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On the mechanism of the “specific bradycardic action” of the verapamil derivative UL-FS 49

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Summary

Membrane currents were measured in single sino-atrial node cells of guinea pig and rabbit hearts as well as in guinea pig ventricular myocytes using the patch-clamp technique. UL-FS 49 blocked the L-type calcium current (ICa) in sino-atrial node cells at drug concentrations wich had little or no effect on the amplitude of the hyperpolarization-activated current ih(f). In guinea pig ventricular myocytes UL-FS 49 also blocked ICa but not as strongly as in sino-atrial node cells. In a computer simulation of the sino-atrial node action potential the extent of rate reduction by block of either ih(f) or ICa was estimated. From the data obtained by single cell measurements and the computations we concluded that rate reduction in primary pacemaker cells by application of UL-FS 49 is mainly due to a use dependent block of the L-type calcium current. Voltage dependent unblock of iCa at potentials more negative than −50 mV together with the lower drug sensitivity of ventricular cells can explain the “specific bradycardic action” of UL-FS 49.

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References

  • Bleeker WK, Mackaay AJC, Masson-Pevet M, Bouman LN, Becker AE (1980) Functional and morphological organization of the rabbit sinus node. Circ Res 46:11–22

    Google Scholar 

  • Boumann LN, Jongsma HJ Opthof T, Van Ginneken ACG (1985) Does if contribute to pace-making in the rabbit sinoatrial node? J Physiol (Lond) 358:51P

    Google Scholar 

  • Brown HF (1982) Electrophysiology of the sinoatrial node. Physiol Rev 62:505–530

    Google Scholar 

  • Dennis PD, Vaughan Williams EM (1986) Further studies of alinidine induced bradycardia in the presence of caesium. Cardiovasc Res 20:375–378

    Google Scholar 

  • DiFrancesco D (1981) A new interpretation of the pace-maker current in calf Purkinje fibres. J Physiol (Lond) 314:359–376

    Google Scholar 

  • DiFrancesco D (1985) The cardiac hyperpolarizing-activated current, if, origins and developements. Prog Biophys Mol Biol 46:163–183

    Google Scholar 

  • DiFrancesco D (1986) Characterization of single pacemaker channels in cardiac sino-atrial node cells. Nature 324:470–473

    Google Scholar 

  • DiFrancesco D (1987) The pacemaker current in the sinus node. Eur Heart 18:19 -23

    Google Scholar 

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

    Google Scholar 

  • Doerr T, Denger R, Trautwein W (1988) Quantitative analyses of the L-type calcium current during the action potential in single sino-atrial node cells of the rabbit heart. Pflügers Arch 412 [Suppl 1]:R 23

    Google Scholar 

  • Doerr T, Denger R, Trautwein W (1989) Calcium currents in single SA nodal cells of the rabbit heart studied with action potential clamp. Pflügers Arch 413:599–603

    Google Scholar 

  • Franke H, Su CAPF, Schumacher K, Seiberling M (1987) Clinical pharmacology of two specific bradycardiac agents. Eur Heart J 8:91–98

    Google Scholar 

  • Gilmour RF Jr, Zipes DP (1983) Basic electrophysiology of the slow inward current. In: Stone PH, Amman EM (eds) Calcium channel blocking agents in the treatment of cardiovascular disorders. Futura, Mount Kisco, New York, pp 1–37

    Google Scholar 

  • Guth BD, Heusch G, Seitelberger R, Matsuzaki M, Ross J (1987) Role of heart rate reduction in the treatment of exercise-induced myocardial ischaemia. Eur Heart J 8: 61–68

    Google Scholar 

  • Hagiwara N, Irisawa H, KameyamaM (1987) Transient-type calcium current contributes to the pace-maker potential in isolated sino-atrial node. J Physiol (Lond) 382:104P

    Google Scholar 

  • Hagiwara N, Irisawa H, Kameyama M (1988) Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J Physiol 395:233–253

    Google Scholar 

  • Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflügers Arch 391:85–100

    CAS  Google Scholar 

  • Harron DWG, Shanks RG (1985) Pharmacology, clinical pharmacology and potential therapeutic uses of the specific bradycardic agent alinidine. Eur Heart J 6:722–729

    Google Scholar 

  • Hohnloser S, Weirich J, Homburger H, Antoni H (1982) Electrophysiological studies on effects of AQ-A 39 in the isolated guinea pig heart and myocardial preparations. Arzneimittelforschung 32 (11):730–734

