Cardiac Arrhythmias

Harris and Kokernot, American Journal of Physiology (1950), 141 found that PHT prevented ectopic contractions in dogs subjected to operative coronary occlusion. By using a method of gradual coronary occlusion, cardiac ischemia was produced causing ventricular arrhythmias. PHT was found to suppress the ectopic discharges in these hearts. Confidence in the interpretation of the results was gained by the observation of quick diminution of frequency of ectopic complexes almost immediately after injection of PHT. Without PHT, these ectopic complexes returned. The authors found that in their experiments it was possible to control all ventricular tachycardias by adequate amounts of PHT.

141. Harris, A. S. and Kokernot, R. H., Effects of diphenylhydantoin sodium (Dilantin sodium) and phenobarbital sodium upon ectopic ventricular tachycardia in acute myocardial infarction, Amer. J. Physiol, 163: 505-516, 1950.

Mosey and Tyler, Circulation (1954), 260 showed that intravenous PHT (10-30 mg/ kg) reversed ouabain-induced ventricular tachycardia in dogs.

260. Mosey, L. and Tyler, M. D., The effect of diphenylhydantoin sodium (Dilantin), procaine hydrochloride, procaine amide hydrochloride, and quinidine hydrochloride upon ouabain-induced ventricular tachycardia in unanesthetized dogs, Circulation, 10: 65-70, 1954.

Scherf, Blumenfeld, Taner and Yildiz, American Heart Journal (1960),410 found that PHT (5 mg/kg) reversed aconitine- and delphinine-induced ventricular and atrial arrhythmias in dogs.

410. Scherf, D., Blumenfeld, S., Taner, D., and Yildiz, M., The effect of diphenylhydantoin (Dilantin) sodium on atrial flutter and fibrillation provoked by focal application of aconitine or delphinine, Amer. Heart J., 60: 936-947, 1960.

Lang, Baziki, Pappelbaum, Gold, Bernstein, Herrold and Corday, American Journal of Cardiology (1965), 2218 demonstrated that intravenous PHT (6-15 mg/kg) reversed aconitine-induced atrial and ventricular arrhythmias, digitalis-induced arrhythmias and cerebral venous shunt-induced arrhythmias in dogs. The use of auto-transplanted heart-lung and cerebral venous shunt preparations permitted the authors to conclude that PHT exerted its beneficial action directly on the myocardium.

2218. Lang, T.W., Bazika, V., Pappelbaum, S., Gold, H., Bernstein, H., Herrold, G. and Corday, E., Autotransplanted heartlung and cerebral venous shunt preparations: two new techniques for pharmacologic assay of cardiovascular drugs, Am. J. Cardiol., 16:695-700,1965.

Cox, Pitt, Brown and Molaro, Canadian Medical Association Journal (1966), 64 using microelectrodes, found that PHT promptly abolished acetylcholine-induced arrhythmias in isolated atrial tissue.

2218. Lang, T.W., Bazika, V., Pappelbaum, S., Gold, H., Bernstein, H., Herrold, G. and Corday, E., Autotransplanted heartlung and cerebral venous shunt preparations: two new techniques for pharmacologic assay of cardiovascular drugs, Am. J. Cardiol., 16:695-700,1965.

Gupta, Vollmer, Bashour and Webb, Federation Proceedings (1967), 2204 Studied the effects of PHT in dog myocardium made ischemic by anterior coronary artery ligation. PHT (10 mg/kg) restored the refractory periods in the ischemic zones to normal and doubled the diastolic threshold. PHT had no effect on refractory period or diastolic threshold of the normal myocardium.

2204. Gupta, D. N., Vollmer, V., Bashour,. F. A. and Webb, W. R., Effect of Dilantin on the excitability of the experimentally infarcted heart, Fed. Proc., 26: 381, 1967.

