Abstract
The bradycardic mechanism of ZD 7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride) was investigated in sheep cardiac Purkinje fibres. The pacemaker if-current measured with the two-microelectrode voltage-clamp technique, as well as the diastolic depolarization rate and the frequency of spontaneously active fibres were evaluated.
ZD 7288 did inhibit if-current. The if-amplitude recorded with a 0.8s-lasting test pulse from about −50 mV to −100 mV was reduced to 50% of control at 0.85 μmol/l and to 5% of control at 10 μmol/l. The threshold potential of if-activation was unaffected at a concentration of 1 μmol/l ZD 7288. The time constant of if-activation at different test potentials was not changed by 1 μmol/l ZD 7288. The drug was equally effective during if-activation with a 0.5 s-lasting test pulse applied at 0.05 Hz or 0.5 Hz. During long lasting (5 s) hyperpolarizing test pulses (−120 mV) the inhibition of if-current was removed.
In constantly stimulated Purkinje fibres (0.5 Hz) the slope of the early diastolic depolarization was decreased by ZD 7288. The half-maximal effect occurred at 0.92 μmol/l. There was strong correlation over the concentration range of 0.01 to 10 μmol/l ZD 7288 between the decrease of the slope of early diastolic depolarization and inhibition of if-amplitude recorded with 0.8s-lasting test pulses to −100 mV. The correlation coefficient was r = 0.97.
These results will explain the decrease in frequency of spontaneously active (about 0.6 Hz) Purkinje fibres. At 0.3 μmol/l ZD 7288 spontaneous activity had stopped in 8 of 11 preparations. Complete recovery of drug-induced effects on the frequency was gained after 3 h of wash-out with drug-free solution.
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References
Aronson RS, Gelles JM, Hoffman BF (1973) A new method for producing short cardiac Purkinje fibers suitable for voltage clamp. J Appl Physiol 34:527–530
Berger F, Borchard U, Hafner D, Kammer T, Weis T (1991) Inhibition of potassium outward currents and pacemaker current in sheep cardiac Purkinje fibres by the verapamil derivative YS 035. Naunyn-Schmiedeberg's Arch Pharmacol 344:653–661
BoSmith RE, Briggs I, Danks P, Sturgess NC (1992) Actions of ICI 7288 on sinoatrial node cellular electrophysiology: whole-cell currents. Br J Pharmacol 107:381 P
BoSmith RE, Briggs I, Sturgess NC (1993) Inhibitory actions of ZENECA ZD 7288 on whole-cell hyperpolarization activated inward current (if) in guinea-pig dissociated sinoatrial node cells. Br J Pharmacol 110:343–349
Boyett MR, Fedida D (1988) The effect of heart rate on the membrane currents of isolated sheep Purkinje fibres. J Physiol (Lond) 399: 467–491
Briggs I, Heapy CG (1992) Action of ICI D 7288 on sinoatrial node cellular electrophysiology: action potentials. Br J Pharmacol 107:382P
Callewaert G, Carmeliet E, Vereecke J (1984) Single cardiac Purkinje cells: general electrophysiology and voltage-clamp analysis of the pace-maker current. J Physiol (Lond) 349:643–661
Carmeliet E (1984) Existence of pacemaker current if in human atrial appendage fibres. J Physiol (Lond) 357, 133P
Deck KA, Kern R, Trautwein W (1964) Voltage clamp technique in mammalian cardiac fibres. Pflügers Arch 280:50–62
Denyer JC, Brown HF (1990) Pacemaking in rabbit isolated sinoatrial node cells during Cs+ block of the hyperpolarization-activated current. J Physiol (Lond) 429:401–409
DiFrancesco D (1981) A new interpretation of the pace-maker current in calf Purkinje fibres. J Physiol (Lond) 314:359–376
DiFrancesco D (1991) The contribution of the “pacemaker” current (if) to generation of spontaneous activity in rabbit sinoatrial node myocytes. J Physiol (Lond) 434:23–40
DiFrancesco D (1993) Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 55:455–472
DiFrancesco D, Noble D (1985) A model of cardiac electrical activity incorporating ion pumps and concentration changes. Phil Trans R Soc Lond (Biol) 307:353–398
Doerr Th, Trautwein W (1990) On the mechanism of the “specific bradycardic action” of the verapamil derivative UL-FS 49. Naunyn-Schmiedeberg's Arch Pharmacol 341:331–340
Glitsch HG, Pusch H, Verdonck F (1986) The contribution of Na and K ions to the pacemaker current in sheep cardiac Purkinje fibres. Pflügers Arch 406:464–471
Goethals M, Raes A, van Bogaert P-P (1993) Use-dependent block of the pacemaker current if in rabbit sinoatrial node cells by zatebradine (UL-FS 49). Circulation 88 (Part 1):2389–2401
Hagiwara N, Irisawa H, Kameyama M (1988) Contribution of two types of calcium currents to the pacemaker potentials of rabbit sinoatrial node cells. J Physiol (Lond) 395:233–253
Marshall PW, Rouse W, Briggs I, Hargreaves RB, Mills SD, McLoughlin BJ (1993) ICI D 7288, a novel sinoatrial node modulator. J Cardiovasc Pharmacol 21:902–906
Noble D, Tsien RW (1968) The kinetics and rectifier properties of the slow potassium current in cardiac Purkinje fibres. J Physiol (Lond) 195:185–214
Noma A, Morad M, Irisawa H (1983) Does the “pacemaker current” generate the diastolic depolarization in the rabbit SA node cells? Pflü]gers Arch 397:190–194
Oei HI, Van Ginneken ACG, Jongsma HJ, Bouman LN (1989) Mechanisms of impulse generation in isolated cells from the rabbit sinoatrial node. J Mol Cell Cardiol 21:1137–1149
Snyders DJ, Van Bogaert P-P (1987) Alinidine modifies the pacemaker current in sheep Purkinje fibers. Pflügers Arch 410:83–91
Thome U, Berger F, Borchard U, Hafner D (1992) Electrophysiological characterization of histamine receptor subtypes in sheep cardiac Purkinje fibres. Agents Actions 37:30–38
Thuringer D, Lauribe P, Escande D (1992) A hyperpolarization-activated inward current in human myocardial cells. J Mol ell Cardiol 24:451–455
Van Bogaert PP, 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
Van Bogaert PP, Goethals M (1992) Blockade of the pacemaker current by intracellular application of UL-FS 49 and UL-AH 99 in sheep cardiac Purkinje fibers. Eur J Pharmacol 229:55–62
Van Bogaert PP, Goethals M, Simoens C (1990) Use- and frequency-dependent blockade by UL-FS 49 of the if pacemaker current in sheep cardiac Purkinje fibres. Eur J Pharmacol 187:241–256
Van Ginneken ACG, Giles W (1991) Voltage clamp measurements of the hyperpolarization-activated inward current if in single cells from rabbit sinoatrial node. J Physiol (Lond) 434:57–83
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Correspondence to: U. Borchard at the above address
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Berger, F., Borchard, U., Gelhaar, R. et al. Effects of the bradycardic agent ZD 7288 on membrane voltage and pacemaker current in sheep cardiac Purkinje fibres. Naunyn-Schmiedeberg's Arch Pharmacol 350, 677–684 (1994). https://doi.org/10.1007/BF00169374
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DOI: https://doi.org/10.1007/BF00169374