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Some properties of the UL-FS 49 block of the hyperpolarization-activated current (i f) in sino-atrial node myocytes

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Abstract

Block of the hyperpolarization-activated “pacemaker” current (i f) by the bradycardic agent UL-FS 49 was studied in isolated sino-atrial (SA) node myocytes. Using repetitive activation/deactivation protocols, micromolar concentrations of UL-FS 49 blockedi f in a dose-dependent fashion. Block development was slow, with time constants decreasing with drug concentration and ranging from 25.8 s at 10 μM to 75.5 s at 1 μM UL-FS 49. Block did not develop in cells held at −35 mV, at which voltagei f channels are closed, indicating that channels must open before blocking occurs. Apparently in contrast with the requirement of negative voltages for block development, block was relieved by hyperpolarization with a time course slower than current kinetics. Due to the hyperpolarization-induced block relief, current/voltage (I/V) relations in the presence of UL-FS 49 displayed inward-going rectification. Experimental data fitted the hypothesis that UL-FS 49 behaves as an “open channel” blocker of “single-ion”i f channels. Block occurs within the pore, at a distance of about 39% of the membrane thickness from its internal side.

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References

  1. Armstrong CM (1966) Time-course of TEA-induced anomalous rectification in squid giant axons. J Gen Physiol 50:491–503

    Google Scholar 

  2. Armstrong CM, Hille B (1972) The inner quaternary ammonium ion receptor in potassium channels of the node of Ranvier. J Gen Physiol 59:388–400

    Google Scholar 

  3. Cohen CJ, McCarthy RT (1987) Nimodipine block of calcium channels in rat anterior pituitary cells. J Physiol (Lond) 387:195–225

    Google Scholar 

  4. Courtney KR (1975) Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA 968. J Pharmacol Exp Ther 195:225–236

    Google Scholar 

  5. DiFrancesco D (1981) A study of the ionic nature of the pacemaker current in calf Purkinje fibres. J Physiol (Lond) 314:377–393

    Google Scholar 

  6. DiFrancesco D (1982) Block and activation of the pacemaker channel in calf Purkinje fibres: effects of potassium, caesium and rubidium. J Physiol (Lond) 329:485–507

    Google Scholar 

  7. DiFrancesco D (1993) Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 55:451–467

    Google Scholar 

  8. DiFrancesco D, Tromba C (1988) Inhibition of the hyperpolarizing-activated current,i f, induced by acetylcholine in rabbit sino-atrial node myocytes. J Physiol (Lond) 405:477–491

    Google Scholar 

  9. DiFrancesco D, Ferroni A, Mazzanti M, Tromba C (1986) Properties of the hyperpolarizing-activated current (i f) in cells isolated from the rabbit sino-atrial node. J Physiol (Lond) 377:61–88

    Google Scholar 

  10. Frace AM, Maruoka F, Noma A (1992) External K+ increases Na+ conductance of the hyperpolarization-activated current in rabbit cardiac pacemaker cells. Pflügers Arch 421:97–99

    Google Scholar 

  11. Hagiwara S, Myiazaki S, Rosenthal NP (1976) Potassium current and the effect of cesium on this current during anomalous rectification of the egg cell membrane of a starfish. J Gen Physiol 67:621–638

    Google Scholar 

  12. Hille B (1992) Ionic channels of excitable membranes, chap. 15. Sinauer, Sunderland

    Google Scholar 

  13. Hille B, Schwarz W (1978) Potassium-channels as multi-ion single-file pores. J Gen Physiol 72:409–442

    Google Scholar 

  14. Hille B, Woodhull AM, Shapiro BI (1975) Negative surface charge near sodium channels of nerve: divalent ions, monovalent ions and pH. Philos Trans R Soc Lond [Biol] 270:301–318

    Google Scholar 

  15. Hondeghem LM, Katzung BG (1984) Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Annu Rev Pharmacol Toxicol 24:387–423

    Google Scholar 

  16. Kobinger W, Lillie C (1984) Alinidine. New Drugs Annu Cardiovasc Drugs 2:193–210

    Google Scholar 

  17. Lillie C, Kobinger W (1987) Investigations differentiating the mechanism of specific bradycardic agents from that of calcium channel blockers. Naunyn Schmiedebergs Arch Pharmacol 335:331–333

    Google Scholar 

  18. Snyders DJ, Van Bogaert P (1987) Alinidine modifies the pacemaker current in sheep Purkinje fibres. Pflügers Arch 658:1–9

    Google Scholar 

  19. Strichartz GR (1973) The inhibition of sodium currents in myelinated nerve by quaternary derivative of lidocaine. J Gen Physiol 62:37–57

    Google Scholar 

  20. Van Bogaert P, Goethals M (1987) Pharmacological influence of specific bradycardic agents on the pacemaker current of sheep cardiac Purkinje fibres. A comparison between three different molecules. Eur Heart J 8 [Suppl L]:35–42

    Google Scholar 

  21. Van Bogaert P, Goethals M, Simoens C (1990) Use- and frequency-dependent blockade by UL-FS 49 of thei f pacemaker current in sheep Purkinje fibres. Eur J Pharmacol 187:241–256

    Google Scholar 

  22. Woodhull AM (1973) Ionic blockage of sodium channels in nerve. J Gen Physiol 61:687–708

    Google Scholar 

  23. Yeh JZ, TenEick RE (1987) Molecular and structural basis of resting and use-dependent block of sodium current defined using disopyramide analogues. Biophys J 51:123–135

    Google Scholar 

  24. Yellen G (1984) Relief of Na+ block of Ca2+-activated K+ channels by external cations. J Gen Physiol 84:187–199

    Google Scholar 

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DiFrancesco, D. Some properties of the UL-FS 49 block of the hyperpolarization-activated current (i f) in sino-atrial node myocytes. Pflügers Arch. 427, 64–70 (1994). https://doi.org/10.1007/BF00585943

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  • DOI: https://doi.org/10.1007/BF00585943

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