Hockman, Mauck and Chu, American Heart Journal (1967),163 using electrical stimulation of diencephalic and mesencephalic loci in dogs and cats induced a spectrum of ventricular arrhythmias which frequently persisted for five minutes or longer after stimulation. Intravenous PHT (10 mg/kg) not only abolished the ectopic ventricular rhythms, but also prevented their induction by a subsequent stimulus for periods varying from thirty minutes to seven hours. The authors suggest that PHT's therapeutic effects on the heart may at least in part be due to its central nervous system action.

163. Hockman, C. H., Mauck, H. P., Jr., and Chu, N., ECG changes resulting from cerebral stimulation. III. Action of diphenylhydantoin on arrhythmias, Amer. Heart J., 74: 256-260, 1967.

Rosati, Alexander, Schaal and Wallace, Circulation Research (1967),308, 519 studied the effects of intravenous PHT (10 mg/ kg) in canine hearts using intraventricularly implanted electrodes. In spontaneously beating hearts and external pacemaker-controlled hearts, PHT increased sinus rate, decreased atrioventricular conduction time, and had little or no effect on Purkinje conduction or total ventricular activation time. PHT raised the threshold of atrial and ventricular muscle, with no change in refractory periods. In chronic heart block, PHT produced no change in ventricular pacemaker activity; but, when ventricular tachycardia was induced by toxic doses of deslanoside, PHT abolished the ectopic arrhythmia and restored the control rhythm.

308. Rosati, R. A., Alexander, J. A., Schaal, S. F., and Wallace, A. G., Influence of diphenylhydantoin on electrophysiological properties of the canine heart, Circ. Res., 21: 757-765, 1967.
519. Rosati, R. and Wallace, A. G., Electrophysiologic effects of diphenylhydantoin (Dilantin) on the heart of awake dogs, Amer. J. Cardiol., 19: 147, 1967.

Stein and Kleinfeld, Circulation (1967),2982 studied the effect of PHT on the sinoatrial node of rabbit heart. Sinoatrial pacemaker action potentials were recorded using intracellular microelectrodes during constant perfusion of varying concentrations of PHT (1-100 µM). PHT slowed the heart rate by decreasing the slope of diastolic depolarization of the action potential. The authors note that the ability of PHT to depress automaticity of sinoatrial cells by reducing or eliminating diastolic depolarization suggests that PHT may have a similar effect on ectopic foci, which may explain its antiarrhythmic actions.

308. Rosati, R. A., Alexander, J. A., Schaal, S. F., and Wallace, A. G., Influence of diphenylhydantoin on electrophysiological properties of the canine heart, Circ. Res., 21: 757-765, 1967.

Bigger, Bassett and Hoffman, Circulation Research (1968),19 studied the effects of PHT (.01-100 µM) on isolated, perfused canine Purkinje fibers. In stimulated fibers which were partially depolarized or had a low rate of rise of the action potential despite a normal resting potential, PHT increased the phase zero rate of rise of the action potential. PHT also protected such fibers from further decreases in action potential rate of rise caused by high-frequency stimulation. In spontaneously firing Purkinje fibers which showed generalized diastolic depolarization and decreased maximum diastolic potential, PHT decreased excessive depolarization and increased resting potential. PHT also protected the fibers from the abnormal automaticity induced by ouabain and isoproterenol, without interfering with the latter's therapeutic effects.The authors emphasize that, unlike quinidine, PHT protects against frequency-dependent decreases in depolarization rate and does not depress conduction velocity or stimulation threshold.

308. Rosati, R. A., Alexander, J. A., Schaal, S. F., and Wallace, A. G., Influence of diphenylhydantoin on electrophysiological properties of the canine heart, Circ. Res., 21: 757-765, 1967.

Helfant, Ricciutti, Scherlag and Damato, American Journal of Physiology (1968),157 studied the effects of digitalis and PHT on myocardial ion fluxes in dogs. Toxic doses of digitalis caused myocardial potassium loss and arrhythmias, both of which were promptly reversed by PHT (5 mg/kg).

308. Rosati, R. A., Alexander, J. A., Schaal, S. F., and Wallace, A. G., Influence of diphenylhydantoin on electrophysiological properties of the canine heart, Circ. Res., 21: 757-765, 1967.