    Google Scholar 

  • Irisawa H (1978) Comparative physiology of the cardiac pacemaker mechanism. Physiol Rev 58:461–498

    Google Scholar 

  • Irisawa H, Noma A (1982) Pacemaker mechanisms of rabbit sinoatrial node cells. In: Bouman LN, Jongsma III (eds) Cardiac rate and rhythm. Martinus Nijhoff, The Hague, pp 35–51

    Google Scholar 

  • Irisawa H, Noma A (1984) Pacemaker currents in mammalian nodal cells. J Mol Cell Cardiol 16:777–781

    Google Scholar 

  • Irisawa H, Yanagihara K (1980) The slow inward current of the rabbit sino-atrial nodal cells. In: Zipes DP, Bailey JC, Elharrar V (eds) The slow inward current and cardiac arrhythmias. Martinus Nijhoff, The Hague, pp 265–284

    Google Scholar 

  • Kobinger W (1985) Specific bradycardic agents, a new approach to therapy in angina pectoris? Prog Pharmacol 5/4:89–100

    Google Scholar 

  • Kobinger W (1989) Specific bradycardiac agents. In: Vaughan Williams EM (ed) Antiarrhythmic drugs. Springer, Berlin Heidelberg New York, pp 423–452 (Handbook of experimental pharmacology, vol 89)

    Google Scholar 

  • Kobinger W, Lillie C (1984) Cardiovascular characterization of UL-FS 49,1,3,4,5-tetrahydro-7,8-dimethoxy-3-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylimino]-propyl]-2H-benzazepin-2-on hydrochloride, a new “specific bradycardic agent”. Eur J Pharmacol 104:9–18

    Article  CAS  PubMed  Google Scholar 

  • Kobinger W, Lillie C (1987) Specific bradycardic agents — a novel pharmacological class? Eur Heart J 8 [Suppl L]:7–15

    Google Scholar 

  • Kobinger W, Lillie C (1988) Falipamil (AQ-A 39) and UL-FS 49. Cardiovasc Drug Rev 6:35–53

    Google Scholar 

  • Kokubun S, Nishimura M, Noma A, Irisawa H (1980) The spontaneous action potential of rabbit atrioventricular node cells. Jpn J Physiol 30:529–540

    Google Scholar 

  • Kokubun S, Nishimura M, Noma A, Irisawa H (1982) Membrane currents in the rabbit atrioventricular node cell. Pfliigers Arch 393:15–22

    Google Scholar 

  • Kreitner D (1985) Electrophysiological study of the two main pacemaker mechanisms in the rabbit sinus node. Cardiovasc Res 19:304–318

    Google Scholar 

  • Krumpl G, Schneider W, Raberger G (1986) Can exercise-induced regional contractile dysfunction be prevented by selective bradycardiac agents? Naunyn-Schmiedeberg's Arch Pharmacol 334:540–543

    Google Scholar 

  • Lillie C, Kobinger W (1983) Comparison of the bradycardic effects of alinidine (St 567), AQ-A 39 and verapamil on guinea-pig sinoatrial node superfused with different Ca2+ and NaCl solutions. Eur J Pharmacol 87:25–33

    Google Scholar 

  • Lillie C, Kobinger W (1984) Decrease in bradycardic effect of AQ-A 39 and alinidine in guinea-pig sinoatrial node depolarized by high external K+-concentration. Naunyn-Schmiedeberg's Arch Pharmacol 328:210–213

    Google Scholar 

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

    Google Scholar 

  • Maylie J, Morad M (1981) Ionic characterization of pacemaker current in voltage clamped rabbit SA node. Biophys J 33:11a

    Google Scholar 

  • Miyamoto J, Kotake H, Mashiba H (1986) Study on bradycardic induced by diltiazem in the rabbit sinoatrial node. Arzneimittelforschung 36:808–810

    Google Scholar 

  • Nakayama T, Kurachi Y, Noma A, Irisawa H (1984) Action potential and membrane currents of single pacemaker cells of the rabbit heart. Pflügers Arch 402:248–257

    Google Scholar 

  • Noble D (1984) The surprising heart: a review of recent progress in cardiac electrophysiology. J Physiol 353:1–50

    Google Scholar 

  • Noma A, Irisawa H (1974) The effect of sodium ion on the initial phase of sinoatrial pacemaker action potentials in rabbits. Jpn J Physiol 24:617–632

