Summary
The effects of imipramine, a tricyclic antidepressant, on action potential characteristics and plateau membrane currents were studied in isolated guineapig ventricular myocytes, using the whole cell configuration of the patch-clamp technique. Imipramine (1, 5 and 15 μmol/l) decreased in a concentration-dependent manner the amplitude and shortened the duration of the action potential, but it had no effect on resting membrane potential. At all three concentrations tested, imipramine decreased the delayed outward potassium current, this effect being apparently voltage-independent since it did not modify the activation curve. Imipramine, 5 and 15 μmol/l, also produced an inhibition of the peak high threshold calcium current, but did not change the shape of the current-voltage relationship or the apparent reversal potential of this current. Therefore, imipramine probably decreased the maximum available calcium conductance. However, the inward rectifying potassium current was not affected by any concentration of imipramine tested. Imipramine, 1 and 5 μmol/l, shortened the duration of the action potentials elicited in the presence of the inorganic calcium channel blocker cobalt chloride, and at 5, but not at 1 μmol/l, also shortened the action potentials obtained in the presence of the sodium channel blocker tetrodotoxin. Washout of imipramine completely reversed all its effects within 15 minutes. All these results suggest that imipramine at a concentration of 1 μmol/l produced a shortening in action potential duration by inhibiting the late sodium current flowing during the plateau phase of the action potential. At concentrations of 5 and 15 μmol/l the effect of imipramine on action potential duration can also be explained by a blocking effect on the high threshold calcium current.
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References
Alexander C, Nino A (1968) Cardiovascular complications in young patients taking psychotropic agents. Am Heart J 78:757–769
Arena JP, Kass RS (1988) Block of heart potassium channels by clofilium and its tertiary analogs. Relationship between drug structure and type of channel blocked. Mol Pharmacol 34:60–66
Belles B, Malecot C, Hescheler J, Trautwein W (1988) “Run-down” of the Ca current during the whole-cell recordings in guinea-pig heart cells: role of phosphorylation and intracellular calcium. Pflügers Arch 411:353–360
Bigger JT Jr, Giardina EGV, Perel JM, Kantor SJ, Glassman AH (1977) Cardiac antiarrhythmic effect of imipramine hydrochloride. N Engl J Med 296:206–208
Byerly L, Hagiwara S (1982) Calcium currents in internally perfused nerve cells bodies of Lymnea stagnalis. J Physiol (Lond) 322: 503–528
Carmeliet E (1985) Electrophysiologic and voltage clamp analysis of the effects of sotalol on isolated cardiac muscle and Purkinje fibers. J Pharmacol Exp Ther 232:817–825
Carmeliet E, Vereecke J (1979) Electrogenesis of action potential and automaticity. In: Berne R, Speralakis N, Geiger S (eds) Handbook of physiology. The cardiovascular system. American Physiological Society, Bethesda, MD, USA, pp 269–334
Colatsky TJ, Follmer CH (1989) K+ channel blockers and activators in cardiac arrhythmias. Cardiovasc Drug Rev 7:199–209
Delpón E, Valenzuela C, Tamargo J (1990) Tonic and frequency-dependent Vmax block induced by imipramine in guinea-pig ventricular muscle fibres. J Cardiovasc Pharmacol 15:414–420
Elonen E, Linoila M, Lukkari I, Mattila MJ (1975) Concentrations of tricyclic antidepressants in plasma, heart and skeletal muscle after their intravenous infusion to anesthetized rabbits. Acta Pharmacol Toxicol 37:272–281
Fekete M, Borsy J (1964) On the antiarrhythmic effect of some thymoleptics. Medna Exp 10:93–100
Follmer CH, Buzby G, Jurkiewicz N, Stein R, Colatsky TJ (1988) Selective block of Na+ and K+ channels in feline ventricular myocytes. Biophys J 53:424a