Hilmi and Regan, American Heart Journal (1968),404 compared the effectiveness of procainamide, lidocaine, propranolol and PHT in digitalis-induced ventricular tachycardia in dogs. PHT and lidocaine were the most successful in conversion of ventricular tachycardia to normal sinus rhythm. PHT restored and maintained normal sinus rhythm in six of seven animals.

308. Rosati, R. A., Alexander, J. A., Schaal, S. F., and Wallace, A. G., Influence of diphenylhydantoin on electrophysiological properties of the canine heart, Circ. Res., 21: 757-765, 1967.

Lesbre, Cathala, Salvador, Florio, Lescure and Meriel, Archives des Maladies du coeur et des Vaisseaux (1969),1264 studied the cardiac effects of PHT in ten digitalis-intoxicated dogs. In the first experiment they found that PHT (10 mg/kg) did not lengthen the P-R interval in seven animals and actually shortened it in three. In another experiment in the same animals, a ligature was placed on both branches of the left coronary artery, creating ventricular dysrhythmias and atrial extrasystoles. In nine of ten cases the arrhythmia and extrasystoles disappeared either during or immediately after injection of PHT. For a thirty-minute period, following intravenous PHT, it was difficult to induce new ventricular arrhythmias by clamping the artery. The authors note that PHT corrects disturbances of both atrial and ventricular excitability without impairing atrioventricular conduction, ventricular contractility or systemic blood pressure.

308. Rosati, R. A., Alexander, J. A., Schaal, S. F., and Wallace, A. G., Influence of diphenylhydantoin on electrophysiological properties of the canine heart, Circ. Res., 21: 757-765, 1967. Sperelakis and Henn, American Journal of Physiology (1970),1580 studied the effect of PHT (.01-18 µM) on membrane potentials of individual chick heart cells in tissue culture. PHT was found to prevent hyperexcitability caused by both strontium and electrical stimulation. While PHT protected against these insults, it did not affect the normal function of heart cells as measured by resting potentials and the maximum rate of rise or duration of the action potential.

1580. Sperelakis, N. and Henn, F. A., Effect of diphenylhydantoin on membrane potentials and Na-K-ATPase of cultured chick heart cells, Amer. J. Physiol., 218: 1224-1227, 1970.

Singh, Sinha, Rastogi, Dua and Kohli, Japanese Journal Of Pharmacology (1971),1557 studied the antiarrhythimic properties of PHT in dogs. Arrhythmias were induced by means of aconitine (injected into the cerebral ventricle or intravenously), ether-epinephrine and coronary ligation. PHT was effective against all types of arrhythmias, irrespective of their central nervous system or peripheral origin.

1557. Singh, N., Sinha, J. N., Rastogi, S. K., Dua, P. R., and Kohli, R. P., An experimental investigation on the antiarrhythmic activity of antiepileptic agents, Jap. J. Pharmacol. 21: 755-761, 1971.

Curtis, University of Michigan Doctoral Thesis (1971),927 reported that PHT (100 µM) was effective in terminating experimentally-induced atrial fibrillation in dogs.

927. Curtis, G. P., Experimental atrial fibrillation, Univ. of Mich., Ann Arbor, Doctoral Thesis, 1971.

Gillis, McClellan, Sauer and Standaert, Journal of Pharmacology and Experimental Therapeutics (1971),2197 in a study of cardiac sympathetic nerve activity, demonstrated that intravenous PHT (up to 20 mg/kg/min) counteracted deslanoside-induced sympathetic nerve firing and simultaneously converted deslanoside-induced ventricular tachycardia to sinus rhythm.

2197. Gillis, R. A., McClellan, J. R., Sauer, T. S. and Standaert, F. G., Depression of cardiac sympathetic nerve activity by diphenylhydantoin, J. Pharmacol. Exp. Ther., 179: 599-600, 1971.

