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The effects of diphenylhydantoin on mechanical and electrical properties of isolated cat myocardium

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Summary

The effects of diphenylhydantoin (DPH) (4×10−5 to 2×10−4M) on contractile activity and electrical properties were studied in isotonically shortening cat papillary muscles exposed to DPH.

  1. 1.

    DPH reduces amplitudes of contraction especially at low stimulation rates (6 to 12/min). At higher, more physiological rates the negative inotropic effect is comparatively small.

  2. 2.

    DPH accentuates the mechanical transients usually following step changes of frequency.

  3. 3.

    DPH reduces the maximum rate of depolarisation (MRD) of the normal action potential (AP) and slows conduction especially at high stimulation rates. AP duration is shortened especially at low stimulation rates.

  4. 4.

    In Ca-mediated “slow responses” DPH reduces MRD, overshoot and AP duration and abolishes the frequency-dependent alterations of these parameters.

  5. 5.

    The results suggest that the antiarrhythmic potency of DPH is due to a cooperative action on both the fast and the slow membrane channels.

  6. 6.

    It is speculated that DPH leads to an accumulation of Ca2+ within a “limited subsarcolemmal space” thereby decreasing the driving force for the slow inward current.

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References

  • Allen, D. G., Jewell, B. R., Wood, E. H., Studies of the contractility of mammalian myocardium at low rates of stimulation. J. Physiol. 254, 1–17 (1976)

    Google Scholar 

  • Bassingthwaighte, J. B., Reuter, H.: Calcium movements and excitation-contraction coupling in cardiac cells. In: Electrical phenomena in the heart (De Mello, W. C., ed.) London-New York: Academic Press 1972

    Google Scholar 

  • Bayer, R., Kalsche, D., Kaufmann, R., Mannhold, R.: Inotropic and electrophysiological actions of verapamil and D600 in mammalian myocardium. III. Effects of the optical isomers on transmembrane action potentials. Naunyn-Schmiedeberg's Arch. Pharmacol. 290, 81–97 (1975)

    Google Scholar 

  • Beneken, J. E., de Wit, B.: Physical base of circulatory transport: Regulation and exchange. Philadelphia: W. B. Saunders Co., 1967

    Google Scholar 

  • Bigger, J. Th., Bassett, A. L., Hoffman, B. F.: Electrophysiological effects of diphenylhydantoin on canine Purkinje fibers. Circulat. Res. 22, 221–236 (1968a)

    Google Scholar 

  • Bigger, J. Th., Schmidt, D. H., Kutt, H.: Relationship between the plasma level of diphenylhydantoin sodium and its cardiac antiarrhythmic effects. Circulation 38, 363–374 (1968b)

    Google Scholar 

  • Blinks, J. R.: Field stimulation as a means of effecting the graded release of autonomic transmitters in isolated heart muscle. J. Pharmacol. exp. Ther. 151, 221–235 (1966)

    Google Scholar 

  • Blinks, J. R., Koch-Weser, J.: Physical factors in the analysis of the actions of drugs on myocardial contractility. Pharmacol. Rev. 15, 531–599 (1961)

    Google Scholar 

  • Brown, A. M., Brown, H. M.: Light response of a giant aplysia neuron. J. gen. Physiol. 62, 239–254 (1973)

    Google Scholar 

  • Cohen, L. S.: Diphenylhydantoin sodium (Dilantin). In: Current cardiocasular topics, Vol. I. Drugs in cardiology, Part I (Donoso, E., ed.) Stuttgart: Thieme 1975

    Google Scholar 

  • Cranefield, P. F.: The conduction of the cardiac impulse. The slow response and cardiac arrhythmias. Mount Kisco, New York: Futura Publishing Company Inc. 1975

    Google Scholar 

  • Cranefield, P. F., Aronson, R. S., Wit, A. L.: Effect of verapamil on the normal action potential and on a calcium dependent slow response of canine cardiac Purkinje fibers. Circulat. Res. 34, 204–213 (1974)

    Google Scholar 

  • Gettes, L. S., Reuter, H.: Slow recovery from inactivation of inward currents in mammalian myocardial fibres. J. Physiol. 240, 703–724 (1974)

    Google Scholar 

  • Grant, A. O., Katzung, B. G.: The effects of quinidine and verapamil on electrically induced automaticity in the ventricular myocardium of guinea pig. J. Pharmacol. exp. Ther. 196, 407–419 (1976)

    Google Scholar 

  • Hammermeister, K. E., Boerth, R. C., Warbasse, J. R.: The comparative inotropic effects of six clinically used antiarrhythmic agents. Amer. Heart J. 5, 643–652 (1972)

