ES, Frankel WN, Gardiner RM, Dolphin AC, Rees M (2001) Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells. J Neurosci 21 6095-6104. 

Dove LS, Abbott LC, Griffith WH (1998) Whole-cell and single-channel analysis of P-type calcium currents in cerebellar Purkinje cells of leaner mutant mice. J Neurosci 18 7687-7699. 

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