\Loh, Federation Proceedings (1974),2224 demonstrated in isolated atrial trabeculae of the frog that PHT produced a net gain of tissue potassium and reduction of potassium efflux with an accompanying prolongation of action potential duration and an elevation of resting potential. The author suggests that PHT's effects on transmembrane potentials are due to its membrane stabilizing actions.

2224. Loh, C. K., Effects of diphenylhydantoin (DPH) on potassium exchange kinetics and transnembrane potentials in amphibian atrium, Fed. Proc., 33: 445, 1974.

Lisander, Jaju and Wang, European Journal of Pharmacology (1975),2720 demonstrated the rapid (one-to three-minute) effectiveness of PHT in treating cardiac arrhythmias resulting from electrical stimulation of the perifornical region of cat hypothalamus. The mean effective dose of PHT required to prevent arrhythmias via the intravenous route was 11.9 mg/kg, and via the vertebral artery route and the fourth ventricular route, less than 2 mg/kg. The authors conclude that, in addition to its direct actions on the heart, PHT has a strong antiarrhythmic effect via the central nervous system.

2720. Lisander, B., Jaju, B., Wang, S. C., CNS site of antiarrhythmic action of diphenylhydantoin (DPH) in the cat, Eur. Pharmacol., 31(1): 53-62, 1975.

Chai, Lee and Wang, Archives Internationales de Pharmacodynamie et de Therapie (1976),1768 studied the effect of PHT on arrhythmias induced by occlusion of the common carotid arteries in cats. Intravenous, intravertebral artery, intracarotid artery, intracerebroventricular and intrahypothalamic routes of administration of PHT were all effective at different doses. The authors conclude that PHT exerts potent antiarrhythmic effects through its action on the central nervous system.

1768. Chai, C. Y., Lee, T. M. and Wang, S. C., Effects of diphenylhydantoin on cardiac arrhythmias induced by carotid occlusion in the cat, Arch. Int. Pharmacodyn., 219: 180-92,1976.

Corr and Gillis, Federation Proceedings (1976),1783 demonstrated, in cats, that pretreatment with PHT significantly reduced premature ventricular contractions following anterior descending coronary artery occlusion. None of the seven treated animals developed ventricular fibrillation. The authors conclude that PHT can suppress premature ventricular contractions and ventricular fibrillation during the early stages of myocardial infarction.

1783. Corr,, P. B. and Gillis, R. A., Beneficial cardiac rhythm effects produced by diphenylhydantoin in experimental myocardial infarction, Fed. Proc., 35: 222, 1976.1900. Hondeghem, L. M., Effects of lidocaine, phenytoin and quinidine on the ischemic canine myocardium, J. Electrocardiol., 9(3): 203-9, 1976.

Ehring and Hondeghem, Proceedings of the Western Pharmacological Society (1978),1815 studied the effects of PHT on isolated guinea pig heart papillary muscle. PHT (60-100 M) decreased action potential Vmax only when stimulus frequency was high or when the cells were depolarized. PHT's effects were less when the cells were hyperpolarized. Based on this evidence, the authors suggest that PHT achieves its antiarrhythmic effects by binding to open sodium channels, thus regulating sodium influx.

1815. Ehring, G. R. and Hondeghem, L. M., Rate, rhythm and voltage dependent effects of phenytoin: a test of a model of the mechanisms of action of antiarrhythmic drugs, Proc. West. Pharmacol. Soc., 21: 63-5, 1978.

Almotrefi and Baker, British Journal of Pharmacology (1980),2143 demonstrated that PHT (3.6-18 M) produces significant dose-dependent increases in electrical stimulation threshold and ventricular fibrillation threshold as measured in the Langendorff perfused rabbit heart.

2143. Almotrefi, A. A. and Baker, J. B. E., Investigation of the antifibrillatory activity of some anticonvulsant .»-aminobutyric acid-transaminase inhibitors in the rabbit isolated heart: comparison with phenytoin and mexiletine, Br. J. Pharmac., 71(2): 635-9,1980.