    Google Scholar 

  • Hasbani, M., Pincus, J. H., Lee, S. H.: Diphenylhydantoin and calcium movement in lobster nerves. Arch. Neurol. 31, 250–254 (1974)

    Google Scholar 

  • Helfant, R. H., Scherlag, B. J., 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)

    Google Scholar 

  • Hennekes, R., Kaufmann, R., Steiner, R.: Why does the cardiac force-velocity relationship not follow a Hill hyperbola? Possible implications of feedback loops involved in cardiac excitationcontraction coupling. J. molec. cell. Cardiol., submitted (1977)

  • Isenberg, G.: Is potassium conductance of cardiac Purkinje fibers controlled by [Ca]i? Nature (Lond.) 253, 273–274 (1975)

    Google Scholar 

  • Isenberg, G.: Cardiac Purkinje fibers: Control of potassium conductance by intracellular calcium. 7th European Congress of Cardiology, abstract book I, p. 138 (1976)

  • Jensen, R. A., Katzung, B. G.: Electrophysiological actions of diphenylhydantoin on rabbit atria: Dependence on stimulation frequency, potassium and sodium. Circulat. Res. 26, 17–27 (1970)

    Google Scholar 

  • Kass, R. S., Tsien, R. W.: Multiple effects of calcium antagonists on plateau currents in cardiac Purkinje fibers. J. gen Physiol. 66, 169–192 (1975)

    Google Scholar 

  • Kass, R. S., Tsien, R. W.: Control of action potential duration by calcium ions in cardiac Purkinje fibers. J. gen. Physiol. 67, 599–617 (1976)

    Google Scholar 

  • Katzung, B. G.: Electrically induced automaticity in ventricular myocardium. Life Science 14, 1133–1140 (1974)

    Google Scholar 

  • Katzung, B. G.: Effects of extracellular calcium and sodium on depolarization-induced automaticity in guinea pig papillary muscle. Circulat. Res. 37, 118–127 (1975)

    Google Scholar 

  • Katzung, B. G., Jensen, R. A.: The depressant action of diphenylhydantoin on electrical and mechanical properties of isolated rabbit and dog atria: Dependence on sodium and potassium. Amer. Heart J. 80, 80–88 (1970)

    Google Scholar 

  • Koch-Weser, J., Blinks, J. R.: The influence of the interval between beats on myocardial contractility. Pharmacol. Rev. 15, 601–652 (1963)

    Google Scholar 

  • Lieberson, A. D., Schumacher, R. R., Childress, R. H., Boyd, D. L., Williams, J. F.: Effect of diphenylhydantoin on left ventricular function in patients with heart disease. Circulation 36, 692–699 (1967)

    Google Scholar 

  • Lipicky, R. J., Gilbert, D. L., Stillman, J. M.: Diphenylhydantoin inhibtion of sodium conductance in squid giant axon. Proc. nat. Acad. Sci. (Wash.) 69, 1758–1760 (1972)

    Google Scholar 

  • Mascher, D.: Electrical and mechanical responses from ventricular muscle fibers after inactivation of the sodium carrying system. Pflügers Arch. ges. Physiol. 317, 355–372 (1970)

    Google Scholar 

  • McGuigan, J. A. S.: Some limitations of the double sucrose gap and its use in a study of the slow outward current in mammalian ventricular muscle. J. Physiol. 240, 775–806 (1974)

    Google Scholar 

  • McGuigan, J. A. S., Bassingthwaighte, J. B.: Possible relationship between [Ca]i and Pk in ventricular muscle. Experientia (Basel) 30, 680 (1974)

    Google Scholar 

  • McGuigan, J. A. S., Fry, C. H., Bassingthwaighte, J. B.: Control of the action potential duration by intracellular calcium. 7th European Congress of Cardiology, abstract book I, p. 139 (1976)

  • McNaughton, P.: Dependence of plateau potassium currents on Ca. 7th European Congress of Cardiology, abstract book I, p. 140 (1976)

  • Meech, R. W.: Intracellular calcium injection causes increased potassium conductance in Aplysia nerve cells. Comp. Biochem. Physiol. 42A, 493 (1972)

    Google Scholar 

  • Mercer, E. N., Osborn, J. A.: The current status of dipenylhydantoin in heart disease. Ann. intern. Med. 67, Suppl. 7, 1084–1106 (1967)

    Google Scholar 

  • Mierzwiak, D. S., Mitchell, J. H., Shapiro, W.: The effect of diphenylhydantoin (Dilantin) and quinidine on left ventricular function in dogs. Amer. Heart J. 74, 780–791 (1967)

    Google Scholar 

  • Mosey, L., 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)

