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Helfant, Scherlag and Damato, Circulation (1967),154 in studies on dogs concluded that PHT (5 mg/kg) consistently reversed the atrioventricular conduction (AVC) prolongations induced by procainamide.
154. Helfant, R. H., Scherlag, B. J., and Damato, A. N., The electrophysiological properties of diphenylhydantoin sodium as compared to procaine amide in the normal and digitalis intoxicated heart, Circulation, 36: 108-118, 1967.
Scherlag, Helfant and Damato, American Heart Journal (1968),327 compared the effects of PHT and procainamide on AVC in digitalis-intoxicated and normal canine heart. PHT consistently converted more acetylstrophanthidin-induced ventricular tachycardia to sinus rhythm than did procainamide and completely restored AVC to control values. In contrast, procainamide, in doses necessary to counteract digitalis-induced ventricular tachycardia, exacerbated the AVC prolongation produced by the glycoside. The authors state that the effect of PHT on AVC makes this a unique drug since it abolishes both the ventricular ectopia and AVC abnormalities produced by the glycoside.
327. Scherlag, B. J., Helfant, R. H., and Damato, A. N., The contrasting effects of diphenylhydantoin and procaine amide on A-V conduction in the digitalis-intoxicated and the normal heart, Amer. Heart J., 75: 200-205, 1968.
Bigger, Strauss and Hoffman, Federation Proceedings (1968),22 studied the effects of PHT on the conducting system in anesthetized dogs with electrodes chronically implanted at selected sites, and in isolated rabbit hearts by means of intracellular microelectrodes. In dogs, PHT (5-10 mg/ kg) accelerated AVC by 20% under control conditions and in the presence of incomplete atrioventricular (AV) block and atrial flutter. In rabbit heart, PHT increased AVC in the presence of partial AV block. PHT also improved impaired AVC caused by acetylcholine (ACh) without altering the ACh-induced sinus bradycardia.
22. Bigger, J. T., Jr., Strauss, H. C., and Hoffmann, B. F., Effects of diphenylhydantoin on atrioventricular conduction, Fed. Proc., 27: 406, 1968.
Wax, Webb and Ecker, Surgical Forum (1969),1668 observed the effect of PHT on the resting potential and action potential of ventricular heart muscle of the rat. With intravenous PHT (5 mg/kg) the resting potential plateau phase and the recovery period were both lengthened. The authors note that these actions of PHT stabilized the heart, making it less susceptible to early reentry from circus mechanisms or other aberrant stimuli.
1668. Wax, S. D., Webb, W. R., and Ecker, R. R., Myocardium stabilization by diphenylhydantoin, Surg. Forum, 20: 164-166, 1969.
Kleinfeld and Stein, Circulation (1968),1221 electrically stimulated isolated canine Purkinje and ventricular fibers and studied the action potentials. They found that PHT (.01-100 µM) decreased the effective refractory period of both fibers, with the greater effect being in the Purkinje fiber.
1221. Kleinfeld, M. and Stein, E., Effects of diphenylhydantoin on action potentials of canine Purkinje and ventricular fibers, Circulation, 38: 116, 1968.
Bigger, Weinberg, Kovalik, Harris, Cranefield and Hoffman, Circulation Research (1970),828 examined the effects of PHT on excitability, automaticity and conduction in the canine heart in situ and on threshold voltage and action potential duration in isolated Purkinje fibers. In the in situ heart, PHT (10 mg/kg) shortened the refractory period and enhanced conduction in ventricular muscle without changing diastolic threshold and only slightly decreasing automaticity in the specialized ventricular conducting system. It also increased fibrillation thresholds in both the atrium and ventricle. Shortening of the refractory period was accompanied by a decrease in the Q-T interval, consistent with clinical observations in PHT-treated patients. In the isolated fibers PHT (0.1 µM) decreased action potential duration and the intracellular current pulse required to bring the fibers to firing threshold, while increasing threshold voltage. The authors comment that PHT's ability to increase membrane responsiveness, thereby enhancing conduction, appears to be an important aspect of its antiarrhythmic actions and adds to its clinical safety.
828. Bigger, J. T., Weinberg, D. I., Kovalik, T. W., Harris, P. D., Cranefield, P. C., and Hoffman, B. F., Effects of diphenylhydantoin on excitability and automaticity in the canine heart, Circ. Res., 26: 1-15, 1970.