    Google Scholar 

  • Noma A, Irisawa H, Kokobun S, Kotake H, Nishimura M, Watanabe Y (1980) Slow current systems in the A — V node of the rabbit heart. Nature 285:228–229

    Google Scholar 

  • Noma A, Morad M, Irisawa H (1983) Does the “pacemaker current” generate the diastolic depolarization in the rabbit SA node cells? Pfliigers Arch 397:190–194

    Google Scholar 

  • Osterrieder W, Pelzer D, Yang QF, Trautwein W (1981) The electrophysiological basis of the bradycardic action of AQA 39 on the sinoatrial node. Naunyn-Schmiedeberg's Arch Pharmacol 317:233–237

    Google Scholar 

  • Pelzer D, Trautwein W, McDonald TIT (1982) Calcium channel block and recovery from block in mammalian ventricular muscle treated with organic channel inhibitors. Pflügers Arch 394:97–105

    Google Scholar 

  • Senges J, Rizos I, Brachmann J, Anders G, Jauernig R, Hamman HD, Kübler W (1983) Effect of nifedipine and AQ-A 39 on the sinoatrial and atrioventricular nodes of the rabbit and their antiarrhythmic action on atrioventricular nodal reentrant tachycardia. Cardiovasc Res 17:132–144

    Google Scholar 

  • Seyama I (1976) Characteristic of the rectifying properties of the sino-atrial node cell of the rabbit. J Physiol 255:379–397

    Google Scholar 

  • Snyders DJ, van Bogaert PP (1987) Alinidine modifies the pace-maker current in sheep Purkinje fibers. Pflügers Arch 410:83–91

    Google Scholar 

  • Taniguchi J, Kokubun S, Noma A, Irisawa H (1981) Spontaneously active cells isolated from the sino-atrial and atrio-ventricular nodes of the rabbit heart. Jpn J Physiol 31:547–558

    Google Scholar 

  • Trautwein W, Pelzer D, McDonald TF, Osterrieder W (1981) AQ-A 39, a new bradycardic agent which blocks myocardial calcium (Ca) channels in a frequency- and voltage-dependent manner. Naunyn-Schmiedeberg's Arch Pharmacol 317:228–232

    Google Scholar 

  • Trautwein W, Pelzer D, McDonald TF (1983) Interval-and voltage-dependent effects of the calcium channel-blocking agents D600 and AQA 39 on mammalian ventricular muscle. Circ Res 52 [Suppl 1]:60–68

    Google Scholar 

  • van Bogaert PP, Goethals M (1987) Pharmacological influence of specific bradycardic agents on the pacemaker current on sheep cardiac Purkinje fibres. A comparison between three different molecules. Eur Heart J 8:35–42

    Google Scholar 

  • van Ginneken ACG, Bouman LN, Jongsma HJ, Duivenvoorden JJ, Opthof T, Giles WR (1987) Alinidine as a model of the mode of action of specific bradycardic agents on SA node activity. Eur Heart J 8:25–33

    Google Scholar 

  • Vaughan Williams EM (1987) Antiarrhythmic action of specific bradycardic agents. Eur Heart J 8:17–18

    Google Scholar 

  • West TC (1955) Ultramicroelectrode recording from the cardiac pacemaker. J Pharmacol Exp Ther 115:283–290

    Google Scholar 

  • West TC (1972) Electrophysiology of the sinoatrial node. In: De Mello WC (ed) Electrical phenomena in the heart. Academic, New York, pp 191–217

    Google Scholar 

  • Yanagihara K, Irisawa H (1980) Inward current activated during hyperpolarization in the rabbit sinoatrial node cell. Pfliigers Arch 385:11–19

    Google Scholar 

  • Yanagihara K, Noma A, Irisawa H (1980) Reconstruction of the sino-atrial node pacemaker potential based on voltage clamp experiments. Jpn J Physiol 30:841–857

    Google Scholar 

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  1. Physiologisches Institut, Universität des Saarlandes, D-6650, Homburg/Saar, Germany

    Th. Doerr & W. Trautwein

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  1. Th. Doerr
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  2. W. Trautwein
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Doerr, T., Trautwein, W. On the mechanism of the “specific bradycardic action” of the verapamil derivative UL-FS 49. Naunyn-Schmiedeberg's Arch Pharmacol 341, 331–340 (1990). https://doi.org/10.1007/BF00180659

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  • DOI: https://doi.org/10.1007/BF00180659

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