Summary
The effects of trimetazidine were studied on plasma membrane structures of cardiac cells which control excitability, as well as on cardiac cells that were cultured in normal physiologic conditions and after intracellular acidification.
When cardiac cells were kept in normal physiologic conditions, trimetazidine at concentrations ranging from 10−8 to 3.10−4 M interacted neither directly nor indirectly with the major ionic transporter systems of cardiac cells, such as ionic channels (Na+, K+), ATPase, Na+/H+, and Na+/Ca2+ exchange systems.
Under acid-load conditions trimetazide acts in a dose- and time-dependent manner, in limiting the accumulation of Na+ and Ca2+ inside cardiac cells and depressing intracellular cell acidosis.
It is proposed that trimetazidine plays a key role in limiting the intracellular accumulation of protons that is responsible for cell acidosis during ischemia.
Trimetazidine, in protecting cardiac cells against accumulation of protons, limits accumulation of Na+ and Ca2+.
Similar content being viewed by others
References
Garlick PB, Radda GK, Seeley PJ. Studies on acidosis in the ischemic heart by phosphorus nuclear magnetic resonance.Biochem J 1979;184:547–554.
Cobbe SM, Poole-Wilson PA. The time of onset and severity of acidosis in myocardial ischemia.J Mol Cell Cardiol 1980;12:745–760.
Opie LH. Metabolic regulation in ischemia and hypoxia.Circ Res 1976; 38(Suppl 1):I-52–I-74.
Rouslin WR, Erickson JL, Solaro RJ. Effects of oligomycin and acidosis on rates of ATP depletion in ischemic heart muscle.Am J Physiol 1986; 250:H503-H508.
Reimer KA, Jennings RB, Tatum AT. Pathobiology of acute myocardial ischemia: Metabolic, functional and ultrastructural studies.Am J Cardiol 1983; 52:72A-81A.
Del Maestro RF, Thaw HH, Bjork J, Planker M. Free radicals as mediators of tissue injury.Acta Physiol Scand 1980; 429:43–57.
Burton KP, Buja LM, Sen A, et al. Accumulation of arachidonate in triacylglycerols and unesterified fatty acids during ischemia and reflow in the isolated rat heart.Am J Pathol 1986; 124:238–245.
Lavanchy N, Martin J, Rossi A. Préservation par la trimétazidine du potential énergétique du myocarde au cours de l'ischémie et de la reperfusion. Etude par spéctroscopie RMN du phosphore sur le coeur isolé.Presse Med 1986; 35:1758–1761.
Libersa C, Honoré E, Adamantidis M, et al. Effects de la trimétazidine sur un modèle d'ischémie myocardiaque in vitro.Presse Med 1986; 35:1758–1761.
Maridonneau-Parini I. Effet de la trimétazidine sur les altérations membranaires induites par les radicaux libres oxygénés dans les globules rouges humains.Presse Med 1986; 35:1762–1764.
Coraboeuf E, Deroubaix E, Hoerter J. Control of ionic permeabilities in normal and ischemic heart.Circ Res 1976; 38(Suppl):I-92–I-98.
Kagiyama Y, Hill JY, Gettes LS. Interaction of acidosis and increased extracellular potassium on action potential characteristics and conduction in Guinea pig ventricular muscle.Circ Res 1982; 51:614–623.
Renaud JF, Kazazoglou T, Lombet A, et al. The Na+ channel in mammalian cells. Two kinds of tetrodotoxin receptors in rat heart membranes.J Biol Chem 1983; 258:8799–8805.
Renaud JF. Use of cell cultures as a tool to elucidate physiological, pharmacological and biochemical membrane properties of the embryonic heart. Biol Cell 1980; 37:97–104.
Galizzi JP, Borsotto M, Barhanin J, et al. Characterization and photoaffinity labeling of receptor sites for the Ca2+ channels inhibitors d-cis-diltiazem (+)-bepridil, desmethoxy-verapamil, and (+)-PN 200–110 in skeletal muscle transverse tubule membrane.J Biol Chem 1986; 261:1393–1397.