Grenader, Ponamareva, Zurabishvili and Vasiev, Biofizika (1982),2557 reported that PHT (2-8 g/ml) decreased the fast inward sodium current in strips of rabbit atrium and ventricle. Consistent with this, refractoriness of the cardiac tissue also increased, more in atrial than ventricular tissue. The authors suggest that these effects are important in PHT's antiarrhythynic ac-tions and note that they are selective for damaged myocardium. Normal myocardium is not affected by PHT.

2557. Grenader, A. K., Ponomareva, V. M., Zurabishvili, G. G., Vasiev, B. N., Changes in the refractoriness of cardiac tissue as a result of a decrease in the fast inward sodium current. Comparison of the atrium and ventricle, Biofizika, 27(5): 911-14,1982.

Quest, Breed and Gillis, Journal Of Cardiovascular Pharmacology (1982),2887 studied the effects of PHT on cardiac slowing produced by peripheral vagus nerve stimulation (1-10 Hz) and by direct injection of acetylcholine. To avoid autonomic reflex mechanisms, vagotomized animals with transacted spinal cords were used. Intravenous PHT (0.5 to 1 mg/kg/min) significantly reduced the bradycardia produced by the higher frequencies of vagal nerve stimulation (3, 5 and 10 Hz). This inhibitory effect appeared immediately after the start of intravenous PHT. Bradycardia produced by high concentrations of acetylcholine was also significantly inhibited by PHT, and this inhibition persisted from 90 to 120 minutes after cessation of PHT.

2887. Quest, J. A., Breed, C. R., Gillis, R. A., Effect of phenytoin on cardiac slowing induced by cholinergic stimulation, J. Cardiovase. Pharmacol., 4: 629-34, 1982.

Sanchez-Chapula and Josephson, Journal of Molecular Cell Cardiology (1983),2922 reported that PHT (20 M) inhibited sodium currents in rat ventricular cells in a voltage-and use-dependent manner. The authors state that PHT's depression of the cardiac sodium current may be an important mechanism of its antiarrhythmic effects. The authors suggest that PHT binds preferentially to inactivated sodium channels and prolongs their recovery.

2922. Sanchez-Chapula, J., Josephson, I. R., Effect of phenytoin on the sodium current in isolated rat ventricular cells, J. Mol. Cell Cordial., 58(8): 515-22, 1983.

Watanabe and Bailey, Annals of the New York Academy of Sciences (1984), 3063 reviewed the regulation of cardiac function by the autonomic nervous system as it relates to various antiarrhythmic drugs, including PHT. The authors note that, in addition to its direct effect on cardiac tissues, PHT modifies sympathetic nerve activity. They cite several animal studies in which PHT has been shown to decrease activity of cardiac sympathetic nerves with resultant reduction in contractile force, blood pressure and heart rate. PHT has also been shown to reduce the excessive cardiac sympathetic nerve stimulation produced by cardiac glycosides. Pretreatment with PHT has been shown to prevent the increase in sympathetic nerve activity and subsequent cardiac arrhythmias induced by posterior hypothalamic electrical stimulation.

3063. Watanabe, A. M., Bailey, J. C., The role of the autonomic central nervous system in mediating and modifying the action of cardiac antiarrhythmic drugs, Ann. N.Y. Acad. Sci., 432: 90-102, 1984.

Hashimoto, Ishii, Komori and Mitsuhashi, Heart and Vessels (1985), 2577 studied the effects of PHT, as well as other antiarrhythmic drugs, on ventricular arrhythmias induced by digitalis, adrenaline, and two-stage coronary ligation. PHT (9.8-12.1 g/ml) was effective in controlling the arrhythmias produced by all three methods.

2577. Hashimoto, K., Ishii, M., Komori, S., Mitsuhashi, H., Canine digitalis arrhythmia as a model for detecting Na-channel blocking antiarrhythmic drugs: a comparative study using other canine arrhythmia models and the new antiarrhythmic drugs, propafenone, tocainide, and SUN 1165, Heart Vessels, 1: 29-35,1985.