Skip to main content
NCBI home page
The Journal of Physiology logoLink to The Journal of Physiology
. 1984 Jul;352:217–241. doi: 10.1113/jphysiol.1984.sp015288

Cat ventricular muscle treated with D600: characteristics of calcium channel block and unblock.

T F McDonald, D Pelzer, W Trautwein
PMCID: PMC1193208  PMID: 6086908

Abstract

Thin preparations of cat ventricular muscle were mounted in a single sucrose gap and superfused with Tyrode solution containing 1-5 microM-D600. In voltage-clamp experiments lasting for 40-180 min, stimulation with standard pulses (-50 to 0 mV, 300 ms) at 0.33 Hz depressed Ca-dependent slow inward current (ICa) to less than 20% of its pre-drug amplitude. A reproducible unblocking of ca. 75% of the blocked Ca channels could be achieved with a single hyperpolarizing pulse (90 s at -90 mV); stimulation (conditioning) at 0.33 Hz re-established full block within thirty pulses. The time and voltage dependence of block and unblock were examined by varying the frequency and duration of voltage-clamp pulses. The time course of unblock was usually monoexponential. The time constant was voltage dependent and declined from 9 min at -50 mV to 5 s at -110 mV. Block appears to depend on channel state, resting channels being highly resistant to block and open channels very susceptible. D600 also binds to inactivated channels but at a much slower rate than to open channels. A small U-shaped component of block was induced by conditioning to potentials between +10 and +80 mV. This block seemed to be unrelated to channel state, suggesting that drug binding may also be dependent on voltage. Quicker rates of block after repetitive conditioning, and slow wash-out of the drug, may indicate the existence of an intramembrane drug pool distinct from the primary pool in the intracellular fluid. The interaction of D600 with Ca channels is discussed in terms of a channel state model. In many respects this interaction resembles that of local anaesthetics with Na channels.