Kazazoglou T, Renaud JF, Rossi B, Lazdunski M. Two classes of ouabain receptors in chick ventricular cardiac cells and their relation to (Na+, K+)-ATPase inhibition, intracellular Na+ accumulation, Ca2+ influx, and cardiotonic effect.J Biol Chem 1983; 258:12163–12170.
Roos A, Boron WF. Intracellular pH.Physiol Rev 1981; 61:296–434.
L'Allemain G, Paris S, Pouyssegur J. Growth factor action and intracellular pH regulation in fibroblasts.J Biol Chem 1984; 259:5809–5815.
Lazdunski M, Renaud JF. The action of cardiotoxins on cardiac plasma membranes.Ann Rev Physiol 1982; 44:463–473.
Lazdunski M, Frelin C, Vigne P. The sodium/hydrogen exchange system in cardiac cells: Its biochemical and pharmacological properties and its role in regulating internal concentration of sodium and internal pH.J Mol Cell Cardiol 1985; 17:1029–1042.
Aronson PS. Kinetic properties of the plasma membrane Na+/H+ exchange.Ann Rev Physiol 1985; 47:545–560.
Mahenensmith RL, Aronson PS. The plasma membrane Na+/H+ exchanger and its role in physiological and pathological processes.Circ Res 1985; 57:773–788.
Piwnica-Worms D, Jacob R, Horres CR, Liberman M. Na+/H+ exchange in cultured chick heart cells, pHi regulation.J Gen Physiol 1985; 85:43–64.
Reeves JP. The sarcolemmal sodium-calcium exchange system. In: Shamoo A, ed.Regulation of Calcium Transport Across Muscle Membranes. New York: Academic Press, 1985.
Coraboeuf E. Ionic basis of electrical activity in cardiac tissues.Am J Physiol 1978; 234:H101-H116.
Noble D. The electrogenic Na-K pump current and actions of the cardiac glycosides in cardiac glycoside receptors and positive inotropy. In: Erdmann E, ed.Basic Res Cardiol 1984; 79(Suppl):72–78.
Gargouil YM, Chahine M. Effets de la trimétazidine sur les mouvements ioniques cellulaires dans le myocarde.Gaz Med France 1984; 91(Suppl 26):40–46.
Moravec J, Ngonzil J, Corsin A, Pocholle P. Analyse de l'effet anti-ischémique de la trimétazidine. Etude sur le coeur isolé de rat soumis à une réduction du débit coronaire: Vastarel 20 mg et ischémie myocardique.Gaz Med 1984; 35–39.
Kiyosue T, Nakamura S, Arita M. Effects of trimetazidine on action potentials and membrane currents of Guinea pig ventricular myocytes.J Mol Cell Cardiol 1986; 18:1301–1311.
Shen AC, Jennings RB. Myocardial calcium and magnesium
Aickin MC, Thomas R. An investigation of ionic mechanism of intracellular pH regulation in mouse soleus muscle fibres.J Physiol (Lond) 1977; 273:295–316.
Shen AC, Jennings RB. Myocardial calcium and magnesium in acute ischaemic injury.Am J Pathol 1972; 67:416–440.
Bourdillon PD, Poole-Wilson PA. Effects of ischaemia and reperfusion on calcium exchange and mechanical function in isolated rabbit myocardium.Cardiovasc Res 1981; 15:121–130.
Bourdillon PD, Poole-Wilson PA. The effects of verapamil, quiescence and cardioplegia on calcium exchange and mechanical function in ischaemic rabbit myocardium.Circ Res 1982; 50:360–368.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Renaud, J.F. Internal pH, Na+, and Ca2+ regulation by trimetazidine during cardiac cell acidosis. Cardiovasc Drug Ther 1, 677–686 (1988). https://doi.org/10.1007/BF02125756
Issue Date:
DOI: https://doi.org/10.1007/BF02125756