Purkinje Effect

The ancillary peaks related to the Bezold-Brucke and the Purkinje Effects are particularly relevant to determining the precise amount of crossover between the spectral absorption characteristics. A putative peak near 390 nm in the aphakic human eye would also be very useful in evaluating these parameters. See Section 17.2.4. 

Purkinje Effect Effect of the behaviour of the human eye, the ratio of photopic vision to scotopic vision, named after the Czech physiologist Jan Evangelista Purkinje. 

Purkinje effect (i)p9r- kin-je-. A phenomenon associated with the human eye, making it more sensitive to blue fight when the illumination is poor (less than about O.lfin/ft ) and to yellow fight when the illumination is good. 

For comparison, a standard white block of magnesia is required, and specifications for a Wesson-type colorimeter are approved, together with provisions for the illuminant and for viewing by visual means. The conditions are very carefully specified. Thus in the viewing booth, the level of external illumination at the top of the colorimeter box shall be not less than 1 nor more than 5 foot-candles. This obviates errors due to the Purkinje effect involving too low a light intensity (rod vision), yet extraneous light is held to a relatively low level. 

Glass lA Antiarrhythmic Agents. Class lA antiarrhythmic agents decrease automaticity, ie, depress pacemaker rates, especially ectopic foci rates produce moderate depression of phase 0 depolarization and thus slow conduction in atria, A-V node, His-Purkinje system, and ventricles prolong repolarization, ie, lengthen action potential duration increase refractoriness and depress excitabiHty. These electrophysiological effects are manifested in the ECG by increases in the PR, QRS, and QT intervals. 

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. 

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. 

To ascertain the effects of non-hERG-mediated QT prolongation, test key compounds in relevant ex vivo (e.g. Langendorff [38], dog purkinje fibers [39]) or in vivo [40] models as early as possible. 

Harmaline has also been found to have neurotoxic effects on Purkinje neurons (O Hearn and Molliver 1997). This likely results from excitotoxic consequences induced by prolonged stimulation of inferior olivary neurons. Whether this occurs in levels reached during human consumption has not been specifically addressed. Prolonged neurological symptoms have not been reported in those who consume the drug. 

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-... 

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 ...

Pharmacology Procainamide, a class lA antiarrhythmic, increases the effective refractory period of the atria, and to a lesser extent the bundle of His-Purkinje system and ventricles of the heart. 

Pharmacology Therapeutic concentrations of lidocaine attenuate phase 4 diastolic depolarization, decrease automaticity and cause a decrease or no change in excitability and membrane responsiveness. Action potential duration and effective refractory period (ERP) of Purkinje fibers and ventricular muscle are decreased, while the ratio of ERP to action potential duration is increased. Lidocaine raises ventricular fibrillation threshold. AV nodal conduction time is unchanged or shortened. Lidocaine increases the electrical stimulation threshold of the ventricle during diastole. 

Mechanism - Structurally like lidocaine, mexiletine inhibits the inward sodium current, thus reducing the rate of rise of the action potential. Phase 0. Mexiletine decreases the effective refractory period (ERP) in Purkinje fibers. The decrease in ERP is of lesser magnitude than the decrease in action potential duration (APD), with a resulting increase in ERP/APD ratio. 

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