Function of the sodium-calcium exchanger during myocardial contraction-relaxation caused by strophanthin administration

Introduction. Cardiac glycosides influence myocardial contractility via affecting Na⁺–Ca²⁺ exchange, but the isolated contribution of this mechanism remains poorly understood. The aim of this study was to determine the effects of strophanthin on cardiac contractions generated by the sodium-calcium exchange system alone.

Materials and methods. Experiments were performed on isolated hearts of Wistar laboratory rats perfused through the aorta using the Langendorff technique. Contractions were induced by perfusion with solutions of varying Na⁺ concentrations. Strophanthin in ampoules that was used as the studied pharmaceuticals was added to the perfusion medium at a final concentration up to 0.5 μmol/L. An equivalent volume of saline was administered in the control series.

Results. Experiments showed that the heart continued to contract and relax with each cycle of Na+–Ca2+exchange activation. However, the rate of contraction in the second repetition was 32 % lower. Strophanthin reduced contraction force in all three repetitions. Particularly significant disturbances were observed during the first stimulation — by 78 %. Muscle contractions and relaxation occurred under gradual increase in muscle tone during diastole. Given that strophanthin can reduce the activity of the Na+/K+-Adenosine Triphosphatase (Na+/K+-ATPase), our experiments clearly demonstrated the glycoside’s ability to increase intracellular sodium, and consequently, calcium concentrations. Repeated calcium efflux from cells via Na+–Ca2+exchange proved ineffective in the presence of strophanthin. The heart continued to experience calcium overload, which was reflected in the increased cardiac diastole stress.

Conclusion. When cardiac cells experience calcium ion overload, the final physiological effect influenced by strophanthin may be negative rather than positive.

1. Gurevich MA, Gavrilin AA. Cardiac glycosides in modern clinical practice (In Russian). Almanac of Clinical Medicine. 2014;(35):101–105. doi: 10.18786/2072-0505-2014-35-101-105

2. Umarova FT, Khasanova MA, Berdieva HYa, et. al. Study of inhibition of Na-, K-ATPase enzyme by cardiac glycosides of the strophanthidin series and their positiveinotropic effect (In Russian). Universum: chemistry and biology. 2022;5(95):1–7. doi: 10.32743/UniChem.2022.95.5.13563

3. Altamirano J, Li X, DeSantiago J, et. al. The inotropic effect of cardioactive glycosides in ventricular myocytes requires Na+–Ca2+ exchanger function. J Physiol. 2006;575(3):845–854. doi: 10.1113/jphysiol.2006.111252

4. Terrar DA. Calcium signaling in the heart. Adv Exp Med Biol. 2020;1131:395–443. doi: 10.1007/978-3-030-12457-1_16

5. Сannell MB, Grantham CJ, Main MJ, et. al. The roles of the sodium and calcium current in triggering calcium release from the sarcoplasmic reticulum. Ann N Y Acad Sci. 1996;779:443–450. doi: 10.1111/j.1749-6632.1996.tb44819

6. Aronsen JM, Swift F, Sejersted OM. Cardiac sodium transport and excitation– contraction coupling.J Mol Cell Cardiol. 2013;61:11–19. doi: 10.1016/j.yjmcc.2013.06.003

7. Weber CR, Piacentino V 3rd, Ginsburg KS, et. al. Na+–Ca2+ exchange current and submembrane [Ca2+] during the cardiac action potential. Circ Res. 2002;90(2):182– 189. doi: 10.1161/hh0202.103940

8. Berezhnova TA, Moshurov IP, Baofeng Ya, et. al. Effect of cyclophosphamide on regulation of heart contractions by means of sodium calcium exchanger. Res. Results Pharmacol. 2025;11(1):1–12. doi: 10.18413/rrpharmacology.11.539

9. Lee HI, Lee BK, Jeong KW, et. al. Potassium-induced cardiac arrest during conventional cardiopulmonary resuscitation in a porcine model of prolonged ventricular fibrillation cardiac arrest: a feasibility study. Resuscitation. 2013;84(3):378– 383. doi: 10.1016/j.resuscitation.2012.08.324

10. Lehnart SE, Maier LS, Hasenfuss G. Abnormalities of calcium metabolism and myocardial contractility depression in the failing heart. Heart Fail Rev. 2009;14(4):213– 224. doi: 10.1007/s10741-009-9146-x

11. Nagy N, Toth N, Nanasi PP. Antiarrhythmic and inotropic effects of selective Na+/ Ca2+ exchanger inhibition: what can we learn from the pharmacological studies? Int J Mol Sci. 2022;23(23):14651. doi: 10.3390/ijms232314651

12. Kuptsova AM, Bugrov RK, Ziyatdinova NI, et. al. The most acute stage of myocardial infarction: the effect of If blockade on the isolated rat heart (In Russian). Ulyanovsk Journal of Medical and Biological Sciences. 2022;3:106–119. doi: 10.34014/2227-1848-2022-3-106-119

13. Metelitsa VI. Handbook of clinical pharmacology of cardiovascular drugs, 3rd edition (In Russian). Moscow: Medical Information Agency; 2005. 1528 p. ISBN 5-89481-320-4

14. Konstantinou DМ, Karvounis H, Giannakoulas G. Digoxin in heart failure with a reduced ejection fraction: a risk factor or a risk marker. Cardiology. 2016;134(3):311– 319. doi: 10.1159/000444078

15. Echteld CJ, Kirkels JH, Eijgelshoven MH, et. al. Intracellular sodium during ischemia and calcium-free perfusion: a 23Na NMR study. J Mol Cell Cardiol. 1991;23(3):297–307. doi: 10.1016/0022-2828(91)90066-u

16. Hamilto Sh, Veress R, Belevych A, et. al. The role of calcium homeostasis remodeling in inherited cardiac arrhythmia syndromes. Pflugers Arch. 2021;473:377–387. doi: 10.1007/s00424-020-02505-y17.

17. Giladi M, Bohbot H, Buki T, et. al. Dynamic features of allosteric Ca2+ sensor in tissue-specific NCX variants. Cell Calcium. 2012;51(6):478–485. doi: 10.1016/j.ceca.2012.04.00718.

18. Toda N. Effects of calcium, sodium and potassium ions on contractility of isolated atria and their responses to noradrenaline. Br J Pharmacol. 1969;36(2):350–367. doi: 10.1111/j.1476-5381.1969.tb09510.x.