Purkinje fibre

Normal rhythmic activity is the result of the activity of the sinus node generating action potentials that are conducted via the atria to the atrioventricular node, which delays further conduction to the His-Tawara-Purkinje system. From the Purkinje fibres, action potentials propagate to the ventricular myocardium. Arrhythmia means a disturbance of the normal rhythm either resulting in a faster rhythm (tachycardia, still rhythmic) or faster arrhythmia (tachyarrhythmia) or slowed rhythm (bradycardia, bradyarrhythmia). 

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. 

Class II drugs are classical (3-adrenoceptor antagonists such as propranolol, atenolol, metoprolol or the short-acting substance esmolol. These drugs reduce sinus rate, exert negative inotropic effects and slow atrioventricular conduction. Automaticity, membrane responsiveness and effective refractory period of Purkinje fibres are also reduced. The typical extracardiac side effects are due to (3-adrenoceptor blockade in other organs and include bronchospasm, hypoglycemia, increase in peripheral vascular resistance, depressions, nausea and impotence. 

Bers, D.M. and Ellis, D. (1982). Intracellular calcium and sodium activity in sheep heart Purkinje fibres. Effects of changes of external sodium and intracellular pH. Pflugers Arch. Eur. J. Physiol. 393, 171-178. 

Kass, R.S., Tsien, R.W. and Weingart, R. (1978). Ionic basis of transient inward current induced by strophanthidin in cardiac Purkinje fibres. J. Physiol. 281, 209-226. 

Blaustein MP, Golovina VA 2001 Structural complexity and functional diversity of endoplasmic reticulum Ca2+ stores. Trends Neurosci 24 602-608 Boyett MR, Hart G, Levi A J 1986 Dissociation between force and intracellular sodium activity with strophanthidin in isolated sheep Purkinje fibres. J Physiol 381 311—331... 

Auhert, M., Osterwalder, R., Wagner, B., Parrilla, I., Cavero, I., Doessegger, L. and Ertel, E.A. (2006) Evaluation of the rahhit Purkinje fibre assay as an in vitro tool for assessing the risk of drug-induced torsades de pointes in humans. Drug Safety, 29, 237-254. 

APD (microelectrode) Purkinje fibres papillary muscle mid-myocardial (M-cell) wedge preparation Abi-Gerges et al.,-88 Gintant et al.,-89 Lu et al. 90 Antzelevitch et al91... 

More recent studies continue to support the unique antifibrillatory activity of bretylium. Kowey et al. [38] have shown that bretylium prevented spontaneous VF and decreased the effects on VF threshold in a feline myocardial infarction model. They attributed this beneficial effect to a decrease in the dispersion of refractoriness between normal and ischaemic regions of the heart. In contrast, clofilium (14, see below), which had little effect on dispersion of refractoriness after coronary occlusion, was unable to prevent spontaneous VF. Similar results were seen in isolated tissue studies with canine subendocardial Purkinje fibres and ventricular muscle which contained both normal and ischaemic regions [39]. In these studies bretylium caused a smaller increase in dispersion of refractoriness in subendocardial Purkinje fibres than either sotalol or clofilium. In ventricular muscle tissue, bretylium decreased dispersion while sotalol and clofilium increased dispersion of refractoriness. 

Welcome [67,68]. Bethanidine was initially patented as a hypotensive agent but was found to have antifibrillatory activity [69]. Attempts to limit the hypotensive effects of bethanidine led to meobentine. At a concentration of 44 fxM, bethanidine has minimal effects on APDioo in propranolol-treated and untreated canine Purkinje fibres (-1-2% and —5%, respectively) [70,71], At 350 //M in untreated fibres, bethanidine increased APDioo t>y about 6%. In contrast, meobentine, which has less sympatholytic activity, increased APDioo t>y 12% at 37 //M in untreated fibres during the same study. Both compounds showed modest decreases of V ax at the stated concentrations. The Class I activity and the sympatholytic activity (for bethanidine) may act to decrease the apparent Class III effects of the two compounds (see below). 

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-... 

Lilly group led to LY190147 (49) [148,149], LY190147 exhibited Class III electrophysiological activity in canine Purkinje fibres at concentrations below 1 M. At concentrations above 1 //M, Class I activity was manifested. 

A benzopyran derivative, RP-58866 (70) is under development by Rhone-Poulenc. Patch clamp studies in guinea-pig ventricular myocytes indicate that RP-58866 inhibits the inward rectifying potassium current (7ki) with no effects on the delayed rectifier, ATP-sensitive potassium currents or calcium currents [200]. RP-58866 increases APD90 of Purkinje fibres by about 45% at 0.3 yuM without affecting K ax [201]. The compound was effective... 

