Effects of Lead and/or Cadmium on the Contractile Function of the Rat Myocardium Following Subchronic Exposure and Its Attenuation with a Complex of Bioprotectors

Background: As by-products of copper smelting, lead and cadmium pollute both workplace air at metallurgical plants and adjacent territories. Their increased levels in the human body pose a higher risk of cardiovascular diseases.

The objective of our study was evaluate changes in the rat myocardium contractile function following moderate subchronic exposure to soluble lead and/or cadmium salts and its attenuation by means of a complex of bioprotectors.

Materials and methods: The subchronic exposure of rats was modelled by intraperitoneal injections of 3-H₂O lead acetate and/or 2.5-H₂O cadmium chloride in single doses, 6.01 mg of Pb and 0.377 mg of Cd per kg of body weight, respectively, 3 times a week during 6 weeks. The myosin heavy chains isoform ratio was estimated by gel electrophoresis. Biomechanical measurements were performed on isolated multicellular preparations of the myocardium (trabeculae and papillary muscles) from the right ventricle.

Results: The subchronic lead exposure slowed down the contraction and relaxation cycle and increased myosin expression towards slowly cycling V3 isomyosins. Cadmium intoxication, on the contrary, shortened the contraction and relaxation cycle and shifted the ratio of isomyosin forms towards rapidly cycling V1. Following the combined exposure to lead and cadmium, some contractile characteristics changed in the direction typical of the effect of lead while others – in that of cadmium. We observed that the metal combination either neutralized or enhanced the isolated damaging effect of each heavy metal. The use of a complex of bioprotectors normalized the myocardial contractility impaired by the exposure to lead and cadmium either partially or completely.

Discussion: Despite the changes in myocardial contractility following the subchronic lead and cadmium exposure, the mechanisms of heterometric regulation were maintained. The adverse cardiotoxic effect of the combination of these industrial contaminants may be weakened by administering a complex of bioprotectors.

1. Trakhtenberg IM, Lubyanova IP, Apykhtina EL. Lead and iron as man-made chemical pollutants in the pathogenesis of cardiovascular diseases. Terapiya. 2010;49(07-08):36–39. (In Russian).

2. Solenkova NV, Newman JD, Berger JS, Thurston G, Hochman JS, Lamas GA. Metal pollutants and cardiovascular disease: mechanisms and consequences of exposure. Am Heart J. 2014;168(6):812–22. doi: 10.1016/j.ahj.2014.07.007

3. Lamas GA, Navas-Acien A, Mark DB, Lee KL. Heavy metals, cardiovascular disease, and the unexpected benefits of chelation therapy. J Am Coll Cardiol. 2016;67(20):2411–2418. doi: 10.1016/j.jacc.2016.02.066

4. Yang WY, Zhang ZY, Thijs L, et al. Left ventricular structure and function in relation to environmental exposure to lead and cadmium. J Am Heart Assoc. 2017;6(2):e004692. doi: 10.1161/JAHA.116.004692

5. Kim YD, Eom SY, Yim DH, et al. Environmental exposure to arsenic, lead, and cadmium in people living near Janghang copper smelter in Korea. J Korean Med Sci. 2016;31(4):489–96. doi: 10.3346/jkms.2016.31.4.489

6. An HC, Sung JH, Lee J, Sim CS, Kim SH, Kim Y. The association between cadmium and lead exposure and blood pressure among workers of a smelting industry: a cross-sectional study. Ann Occup Environ Med. 2017;29:47. doi: 10.1186/s40557-017-0202-z

7. Glenn BS, Stewart WF, Links JM, Todd AC, Schwartz BS. The longitudinal association of lead with blood pressure. Epidemiology. 2003;14(1):30–6. doi: 10.1097/00001648-200301000-00011

8. Glenn BS, Bandeen-Roche K, Lee BK, Weaver VM, Todd AC, Schwartz BS. Changes in systolic blood pressure associated with lead in blood and bone. Epidemiology. 2006;17(5):538–44. doi: 10.1097/01.ede.0000231284.19078.4b

9. Navas-Acien A, Guallar E, Silbergeld EK, Rothenberg SJ. Lead exposure and cardiovascular disease – a systematic review. Environ Health Perspect. 2007;115(3):472–82. doi: 10.1289/ehp.9785

10. Eum KD, Lee MS, Paek D. Cadmium in blood and hypertension. Sci Total Environ. 2008;407(1):147–53. doi: 10.1016/j.scitotenv.2008.08.037

11. Gallagher CM, Meliker JR. Blood and urine cadmium, blood pressure, and hypertension: a systematic review and meta-analysis. Environ Health Perspect. 2010;118(12):1676–84. doi: 10.1289/ehp.1002077

12. Fiorim J, Ribeiro Jr RF, Silveira EA, et al. Low-level lead exposure increases systolic arterial pressure and endothelium-derived vasodilator factors in rat aortas. PLoS One. 2011;6(2):e17117. doi: 10.1371/journal.pone.0017117

13. Lee MS, Park SK, Hu H, Lee S. Cadmium exposure and cardiovascular disease in the 2005 Korea National Health and Nutrition Examination Survey. Environ Res. 2011;111(1):171–6. doi: 10.1016/j.envres.2010.10.006

14. Caciari T, Sancini A, Fioravanti M, et al. Cadmium and hypertension in exposed workers: A meta-analysis. Int J Occup Med Environ Health. 2013;26(3):440–56. doi: 10.2478/s13382-013-0111-5

15. Franceschini N, Fry RC, Balakrishnan P, et al. Cadmium body burden and increased blood pressure in middle-aged American Indians: the Strong Heart Study. J Hum Hypertens. 2017;31(3):225–230. doi: 10.1038/jhh.2016.67

16. Chao SH, Suzuki Y, Zysk JR, Cheung WY. Activation of calmodulin by various metal cations as a function of ionic radius. Mol Pharmacol. 1984;26(1):75–82.