Rosen, Danilo, Alonso and Pippenge, Journal of Pharmacology and Experimental Therapeutics (1976),2055 demonstrated in isolated Purkinje fibers that the effect of PHT is determined by the initial state of conduction in the fiber which was experimentally altered by stretch, exposure to ouabain or perfusion with a solution in which all sodium ions were replaced by tetraethylamrnoniurn. Depending upon the state of conduction in the fiber, PHT was shown either to enhance or to reduce conduction.
2055. Rosen, M. R., Danilo, P., Alonso, M. and Pippenger, C. E., Effects of therapeutic concentrations of diphenylhydantoin on transmembrane potentials of normal and depressed Purkinje fibers, J. Pharmacol. Exp. Ther., 197(3): 594-604, 1976.
El-Sherif and Lazzara, Circulation (1978),1822 studied the mechanism of action of PHT on reentrant ventricular arrhythmias in dogs, utilizing direct recordings of the reentrant pathway from the epicardial surface of the infarction zone. PHT, in therapeutic doses, consistently prolonged refractoriness of potentially reentrant pathways in the infarction zone. On the other hand, PHT had no significant effect on conduction in the normal adjacent zone.
1822. El-Sherif, N. and Lazzara, R., Re-entrant ventricular arrhythmias in the late myocardial infarction period, 5. Mechanism of action of diphenylbydantoin, Circulation, 57(3): 465-73, 1979.
Arnsdorf and Mehlman, Journal of Pharmacology and Experimental Therapeutics (1978),1726 observed in sheep cardiac Purkinje fibers, injured by ischemia or stretch, that PHT (5 µg/ml) can restore impulse propagation by causing normalization of the action potential. The authors note that clinically PHT can eliminate functional bundle branch block.
1726. Arnsdorf, M. F. and Meblman, D. J., Observations on the effects of selected antiarrhythmic drugs on mammalian cardiac Purkinje fibers with two levels of steady-state potential: Influences of lidocaine, phenytoin, propranolol, disopyramide and procainamide on repolarization, action potential shape and conduction, J. Pharmacol. Exp. Ther., 207(3): 983-91, 1978.
Wasserstrom and Ferrier, Journal of Molecular and Cellular Cardiology (1982),3062 reported that both PHT (7.9-12 ÁM) and quinidine (1.6 ÁM) abolished or reduced acetylstrophanthidin-induced oscillatory afterpotentials and aftercontractions in isolated canine false tendons and Purkinje tissue. PHT hyperpolarized the tissue, but did not alter the threshold; whereas quinidine raised the threshold. Both drugs partially reversed the inotropic effects of acetylstrophanthidin. The authors note that PHT is clinically effective against digitalis-induced arrhythmias, but that quinidine is contraindicated because it can depress conduction and thereby precipitate arrhythmias.
3062. Wasserstrom, J. A., Ferrier, G. B., Effects of phenytoin and quinidine on digitalis-induced oscillatory afterpotentials, aftercontractions, and inotropy in canine ventricular tissues, Mol. Cell Cardiol., 14: 725-36, 1982.
Scheuer and Kass, Circulation Research (1983),2931 investigated the effects of PHT (5-100 ÁM) on electrical and mechanical activity of isolated calf and dog Purkinje fibers. In addition to lowering and shortening the plateau phase of the action potential and twitch tension, PHT also reduced voltage-dependent calcium current.
2931. Scheuer, T., Kass, R. S., Phenytoin reduces calcium current in the cardiac Purkinje fiber, Cir. Res., 53: 16-23, 1983.
Peon, Ferrier and Moe, Circulation Research (1978),3624 studied the relationship between interelectrode conduction time and "take-off" potential (TOP) with microelectrode techniques in isolated canine false tendons. Conduction of regular or test beats initiated during phase 4 depolarization or late phase 3 repolarization speeded as TOP decreased. Similarly, beats initiated during digitalis-induced oscillatory afterpotentials demonstrated more rapid conduction at lower TOP. Because of the frequency-coupled nature of the oscillations, conduction times became rate dependent. Phenytoin antagonized digitalis oscillations and reversed speeding of conduction attributable to the oscillations. No uniform relationship between speed of conduction and maximum upstroke velocity of the action potential could be demonstrated in the above experiments or when speed of conduction was varied by changes in concentration of K+ or Ca2+.
3624. Peon, J., Ferrier, G.R., and Moe, G.K., The relationship of excitability to conduction velocity in canine purkinje tissue, Circ. Res., 43(1): 125-35, 1978.
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