toxreviewТоксикологический вестникToxicological Review0869-79223034-4611Federal Scientific Center of Hygiene named after F.F. Erisman10.36946/0869-7922-2018-5-22-32toxreview-140Research ArticleСтатьиВЛИЯНИЕ СУБХРОНИЧЕСКОЙ СВИНЦОВОЙ ИНТОКСИКАЦИИ НА СОКРАТИМОСТЬ МИОКАРДА КРЫСЫEFFECTS OF SUBCHRONIC LEAD INTOXICATION ON THE MYOCARDIUM CONTRACTILITY OF RATSКацнельсонБ. А.KatsnelsonB. A.

д.м.н., профессор, заслуженный деятель науки РФ, заведующий отделом токсикологии и биопрофилактики ФБУН ЕМНЦ ПОЗРПП Роспотребнадзора,

620014,  г. Екатеринбург

620014, Ekaterinburg

bkaznelson@etel.ruПроценкоЮ. Л.ProtsenkoYu. L.

д.б.н., главный научный сотрудник лаборатории биологической подвижности ФГБУН ИИФ УрО РАН,

620049, г. Екатеринбург

620049, Ekaterinburg

y.protsenko@iip.uran.ruКлиноваС. В.KlinovaS. V.

младший научный сотрудник лаборатории промышленной токсикологии ФБУН ЕМНЦ ПОЗРПП Роспотребнадзора,

620014, г. Екатеринбург

620014, Ekaterinburg

klinovasv@ymrc.ruЛукинО. Н.LookinO. N.

к.б.н., старший сотрудник лаборатории биологической подвижности ФГБУН ИИФ УрО РАН,

620049, г. Екатеринбург

620049, Ekaterinburg

o.lookin@iip.uran.ruБалакинА. А.BalakinA. A.

к.б.н., старший научный сотрудник лаборатории биологической подвижности ФГБУН ИИФ УрО РАН,

620049, г. Екатеринбург

620049, Ekaterinburg

balakin_a_a@mail.ruНикитинаЛ. В.NikitinaL. V.

д.б.н., ведущий научный сотрудник лаборатории биологической подвижности ФГБУН ИИФ УрО РАН,

620049, г. Екатеринбург

620049, Ekaterinburg

l.nikitina@iip.uran.ruКацнельсонЛ. Б.KatsnelsonL. B.

д.ф.-м.н., ведущий научный сотрудник лаборатории математической физиологии ФГБУН ИИФ УрО РАН,

620049, г. Екатеринбург

620049, Ekaterinburg

lbk@efif.uran.ruГерценО. П.GerzenO. P.

аспирант ФГБУН ИИФ УрО РАН,

620049, г. Екатеринбург

620049, Ekaterinburg

o.p.gerzen@gmail.comМинигалиеваИ. А.MinigalievaI. A.

к.б.н., старший научный сотрудник, заведующая лабораторией промышленной токсикологии ФБУН ЕМНЦ ПОЗРПП Роспотребнадзора,

620014, г. Екатеринбург

620014, Ekaterinburg

ilzira-minigalieva@yandex.ruПриваловаЛ. И.PrivalovaL. I.

д.м.н., профессор, заведующий лабораторией научных основ биологической профилактики ФБУН ЕМНЦ ПОЗРПП Роспотребнадзора,

620014, г. Екатеринбург

620014, Ekaterinburg

privalova@ymrc.ruГурвичВ. Б.GurvichV. B.

д.м.н., директор ФБУН ЕМНЦ ПОЗРПП Роспотребнадзора,

620014, г. Екатеринбург

620014, Ekaterinburg

gurvich@ymrc.ruСутунковаМ. П.SutunkovaM. P.

к.м.н., заведующая лабораторией токсикологии среды обитания ФБУН ЕМНЦ ПОЗРПП Роспотребнадзора,

620014, г. Екатеринбург

620014, Ekaterinburg

sutunkova@ymrc.ruФБУН «Екатеринбургский медицинский - научный центр профилактики и охраны здоровья рабочих промпредприятий» РоспотребнадзораРоссияThe Medical Research Center for Prophylaxis and Health Protection in Industrial WorkersRussian FederationФГБУН «Институт иммунологии и физиологии» УрО РАНРоссияInstitute of Immunology and Physiology of the Ural Branch of the Russian Academy of SciencesRussian Federation201828102018052232Copyright © Кацнельсон Б.А., Проценко Ю.Л., Клинова С.В., Лукин О.Н., Балакин А.А., Никитина Л.В., Кацнельсон Л.Б., Герцен О.П., Минигалиева И.А., Привалова Л.И., Гурвич В.Б., Сутункова М.П., 20182018Кацнельсон Б.А., Проценко Ю.Л., Клинова С.В., Лукин О.Н., Балакин А.А., Никитина Л.В., Кацнельсон Л.Б., Герцен О.П., Минигалиева И.А., Привалова Л.И., Гурвич В.Б., Сутункова М.П.Katsnelson B.A., Protsenko Y.L., Klinova S.V., Lookin O.N., Balakin A.A., Nikitina L.V., Katsnelson L.B., Gerzen O.P., Minigalieva I.A., Privalova L.I., Gurvich V.B., Sutunkova M.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.toxreview.ru/jour/article/view/140