17. Chao SH, Bu CH, Cheung WY. Activation of troponin C by Cd2+ and Pb2+. Arch Toxicol. 1990;64(6):490–6. doi: 10.1007/BF01977632

18. Richardt G, Federolf G, Habermann E. Affinity of heavy metal ions to intracellular Ca2+-binding proteins. Biochem Pharmaco1. 1986;35(8):1331–5. doi: 10.1016/0006-2952(86)90278-9

19. Staessen JA, Roels H, Fagard R. Lead exposure and conventional and ambulatory blood pressure: a prospective population study. PheeCad Investigators. JAMA. 1996;275(20):1563–70.

20. Nawrot TS, Thijs L, Den Hond EM, Roels HA, Staessen JA. An epidemiological re-appraisal of the association between blood pressure and blood lead: a meta-analysis. J Hum Hypertens. 2002;16(2):123–31. doi: 10.1038/sj.jhh.1001300

21. Staessen JA, Lauwerys RR, Buchet JP, et al. Impairment of renal function with increasing blood lead concentrations in the general population. The Cadmibel Study Group. N Engl J Med. 1992;327(3):151–156. doi: 10.1056/NEJM199207163270303

22. Kopp SJ, Bárány M, Erlanger M, Perry EF, Perry Jr HM. The influence of chronic low-level cadmium and/or lead feeding on myocardial contractility related to phosphorylation of cardiac myofibrillar proteins. Toxicol Appl Pharmacol. 1980;54(1):48–56. doi: 10.1016/0041-008x(80)90007-1

23. Kopp SJ, Perry Jr M, Glonek T, et al. Cardiac physiologic-metabolic changes after chronic low-level heavy metal feeding. Am J Physiol. 1980;239(1):H22–30. doi: 10.1152/ajpheart.1980.239.1.H22

24. Ozturk IM, Buyukakilli B, Balli E, Cimen B, Gunes S, Erdogan S. Determination of acute and chronic effects of cadmium on the cardiovascular system of rats. Toxicol Mech Methods. 2009;19(4):308–17. doi: 10.1080/15376510802662751

25. Ferramola ML, Pérez Díaz MFF, Honoré SM, et al. Cadmium-induced oxidative stress and histological damage in the myocardium. Effects of a soy-based diet. Toxicol Appl Pharmacol. 2012;265(3):380–9. doi: 10.1016/j.taap.2012.09.009

26. Turdi S, Sun W, Tan Y, Yang X, Cai L, Ren J. Inhibition of DNA methylation attenuates low-dose cadmium-induced cardiac contractile and intracellular Ca(2+) anomalies. Clin Exp Pharmacol Physiol. 2013;40(10):706–12. doi: 10.1111/1440-1681.12158

27. Chen CY, Zhang SL, Liu ZY, Tian Y, Sun Q. Cadmium toxicity induces ER stress and apoptosis via impairing energy homoeostasis in cardiomyocytes. Biosci Rep. 2015;35(3):e00214. doi: 10.1042/BSR20140170

28. Reiser PJ, Kline WO. Electrophoretic separation and quantitation of cardiac myosin heavy chain isoforms in eight mammalian species. Am J Physiol. 1998;274(3):H1048–53. doi: 10.1152/ajpheart.1998.274.3.H1048

29. Panov VG, Katsnelson BA, Varaksin AN, et al. Further development of mathematical description for combined toxicity: A case study of lead–fluoride combination. Toxicol Rep. 2015;2:297–307. doi: 10.1016/j.toxrep.2015.02.002

30. Klinova SV, Minigalieva IA, Privalova LI, et al. Further verification of some postulates of the combined toxicity theory: New animal experimental data on separate and joint adverse effects of lead and cadmium. Food Chem Toxicol. 2020;136:110971. doi: 10.1016/j.fct.2019.110971

31. Gorza L, Mercadier JJ, Schwartz K, Thornell LE, Sartore S, Schiaffino S. Myosin types in the human heart. An immunofluorescence study of normal and hypertrophied atrial and ventricular myocardium. Circ Res. 1984;54(6):694–702. doi: 10.1161/01.res.54.6.694

32. Hirzel HO, Tuchschmid CR, Schneider J, Krayenbuehl HP, Schaub MC. Relationship between myosin isoenzyme composition, hemodynamics, and myocardial structure in various forms of human cardiac hypertrophy. Circ Res. 1985;57(5):729–40. doi: 10.1161/01.res.57.5.729

33. Sugiura S, Yamashita H. Functional characterization of cardiac myosin isoforms. Jpn J Physiol. 1998;48(3):173–9. doi: 10.2170/jjphysiol.48.173

34. Chen A, Kim SS, Chung E, Dietrich KN. Thyroid hormones in relation to lead, mercury, and cadmium exposure in the National Health and Nutrition Examination Survey, 2007–2008. Environ Health Perspect. 2013;121(2):181–6. doi: 10.1289/ehp.1205239

35. Granzier HL, Labeit S. The giant protein titin: a major player in myocardial mechanics, signaling, and disease. Circ Res. 2004;94(3):284–95. doi: 10.1161/01.RES.0000117769.88862.F8

36. Linke WA. Titin gene and protein functions in passive and active muscle. Annu Rev Physiol. 2018;80:389–411. doi: 10.1146/annurev-physiol-021317-121234

37. Privalova LI, Klinova SV, Minigalieva IA, et al. An experimental trial of bioprophylactic formula designed to minimize combined toxicity of both lead and cadmium. Gigiena i Sanitariya. 2020;99(1):85–89. (In Russian). doi: 10.33029/0016-9900-2020-99-1-85-89