Full text

PDF
217

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antman E. M., Stone P. H., Muller J. E., Braunwald E. Calcium channel blocking agents in the treatment of cardiovascular disorders. Part I: Basic and clinical electrophysiologic effects. Ann Intern Med. 1980 Dec;93(6):875–885. doi: 10.7326/0003-4819-93-6-875. [DOI] [PubMed] [Google Scholar]
  2. Armstrong C. M. Sodium channels and gating currents. Physiol Rev. 1981 Jul;61(3):644–683. doi: 10.1152/physrev.1981.61.3.644. [DOI] [PubMed] [Google Scholar]
  3. Bayer R., Kalusche D., Kaufmann R., Mannhold R. Inotropic and electrophysiological actions of verapamil and D 600 in mammalian myocardium. III. Effects of the optical isomers on transmembrane action potentials. Naunyn Schmiedebergs Arch Pharmacol. 1975;290(1):81–97. doi: 10.1007/BF00499991. [DOI] [PubMed] [Google Scholar]
  4. Brehm P., Eckert R., Tillotson D. Calcium-mediated inactivation of calcium current in Paramecium. J Physiol. 1980 Sep;306:193–203. doi: 10.1113/jphysiol.1980.sp013391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cahalan M. D., Almers W. Interactions between quaternary lidocaine, the sodium channel gates, and tetrodotoxin. Biophys J. 1979 Jul;27(1):39–55. doi: 10.1016/S0006-3495(79)85201-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cahalan M. D. Local anesthetic block of sodium channels in normal and pronase-treated squid giant axons. Biophys J. 1978 Aug;23(2):285–311. doi: 10.1016/S0006-3495(78)85449-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chen C. M., Gettes L. S., Katzung B. G. Effect of lidocaine and quinidine on steady-state characteristics and recovery kinetics of (dV/dt)max in guinea pig ventricular myocardium. Circ Res. 1975 Jul;37(1):20–29. doi: 10.1161/01.res.37.1.20. [DOI] [PubMed] [Google Scholar]
  8. Cohen C. J., Bean B. P., Colatsky T. J., Tsien R. W. Tetrodotoxin block of sodium channels in rabbit Purkinje fibers. Interactions between toxin binding and channel gating. J Gen Physiol. 1981 Oct;78(4):383–411. doi: 10.1085/jgp.78.4.383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Courtney K. R. Comparative actions of mexiletine on sodium channels in nerve, skeletal and cardiac muscle. Eur J Pharmacol. 1981 Aug 27;74(1):9–18. doi: 10.1016/0014-2999(81)90317-4. [DOI] [PubMed] [Google Scholar]
  10. Courtney K. R. Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. J Pharmacol Exp Ther. 1975 Nov;195(2):225–236. [PubMed] [Google Scholar]
  11. Ehara T., Daufmann R. The voltage- and time-dependent effects of (-)-verapamil on the slow inward current in isolated cat ventricular myocardium. J Pharmacol Exp Ther. 1978 Oct;207(1):49–55. [PubMed] [Google Scholar]
  12. Hagiwara S., Byerly L. Calcium channel. Annu Rev Neurosci. 1981;4:69–125. doi: 10.1146/annurev.ne.04.030181.000441. [DOI] [PubMed] [Google Scholar]
  13. Heistracher P. Mechanism of action of antifibrillatory drugs. Naunyn Schmiedebergs Arch Pharmakol. 1971;269(2):199–212. doi: 10.1007/BF01003037. [DOI] [PubMed] [Google Scholar]
  14. Hescheler J., Pelzer D., Trube G., Trautwein W. Does the organic calcium channel blocker D600 act from inside or outside on the cardiac cell membrane? Pflugers Arch. 1982 Jun;393(4):287–291. doi: 10.1007/BF00581411. [DOI] [PubMed] [Google Scholar]
  15. Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol. 1977 Apr;69(4):497–515. doi: 10.1085/jgp.69.4.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hondeghem L. M., Katzung B. G. Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta. 1977 Nov 14;472(3-4):373–398. doi: 10.1016/0304-4157(77)90003-x. [DOI] [PubMed] [Google Scholar]
  17. JOHNSON E. A., McKINNON M. G. The differential effect of quinidine and pyrilamine on the myocardial action potential at various rates of stimulation. J Pharmacol Exp Ther. 1957 Aug;120(4):460–468. [PubMed] [Google Scholar]
  18. Kass R. S., Tsien R. W. Multiple effects of calcium antagonists on plateau currents in cardiac Purkinje fibers. J Gen Physiol. 1975 Aug;66(2):169–192. doi: 10.1085/jgp.66.2.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Khodorov B. I. Sodium inactivation and drug-induced immobilization of the gating charge in nerve membrane. Prog Biophys Mol Biol. 1981;37(2):49–89. doi: 10.1016/0079-6107(82)90020-7. [DOI] [PubMed] [Google Scholar]
  20. 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. Pflugers Arch. 1972;335(4):309–322. doi: 10.1007/BF00586221. [DOI] [PubMed] [Google Scholar]
  21. Kohlhardt M., Mnich Z. Studies on the inhibitory effect of verapamil on the slow inward current in mammalian ventricular myocardium. J Mol Cell Cardiol. 1978 Nov;10(11):1037–1052. doi: 10.1016/0022-2828(78)90400-5. [DOI] [PubMed] [Google Scholar]
  22. Ludwig C., Nawrath H. Effects of D-600 and its optical isomers on force of contraction in cat papillary muscles and guinea-pig auricles. Br J Pharmacol. 1977 Mar;59(3):411–417. doi: 10.1111/j.1476-5381.1977.tb08394.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. McCans J. L., Lindenmayer G. E., Munson R. G., Evans R. W., Schwartz A. A dissociation of positive staircase (Bowditch) from ouabain-induced positive inotropism. Circ Res. 1974 Sep;35(3):439–447. doi: 10.1161/01.res.35.3.439. [DOI] [PubMed] [Google Scholar]
