Advertisement

Pflügers Archiv

, Volume 393, Issue 4, pp 287–291 | Cite as

Does the organic calcium channel blocker D600 act from inside or outside on the cardiac cell membrane?

  • J. Hescheler
  • D. Pelzer
  • G. Trube
  • W. Trautwein
Excitable Tissues and Central Nervous Physiology

Abstract

The effects of extra- and intracellularly applied D600 (methoxyverapamil) and D890 (a quarternary derivative) on the action potentials of isolated guinea pig myocytes were compared. We also studied the extracellular effects of these drugs on the calcium current (hybride sucrose gap) and contractile force of right ventricular trabeculae of the cat heart.

The following results were obtained:
  1. 1.

    In ventricular trabeculae D600 suppressed the calcium current, tension and the plateau of the action potential. In contrast, D890 even in a 50 times higher concentration did not display any effect on these parameters.

     
  2. 2.

    In single isolated cells external application of D890 did not alter the configuration of the action potential. In contrast, external application of D600 suppressed the plateau and shortened the action potential in a dose-dependent way.

     
  3. 3.

    Intracellular injection of D600 or D890 strongly lowered the height of the plateau and abbreviated the action potential. The onset of the effects of both drugs was more rapid on intracellular application than that of external D600. Whereas the effect of an inracellular injection of D600 was reversible, that of D890 was not.

     

These results support the hypothesis that the organic calcium channel blocker D600 enters the cell in the uncharged lipid soluble form and reaches its receptor associated with the calcium channel from inside. Because of its inability to pass the hydrophobic cell membrane, D890 is ineffective from outside but displays blocking effects on intracellular application.

Key words

Isolated ventricular cells Action potential Intra- and extracellular application Organic calcium channel blockers 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Cahalan M, Shapiro BI, Almers W (1980) Relationship between inactivation of sodium channels and block by quarternary derivatives of local anesthetics and other compounds. In: Fink BR (ed) Progress in anesthesiology. Vol 2, Molecular mechanisms of anesthesia. Raven Press, New York, pp 17–33Google Scholar
  2. Courtney KR (1975) Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA968. J Pharmacol Exp Ther 195:225–236Google Scholar
  3. Dörrscheidt-Käfer M (1977) The action of D600 on frog skeletal muscle: facilitation of excitation-contraction coupling. Pflügers Arch 369:259–267Google Scholar
  4. Grant AO, Strauss LJ, Wallace AG, Strauss HC (1980) The influence of pH on the electrophysiological effects of lidocaine in guinea pig ventricular myocardium. Circ Res 47:542–550Google Scholar
  5. Hescheler J, Pelzer D, Trube G, Trautwein W (1981) Action potentials of isolated ventricular cells following intracellular or extracellular application of D600 and its quarternary derivative. Pflügers Arch (Suppl) 391:R1Google Scholar
  6. Hille B (1977a) The pH-dependent rate of action of local anesthetics on the node of Ranvier. J Gen Physiol 69:475–496Google Scholar
  7. Hille B (1977b) Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol 69:497–515Google Scholar
  8. Hironaka T, Morimoto S (1979) The resting membrane potential of frog sartorius muscle. J Physiol (Lond) 297:1–8Google Scholar
  9. Isenberg G, Klöckner U (1980) Glycocalix is not required for slow inward calcium current in isolated rat heart myocytes. Nature 284:358–360Google Scholar
  10. Ludwig C, Nawrath H (1977) Effects of D600 and its optical isomers on force of contraction in cat papillary muscles and guinea pig auricles. Br J Pharmacol 59:411–417Google Scholar
  11. Mannhold R, Steiner R, Haas W, Kaufmann R (1978) Investigations on the structure-activity relationships of verapamil. Naunyn-Schmiedeberg's Arch PHarmacol 302:217–226Google Scholar
  12. McDonald TF, Trautwein W (1978) Membrane currents in cat myocardium: separation of inward and outward components. J Physiol (Lond) 274:193–216Google Scholar
  13. McDonald TF, Pelzer D, Trautwein W (1981) On the mechanism of slow calcium channel block in heart. Pflügers Arch 385:175–179Google Scholar
  14. McDonald TF, Pelzer D, Trautwein W (1981) Does the calcium current modulate the contraction of the accompanying beat? A study of EC coupling in mammalian ventricular muscle using cobalt ions. Circ Res 49:576–583Google Scholar
  15. Nattel S, Elharrar V, Zipes D, Bailey JC (1981) pH dependent electrophysiological effects of quinidine and lidocaine on canine cardiac Purkinje fibers. Circ Res 48:55–61Google Scholar
  16. Pelzer D, Trautwein W, McDonald TF (1982) Calcium channel block and recovery from block in mammalian ventricular muscle treated with organic channel inhibitors. Pflügers Arch (in press)Google Scholar
  17. Strichartz GR (1973) The inhibition of sodium currents in myelinated nerve by quarternary derivatives of lidocaine. J Gen Physiol 62:37–57Google Scholar
  18. Trautwein W, Pelzer D, McDonald TF, Osterrieder W (1981) AQA39, a new bradycardic agent which blocks myocardial calcium (Ca) channels in a frequency- and voltage-dependent manner. Naunyn-Schmiedeberg's Arch Pharmacol 317:228–232Google Scholar
  19. Trautwein W, Pelzer D, McDonald TF (1982) Interval- and voltage-dependent effects of the calcium channel blocking agents D600 and AQA39 on mammalian ventricular muscle. Circ Res, in pressGoogle Scholar
  20. Trautwein W, Taniguchi J, Noma A (1982) The effect of intracellular cyclic nucleotides and calcium on the action potential and acetylcholine response of isolated cardiac cells. Pflügers Arch 392:307–314Google Scholar

Copyright information

© Springer-Verlag 1982

Authors and Affiliations

  • J. Hescheler
    • 1
  • D. Pelzer
    • 1
  • G. Trube
    • 1
  • W. Trautwein
    • 1
  1. 1.H. Physiologisches InstitutUniversität des SaarlandesHomburg/SaarFederal Republic of Germany

Personalised recommendations