Purkinje fibre canine

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. 

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 ...

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

There are comparatively few reports concerned with the stereoselective pharmacodynamics and pharmacokinetics of flecainide enantiomers. In vivo studies have revealed equipotency and equiactivity for the two enantiomers in mouse and dog models of arrhythmia. In vitro tests on canine Purkinje fibres have also shown that the enantiomers have comparable electrophysiologic activities. The two enantiomers have also shown similar affinities to a receptor site associated with cardiac sodium channels in isolated rat cardiac myocytes. ... 

Riccioppo Neto F (1993) Electropharmacological effects of berberine on canine cardiac Purkinje fibres and ventricular muscle and atrial muscle of the rabbit. Br J Pharmacol 108(2) 534-537... 

Interestingly, Han et al. (2000) have explored channel heterogeneity and shown that canine Purkinje fibres express Ac currents that are functionally and pharmacologically different from ventricular Ao currents. Clinically, such heterogeneity also exists in 7to current. 

In this chapter, we will focus on the papillary muscle action potential assay and compare the predictive value of this model in terms of sensitivity and specificity to that of the IKr assay, the canine Purkinje fibre action potential and the in vivo dog and monkey QT. 

Table 3 Sensitivity and specificity of non-clinical QT assays to predict the outcome of a clinical QT study. A preclinical result is considered positive for a compound if, at a preclinical concentration exposure (1-, 10- or 30-fold the unbound drug concentrations achieved in the clinic), a minimum 10 % increase is observed (hERG and canine Purkinje fibre assays) or a minimum 10 ms increase in QT is recorded (in vivo dog) vs. baseline values...

Clinical hERG Canine Purkinje fibre hi vivo dog ... 

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