  24. McDonald T. F., Pelzer D., Trautwein W. Cat ventricular muscle treated with D600: effects on calcium and potassium currents. J Physiol. 1984 Jul;352:203–216. doi: 10.1113/jphysiol.1984.sp015287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. McDonald T. F., Pelzer D., Trautwein W. On the mechanism of slow calcium channel block in heart. Pflugers Arch. 1980 May;385(2):175–179. doi: 10.1007/BF00588699. [DOI] [PubMed] [Google Scholar]
  26. McDonald T. F. The slow inward calcium current in the heart. Annu Rev Physiol. 1982;44:425–434. doi: 10.1146/annurev.ph.44.030182.002233. [DOI] [PubMed] [Google Scholar]
  27. McDonald T. F., Trautwein W. Membrane currents in cat myocardium: separation of inward and outward components. J Physiol. 1978 Jan;274:193–216. doi: 10.1113/jphysiol.1978.sp012143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. McDonald T. F., Trautwein W. The potassium current underlying delayed rectification in cat ventricular muscle. J Physiol. 1978 Jan;274:217–246. doi: 10.1113/jphysiol.1978.sp012144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Narahashi T., Frazier D. T., Moore J. W. Comparison of tertiary and quaternary amine local anesthetics in their ability to depress membrane ionic conductances. J Neurobiol. 1972;3(3):267–276. doi: 10.1002/neu.480030309. [DOI] [PubMed] [Google Scholar]
  30. Nawrath H., Eick R. E., McDonald T. F., Trautwein W. On the mechanism underlying the action of D-600 on slow inward current and tension in mammalian myocardium. Circ Res. 1977 Apr;40(4):408–414. doi: 10.1161/01.res.40.4.408. [DOI] [PubMed] [Google Scholar]
  31. Osterrieder W., Pelzer D., Yang Q. F., Trautwein W. The electrophysiological basis of the bradycardic action of AQA 39 on the sinoatrial node. Naunyn Schmiedebergs Arch Pharmacol. 1981 Nov;317(3):233–237. doi: 10.1007/BF00503823. [DOI] [PubMed] [Google Scholar]
  32. Pelzer D., Trautwein W., McDonald T. F. Calcium channel block and recovery from block in mammalian ventricular muscle treated with organic channel inhibitors. Pflugers Arch. 1982 Aug;394(2):97–105. doi: 10.1007/BF00582909. [DOI] [PubMed] [Google Scholar]
  33. Reuter H., Scholz H. A study of the ion selectivity and the kinetic properties of the calcium dependent slow inward current in mammalian cardiac muscle. J Physiol. 1977 Jan;264(1):17–47. doi: 10.1113/jphysiol.1977.sp011656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schwarz W., Palade P. T., Hille B. Local anesthetics. Effect of pH on use-dependent block of sodium channels in frog muscle. Biophys J. 1977 Dec;20(3):343–368. doi: 10.1016/S0006-3495(77)85554-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Singh B. N., Williams E. M. Effect of altering potassium concentration on the action of lidocaine and diphenylhydantoin on rabbit atrial and ventricular muscle. Circ Res. 1971 Sep;29(3):286–295. doi: 10.1161/01.res.29.3.286. [DOI] [PubMed] [Google Scholar]
  36. Strichartz G. R. The inhibition of sodium currents in myelinated nerve by quaternary derivatives of lidocaine. J Gen Physiol. 1973 Jul;62(1):37–57. doi: 10.1085/jgp.62.1.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Trautwein W., McDonald T. F., Tripathi O. Calcium conductance and tension in mammalian ventricular muscle. Pflugers Arch. 1975;354(1):55–74. doi: 10.1007/BF00584503. [DOI] [PubMed] [Google Scholar]
  38. Trautwein W., Pelzer D., McDonald T. F., Osterrieder W. AQA 39*, a new bradycardic agent which blocks myocardial calcium (Ca) channels in a frequency- and voltage-dependent manner. Naunyn Schmiedebergs Arch Pharmacol. 1981 Nov;317(3):228–232. doi: 10.1007/BF00503822. [DOI] [PubMed] [Google Scholar]
  39. Tritthart H., Fleckenstein B., Fleckenstein A. Some fundamental actions of antiarrhythmic drugs on the excitability and the contractility of singel myocardial fibers. Naunyn Schmiedebergs Arch Pharmakol. 1971;269(2):212–219. doi: 10.1007/BF01003038. [DOI] [PubMed] [Google Scholar]
  40. Tsien R. W. Calcium channels in excitable cell membranes. Annu Rev Physiol. 1983;45:341–358. doi: 10.1146/annurev.ph.45.030183.002013. [DOI] [PubMed] [Google Scholar]
  41. WATANABE Y., DREIFUS L. S., LIKOFF W. ELECTROPHYSIOLOGIC ANTAGONISM AND SYNERGISM OF POTASSIUM AND ANTIARRHYTHMIC AGENTS. Am J Cardiol. 1963 Nov;12:702–710. doi: 10.1016/0002-9149(63)90263-7. [DOI] [PubMed] [Google Scholar]
  42. WEIDMANN S. Effects of calcium ions and local anesthetics on electrical properties of Purkinje fibres. J Physiol. 1955 Sep 28;129(3):568–582. doi: 10.1113/jphysiol.1955.sp005379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. 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. Circ Res. 1974 Sep;35(3):413–425. doi: 10.1161/01.res.35.3.413. [DOI] [PubMed] [Google Scholar]
  44. Woodhull A. M. Ionic blockage of sodium channels in nerve. J Gen Physiol. 1973 Jun;61(6):687–708. doi: 10.1085/jgp.61.6.687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Yeh J. Z. Dynamics of 9-aminoacridine block of sodium channels in squid axons. J Gen Physiol. 1979 Jan;73(1):1–21. doi: 10.1085/jgp.73.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Physiology are provided here courtesy of The Physiological Society

RESOURCES