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Inotropic and electrophysiological actions of verapamil and D 600 in mammalian myocardium

III. Effects of the optical isomers on transmembrane action potentials
  • R. Bayer
  • D. Kalusche
  • R. Kaufmann
  • R. Mannhold
Article

Summary

Excitability, maximum velocity of depolarization (MVD), conduction velocity, discharge rate and the duration of transmembrane action potentials as a function of frequency of stimulation were studied in isolated cardiac tissues exposed to the optical isomers of verapamil and D 600.
  1. 1.

    In isolated papillary muscles depression of the MVD and the conduction velocity depend on concentration (1–8 μg/ml) of (+)-verapamil and (+)-D 600.

     
  2. 2.

    (+)-Verapamil and (+)-D 600 (1–30 μg/ml) increase frequency-dependently the threshold intensity of electrical stimuli needed to elicit conducted action potentials.

     
  3. 3.

    (-)-Verapamil and (-)-D 600 are about one order of magnitude less effective than the corresponding (+)-isomers.

     
  4. 4.

    Both (+)- and (-)-isomers slightly prolong the transmembrane action potential at 90% repolarization level, particularly at low frequencies. In addition, the (-)-isomers induce a frequency-dependent depression of the plateau phase.

     
  5. 5.

    The results indicate that, at least in ventricular myocardium, the (+)-isomers of verapamil and D 600 have a quite specific inhibitory effect on the fast Na-inward current and, therefore, may contribute to some extent to the anti-dysrhythmic potency of the racemic drugs.

     
  6. 6.

    In isolated cat SA-nodes, both (+)- and (-)-isomers of verapamil and D 600 (0.2–1.0 μg/ml) reduce the discharge rate to the point of complete suppression of automaticity; different mechanisms are responsible for the effects.

     
  7. 7.

    The (-)-isomers (0.3–0.6 μg/ml) slightly reduce the slope of the slow diastolic depolarization, while causing a more effective depression of MVD and nodal conduction velocity until partial or complete nodal conduction blocks occur.

     
  8. 8.

    The (+)-isomers (1–2μg/ml) do not affect MVD or nodal conduction, but obviously shift the threshold voltage for the fast depolarization to less negative voltages. Cessation of automaticity occurs with a stable membrane potential and the ability to generate conducted action potentials by electrical stimulation persists.

     