    Google Scholar 

  • Pappano, A. J.: Calcium-dependent action potentials produced by catecholamines in guinea pig atrial muscle fibers depolarized by potassium. Circulat. Res. 28, 379–390 (1970)

    Google Scholar 

  • Pincus, J. H., Lee, S. H.: Diphenylhydantoin and calcium: Relation to norepinephrine release from brain slices. Arch. Neurol. 29, 239–244 (1973)

    Google Scholar 

  • Reuter, H.: Divalent cations as charge carriers in excitable membranes. Progr. biophys. molec. Biol. 26, 1–43 (1973a)

    Google Scholar 

  • Reuter, H.: Time- and voltage-dependent contractile responses in mammalian cardiac muscle. Europ. J. Cardiol. 1, 177–181 (1973b)

    Google Scholar 

  • Rosati, R., Wallace, A. G., Durham, N. C.: Electrophysiologic effects of diphenyhydantoin (Dilantin) on the heart of awake dogs. Amer. J. Cardiol. 19, 147 (1967)

    Google Scholar 

  • Sano, T., Suzuki, F., Sato, S., Jida, Y.: Mode of action of new anti-arrhythmic agents. Jap. Heart J. 9, 161–168 (1968)

    Google Scholar 

  • Schaefer, J., van Zwieten, P. A.: I. Quantitative studies on the time course of changes in contractile force provoked by changes in heart rate. II. Influence of noradrenaline and hexobarbital-Na. Arch. int. Physiol. Biochim. 79, 727–741 (1971)

    Google Scholar 

  • Scherlag, B. J., Helfant, R. H., Damato, A. N.: The contrasting effects of diphenylhydantoin and procaine amide on AV conduction in the digitalis-intoxicated and the normal heart. Amer. Heart J. 75, 200–205 (1968)

    Google Scholar 

  • Simurda, J., Simurdova, M., Braveny, P., Sumbera, J.: Slow inward current and action potentials of papillary muscles under non-steady state conditions. Pflügers Arch. 362, 209–218 (1976)

    Google Scholar 

  • Singh, B. N.: Comparative mechanisms of antiarrhythmic agents. Amer. J. Cardiol. 28, 240–241 (1971)

    Google Scholar 

  • Singh, B. N., Vaughan-Williams, E. M.: Effect of altering potassium concentration on the action of lidocaine and diphenylhydantoin on rabbit atrial and ventricular muscle. Circulat. Res. 29, 286–294 (1971)

    Google Scholar 

  • Sohn, R. S., Ferrendelli, J. A.: Inhibition of Ca2+ transport into rat brain synaptosomes by diphenylhydantoin (DPH). J. Pharmacol. exp. Ther. 185, 272–275 (1973)

    Google Scholar 

  • Strauss, H. C., Bigger, J. Th., Bassett, A. L., Hoffmann, B. F.: Actions of diphenylhydantoin on the electrical properties of isolated rabbit and canine atria. Circulat. Res. 23, 463–477 (1968)

    Google Scholar 

  • Thyrum, P. T.: Inotropic stimuli and systolic transmembrane calcium flow in depolarized guinea-pig atria. J. Pharmacol. exp. Ther. 188, 166–179 (1974)

    Google Scholar 

  • Tritthart, H., Volkmann, R., Weiss, R., Eibach, E.: The interrelationship of calcium-mediated action potentials and tension development in cat ventricular myocardium. J. molec. cell. Cardiol 8, 249–261 (1976)

    Google Scholar 

  • Vaughan-Williams, E. M.: Classification of antiarrhythmic drugs. Symposium on Cardiac Arrhythmias (Sandoe, E., Flenstedt-Jensen, R., and Olesen, K. H., eds.). Elsinore 1970

  • Weiss, R., Tritthart, H., Walter, B.: Correlation of Na-withdrawal effects on Ca-mediated action potentials and contractile activity in cat ventricular myocardium. Pflügers Arch. 350, 299–307 (1974)

    Google Scholar 

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Authors and Affiliations

  1. Lehrstuhl für Klinische Physiologie, Physiologisches Institut der Universität Düsseldorf, Universitätsstrasse 1, D-4000, Düsseldorf, Germany

    R. Bayer, R. Kaufmann & M. Gudjons

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  1. R. Bayer
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  2. R. Kaufmann
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  3. M. Gudjons
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Bayer, R., Kaufmann, R. & Gudjons, M. The effects of diphenylhydantoin on mechanical and electrical properties of isolated cat myocardium. Naunyn-Schmiedeberg's Arch. Pharmacol. 298, 273–282 (1977). https://doi.org/10.1007/BF00500900

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