Mitsui Pharmaceuticals is pursuing the development of MS-551 (77), which utilizes the 4-nitrophenyl Class III pharmacophore. Studies in canine Purkinje fibre have shown that 10 / M of MS-551 increases APD90 by 36% with no effects on Kmax [215]. Further, MS-551 at 0.03-0.3 mg/kg given intravenously eonverted atrial flutter to sinus rhythm in 7 of 8 dogs [216]. 

Table 2.2 EFFECT OF THE PHENYL SUBSTITUENT ON CLASS III ELECTRO-PHYSIOLOGICAL ACTIVITY IN CANINE CARDIAC PURKINJE FIBRES ...

It is an amide local anaesthetic and has rapid onset of action. It depresses diastolic depolarization and automaticity in ectopic foci in ventricular tissue. Phase 4 depolarization in partially depressed Purkinje fibres and after depolarizations are antagonised. It does not depress AV conduction and decreases action potential duration, effective refractory period. It has no effect on BP. 

The antiarrhythmic action is due to cardiac adrenergic blockade. It decreases the slope of phase 4 depolarization and automaticity in SA node, Purkinje fibres and other ectopic foci. It also prolongs the effective refractory period of AV node and impedes AV conduction. ECG shows prolonged PR interval. It is useful in sinus tachycardia, atrial and nodal extrasystoles. It is also useful in sympathetically mediated arrhythmias in pheochromocytoma and halothane anaesthesia. 

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. 

This is a class IB drug used primarily for the emergency treatment of ventricular arrhythmias. It has little effect on sinus node automaticity but depresses normal and abnormal forms of automaticity in Purkinje fibres. It is generally ineffective against supraventricular and accessory pathway-induced (e.g. WPW syndrome) arrhythmias. Lidocaine is relatively safe and free from adverse cardiovascular side effects. It causes minimal cardiodepression, although high doses can cause heart block. The most common side effect is a dose-related CNS toxicity. It is given intravenously as a bolus of 1 mg-kg-1 followed by an infusion of 20-50 pg-kg-l-min-1. 

Noble D, Tsien RW. The kinetics and rectifier properties of the slow potassium current in cardiac Purkinje fibres. J Physiol 1968 195 185-214. 

Boyett, M. R., Hart, G., Levi, A. J. and Roberts, A. Effects of repetitive activity on developed force and intracellular sodium in isolated sheep and dog Purkinje fibres. Journal of Physiology 1987, 388 295-322. 

Q4 The cardiac impulse arises in the pacemaker tissue of the heart, the SA node. The nodal tissues of the heart-the SA and AV nodes in the right atrium - are spontaneously rhythmic. The impulse generated by the SA node spreads, rather like ripples on a pond, over the atria and reaches the AV node to excite it. From the AV node the impulse travels via the bundle of His along the Purkinje fibres, which are enlarged muscle cells with a high conduction velocity, to the ventricles. The cardiac impulse reaches the apex of the heart first and then spreads over the muscle of the two ventricles. 

Puisieux F, Adamantidis M, Dumotier B, et al. Cisapride-induced prolongation of cardiac action potential and early after depolarizations in rabbit Purkinje fibres. Br / Pharmacol. 1996,117,1377-1379. 

Shin and Kim [186] investigated the effects of three phenothiazines, thioridazine, CPZ and TFZ, on the cardiac action potential duration in rabbits. Purkinje fibres were excised from the rabbit left ventricle and stored in a chamber super-fused with a normal Tyrode solution. The phenothiazine drugs displayed different effects on the duration of cardiac action potential. The obtained results indicated that it would be necessary to propose an assay for the cardiac action potential duration, in order to elucidate the electro-physiological effects of these phenothiazines on the heart. 

Aubert M, Osterwalder R, Wagner B et al (2006) Evaluation of the rabbit Purkinje fibre assay as an in vitro tool for assessing the risk of... 

Prediction of the risk of Torsade de Pointes using the model of isolated canine Purkinje fibres. Br J Pharmacol 144(3) 376-385... 

Ellis, D., The intracellular sodium ion concentration of sheep heart Purkinje fibres and its relationship to external sodium. J. Physiol. (London) 266, 74P (1977). 

In cardiac cells, there are two time-dependent outward currents which contribute to repolarization of the cell. Both of these outward currents may be decreased by calcium channel blocking drugs. Since an increase in the intracellular Ca2 + concentration activates one of the outward currents (7to), all the calcium channel blocking drugs should reduce Ito [ 159]. This has been shown with D600, nisoldipine and diltiazem [41-43, 159], The other time-dependent outward current (7X, delayed rectifier) is not calcium-activated [ 160]. Hume has found that D600, diltiazem and nisoldipine inhibit 7X in frog atrial cells [ 160]. However, a similar concentration of nisoldipine does not affect 7X in calf Purkinje fibres [43]. 

A. E. Hall, O. F. Hutter, and D. Noble, Current-Voltage Relations of Purkinje Fibres in Sodium-Deficient Solutions, J. Physiol. London), 166, 225 (1963). 

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