Key words

Verapamil D 600 Optical Isomers Cardiac Muscle Transmembrane Action Potential 

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References

  1. Aronson, R. S., Cranefield, P. F.: The electrical activity of canine cardiac purkinje fibers in sodium-free, calcium-rich solutions. J. gen. Physiol. 61, 786–808 (1973)Google Scholar
  2. Baker, P. F., Meves, H., Ridgway, E. B.: Effects of manganese and other agents on the calcium uptake that follows depolarization of squid axons. J. Physiol. (Lond.) 231, 511–526 (1973)Google Scholar
  3. Bayer, R., Hennekes, R., Kaufmann, R., Mannhold, R.: Inotropic and electrophysiological actions of verapamil and D 600 in mammalian myocardium. I. Pattern of inotropic effects of the racemic compounds. Naunyn-Schmiedeberg's Arch. Pharmacol. 290, 49–68 (1975a)Google Scholar
  4. Bayer, R., Kaufmann, R., Mannhold, R.: Inotropic and electrophysiological actions of verapamil and D 600 in mammalian myocardium. II. Pattern of inotropic effects of the optical isomers. Naunyn-Schmiedeberg's Arch. Pharmacol. 290, 69–80 (1975b)Google Scholar
  5. Belz, G. G., Bender, F.: Therapie der Herzhythmusstörungen mit Verapamil. Stuttgart: G. Fischer 1974Google Scholar
  6. Benitez, D., Mascher, D., Alanis, J.: The electrical activity of the bundle of His. The fast and slow inward currents. Pflügers Arch. 345, 61–72 (1973)Google Scholar
  7. Carmeliet, E., Vereecke, J.: Adrenaline and the plateau phase of the cardiac action potential. Importance of Ca2+, Na+ and K+ conductance. Pflügers Arch. 313, 300–315 (1969)Google Scholar
  8. 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
  9. Cranefield, P. F., Wit, A. L., Hoffman, B. F.: Conduction of the cardiac impulse. III. Characteristics of very slow conduction. J. gen. Physiol. 59, 227–246 (1972)Google Scholar
  10. Grün, G., Fleckenstein, A.: Die elektromechanische Entkoppelung der glatten Gefäßmuskulatur als Grundprinzip der Coronardilatation durch 4-(2′-Nitrophenyl)-2, 6-dimethyl-1,4-dihydropyridin-3,5-dicarbonsäuredimethylester (BAY a 1040, Nifedipine). Arzneimittel-Forsch. (Drug Res.) 22, 334–344 (1972)Google Scholar
  11. Katzung, B.: Electrically induced automaticity in ventricular myocardium. Life Sci. 14, 1133–1140 (1974)Google Scholar
  12. Kaufmann, R., Bayer, R., Hennekes, R., Kalusche, D., Mannhold, R.: Antidisrhythmic and Ca-antagonistic actions of verapamil and D 600: Stereoselectivity of optical isomers? Naunyn-Schmiedeberg's Arch. Pharmacol., Suppl. 285, R39 (1974)Google Scholar
  13. Kaumann, A. J., Aramendia, P.: Prevention of ventricular fibrillation induced by coronary ligation. J. Pharmacol. exp. Ther. 164, 326–332 (1968)Google Scholar
  14. Kaumann, A. J., Serur, J.: Prevention of ventricular fibrillation by canine coronary artery ligation with optical isomers of verapamil. Proc. 6th Int. Congr. Pharmacol., Helsinki, July 20–25, 1975Google Scholar
  15. Kohlhardt, M., Bauer, B., Krause, H., Fleckenstein, A.: Differentiation of the transmembrane Na and Ca channels in mammalian cardiac fibres by the use of specific inhibitors. Pflügers Arch. 335, 309–322 (1972)Google Scholar
  16. Kohlhardt, M., Figulla, H. R., Tripathi, O.: Key-role of the transmembrane slow inward current for the excitation of the sinoatrial node. Naunyn-Schmiedeberg's Arch. Pharmacol., Suppl. 287, R39 (1975)Google Scholar
  17. Kohlhardt, M., Kübler, M., Herdey, A.: Characteristics of the recovery process of the Ca membrane channel in myocardial fibres. Pfiügers Arch., Suppl. 347, R2 (1974)Google Scholar
  18. Lenfant, J., Mironneau, J., Gargouil, Y. M., Galand, G.: Analyse de l'activité électrique spontanée du centre de l'automatisme cardiaque de lapin par les inhibiteurs de perméabilités membranaires. C. R. Acad. Sci. (D) (Paris) 268, 901–904 (1968)Google Scholar
  19. McLean, M. J., Shigenobu, K., Sperelakis, N.: Two pharmacological types of cardiac slow Na+ channels as distinguished by verapamil. Europ. J. Pharmacol. 26, 379–382 (1974)Google Scholar
  20. Melville, K. I., Shister, H. E., Hug, S.: Iproveratril: Experimental data on coronary dilatation and anti-disrhythmic action. Canad. med. Ass. J. 90, 761–770 (1964)Google Scholar
  21. Paes de Carvalho, A., Hoffman, B. F., de Paula Carvalho, M.: Two components of the cardiac action potential. I. Voltage-time course and the effect of acetylcholine on atrial and nodal cells of the rabbit heart. J. Gen. Physiol. 54, 607–635 (1969)Google Scholar
  22. Pappano, A. J.: Calcium-dependent action potentials produced by catecholamines in guinea pig atrial muscle fibers depolarized by potassium. Circulat. Res. 27, 379–390 (1970)Google Scholar
  23. Raschack, M.: Stereospecific differences in the relation of antiarrhythmic to inotropic activity in the optical isomers of verapamil. Proc. 6th Int. Congr. Pharmacol., Helsinki, July 20–25, 1975Google Scholar
  24. Reuter, H.: Divalent cations as charge carriers in excitable membranes. Progr. Biophys. molec. Biol. 26, 3–43 (1973)Google Scholar
  25. Rodriguez-Pereira, E., Viana, A. P.: The actions of verapamil on experimental arrhythmias. Arzneimittel-Forsch. (Drug Res.) 18, 175–179 (1968)Google Scholar
  26. Rougier, O., Vassort, G., Garnier, D., Gargouil, Y. M., Coraboeuf, E.: Existence and role of a slow inward current during the frog atrial action potential. Pflügers Arch. 308, 91–110 (1969)Google Scholar
  27. Shigenobu, K., Schneider, J. A., Sperelakis, N.: Verapamil blockade of slow Na+ and Ca2+ responses in myocardial cells. J. Pharmacol. exp. Ther. 190, 280–288 (1974)Google Scholar
  28. Singh, B. N., Vaughan Williams, E. M.: A fourth class of anti-disrhythmic action? Effect of verapamil on ouabain toxicity, on atrial and ventricular intracellular potentials, and on other features of cardiac function. Cardiovasc. Res. 6, 109–119 (1972)Google Scholar
  29. Spurell, R. A. J., Krikler, D. M., Sowton, E.: Effects of verapamil on electrophysiological properties of anomalous atrioventricular connexion in Wolff-Parkinson-White syndrome. Brit. Heart J. 36, 256–264 (1974)Google Scholar
  30. Trautwein, W.: Membrane currents in cardiac muscle fibers. Physiol. Rev. 53, 793–835 (1973)Google Scholar
  31. Tritthart, H., Volkmann, R., Weiss, R., Fleckenstein, A.: Calcium-mediated action potentials in mammalian myocardium. Alteration of membrane response as induced by changes of Cae or by promoters and inhibitors of transmembrane Ca inflow. Naunyn-Schmiedeberg's Arch. Pharmacol. 280, 239–352 (1973)Google Scholar
  32. Weidmann, S.: Heart: Electrophysiology. Ann. Rev. Physiol. 36, 155–169 (1974)Google Scholar
  33. Wit, A. L., Cranefield, P. F.: Effect of verapamil on the sinoatrial and atrioventricular nodes of the rabbit and the mechanism by which it arrests reentrant atrioventricular nodal tachycardia. Circulat. Res. 35, 413–425 (1974)Google Scholar
  34. Zipes, D. P., Fischer, J. C.: Effects of agents which inhibit the slow channel on sinus node automaticity and atrioventricular conduction in the dog. Circulat. Res. 34, 184–192 (1974)Google Scholar
  35. Zipes, D. P., Mendez, C.: Action of manganese ions and tetrodotoxin on atrioventricular nodal transmembrane potentials in isolated rabbit hearts. Circulat. Res. 32, 447–454 (1973)Google Scholar

Copyright information

© Springer-Verlag 1975

Authors and Affiliations

  • R. Bayer
    • 1
  • D. Kalusche
    • 1
  • R. Kaufmann
    • 1
  • R. Mannhold
    • 1
  1. 1.Lehrstuhl für Klinische PhysiologiePhysiologisches Institut der Universität DüsseldorfDüsseldorfGermany

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