Follmer CH, Colatsky TJ (1990) Block of delayed rectifier potassium current, IK, by flecainide and E-4031 in cat ventricular myocytes. Circulation 82:289–293
Garcia de - Jalón P, Rodriguez SM, Tamargo J (1978) Electrophysiological effects of imipramine in guinea-pig myocardium. Br J Pharmacol 63:373P
Glassman AH, Perel JM (1973) The clinical pharmacology of imipramine. Arch Gen Psychiatry 28:649–653
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
Isenberg G, Klöckner U (1982a) Calcium tolerant ventricular myocytes prepared by preincubation in a “KB medium”. Pflügers Arch 395:6–18
Isenberg G, Klöckner U (1982b) Calcium currents of isolated bovine ventricular myocytes are fast and of large amplitude. Pflügers Arch 395:30–41
Isenberg G, Tamargo J (1985) Effect of imipramine on calcium and potassium currents in isolated bovine ventricular myocytes. Eur J Pharmacol 108:121–131
Jandhyala BS, Steenberg ML, Perel JM, Manian AA, Buckley JP (1977) Effects of several tricyclic antidepressants on the hemodynamics and myocardial contractility of the anesthetized dogs. Eur J Pharmacol 42:403–410
Jefferson J (1975) A review of the cardiovascular effects and toxicity of tricyclic antidepressants. Psychosom Med 37:160–179
Kiyosue T, Arita M (1989) Late sodium current and its contribution to action potential configuration in guinea-pig ventricular myocytes. Circ Res 64:389–397
Manzanares J, Tamargo J (1983) Electrophysiological effects of imipramine in non-treated and in imipramine-pretreated rat atrial fibres. Br J Pharmacol 79:167–175
Marshall JB, Forker AD (1982) Cardiovascular effects of tricyclic antidepressant drugs: Therapeutic usage, overdose and management of complications. Am Heart J 103:401–414
Matsuura H, Ehara T, Imoto Y (1987) An analysis of the delayed outward current in single ventricular cells of the guinea-pig. Pflügers Arch 410:596–603
Ogata N, Narahashi T (1989) Block of sodium channels by psychotropic drugs in single guinea-pig cardiac myocytes. Br J Pharmacol 97:905–913
Raeder E, Burchardt D, Neubauer H, Walter R, Gastpar M (1978) Longterm tri- and tetra-cyclic antidepressants, myocardial contractility and cardiac rhythm. Br Med J ii:666–667
Rawling DA, Fozzard HA (1979) Effects of imipramine on cellular electrophysiological properties of cardiac Purkinje fibers. J Pharmacol Exp Ther 209:371–375
Roden DM, Bennett PB, Snyders DJ, Balser JR, Hondeghem LM (1988) Quinidine delays IK activation in guinea-pig ventricular myocytes. Circ Res 62:1055–1058
Rodriguez S, Tamargo J (1980) Electrophysiological effects of imipramine on bovine ventricular muscle and Purkinje fibres. Br J Pharmacol 70:15–23
Sánchez-Chapula J (1988) Effects of bupivacaine on membrane currents of guinea-pig ventricular myocytes. Eur J Pharmacol 156: 303–308
Sanguinetti MC, Jurkiewicz NK (1990) Two components of cardiac delayed rectifier K+ current. J Gen Physiol 96:195–215
Schmitt H, Cheymd G, Gilbert J (1970) Effects anti-arryhtmisants et hémodynamiques de Pimipramine et de la chlorimipramine. Arch Int Pharmacodyn 184:158–174
Snyders D, Katzung B (1985) Clofilium reduces de plateau potassium current in isolated cardiac myocytes. Circulation 72:S111–233
Snyders D, Katzung B (1986) Intracellular clofilium reduces IK in isolated adult cardiac myocytes. Biophys J 49:401a
Wallenstein S, Zycker C, Fleiss J (1980) Some statistical methods useful in circulation research. Circ Res 47:1–8
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Delpón, E., Tamargo, J. & Sánchez-Chapula, J. Further characterization of the effects of imipramine on plateau membrane currents in guinea-pig ventricular myocytes. Naunyn-Schmiedeberg's Arch Pharmacol 344, 645–652 (1991). https://doi.org/10.1007/BF00174748
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DOI: https://doi.org/10.1007/BF00174748