Известно, что хроническая свинцовая интоксикация вызывает артериальную гипертензию как у людей, так и у крыс и, таким образом, является причиной некоторых вторичных на-рушений функции сердца. Однако нет никаких неопровержимых доказательств того, что сама интоксикация непосредственно влияет на сократимость миокарда. В наших экспериментах аутбредным крысам-самцам многократно внутрибрюшинно вводили сублетальные дозы ацетата свинца 3 раза в неделю в течение 5 недель. Мы наблюдали явную, хотя и умеренную субхроническую свинцовую интоксикацию. На следующий день после последней инъекции сердце каждого животного было извлечено; трабекулы и папиллярные мышцы из правого желудочка были выделены для моделирования цикла сокращения-расслабления in vitro в изометрических режимах; оставшаяся ткань сердца гомогенизировалась для определения изоформ миозина. Было обнаружено, что свинцовая интоксикация приводила к снижению (по сравнению с контрольными крысами) времени и скорости изометрического сжатия препаратов миокарда in vitro, в то время как сохранялась его амплитуда и уменьшалось пассивное напряжение трабекул. Показано, что отношение миозина сдвигалось в сторону медленной изоформы. Обсуждаются механические и токсикологические выводы из полученных результатов.

While it is known that chronic lead intoxication in humans induces arterial hypertension and thus can lead to some secondary disturbances of heart function, possible effects of this intoxication on myocardium contractility has never been proved. In our experiments outbred male rats were repeatedly injected IP with sub-lethal doses of lead acetate 3 times a week during 5 weeks. They developed an explicit even if moderate lead intoxication characterized by typical hematological and some other features. Next day after the last injection the heart of each animal was excised, and trabecules and papillary muscles from right ventricle were used for modeling in vitro isometric regimes of contraction-relaxation cycle. Several well-established parameters of this model proved to be changed as compared with preparations taken from hearts of healthy control rats. Against the background of in vivocalcium treatment both systemic and cardiotoxic effects of lead were somewhat attenuated. For the first time we showed that at subchronic intoxication with lead the myocardial preparations in a wide range of lengths react with decrease in their time and speed parameters of isometric contraction while keeping its amplitude, and with decrease in the passive stiffness of the trabecules. Features of the reaction of different structures of the heart and the shifting of isomyosin ratio to the slow isoform were demonstrated. Mechanistic and toxicological inferences from the results obtained are discussed.

свинцовая интоксикациясократимость миокардаизоформы миозинаleadintoxicationmyocardial contractilitymyosin isoformsРабота была частично выполнена в рамках тем ИИФ УрО РАН № AAA-A18-118020590031-8 и № AAAA-A18-118020590135ReferencesGlenn B.S., Stewart W.F., Links J.M., Todd A.C., Schwartz B.S. The longitudinal association of lead with blood pressure. Epidemiol. 2003; 14: 30–36.Glenn B.S., Stewart W.F., Links J.M., Todd A.C., Schwartz B.S. The longitudinal association of lead with blood pressure. Epidemiol. 2003; 14: 30–36.Glenn B.S., Bandeen-Roche K., Lee B.K., Weaver V.M., Todd A.C., Schwartz B.S. Changes in systolic blood pressure associated with lead in blood and bone. Epidemiol. 2006; 17: 538–544.Glenn B.S., Bandeen-Roche K., Lee B.K., Weaver V.M., Todd A.C., Schwartz B.S. Changes in systolic blood pressure associated with lead in blood and bone. Epidemiol. 2006; 17: 538–544.Navas-Acien A., Guallar E., Silbergeld E.K., Rothenberg S.J. Lead exposure and cardiovascular disease–a systematic review. Environ. Health. Perspect. 2007; 115: 472–482.Navas-Acien A., Guallar E., Silbergeld E.K., Rothenberg S.J. Lead exposure and cardiovascular disease–a systematic review. Environ. Health. Perspect. 2007; 115: 472–482.Fiorim J., Ribeiro R.F., Silveira E.A., Padilha A.S., Vescovi M.V., de Jesus H.C. et al. Low-level lead exposure increases systolic arterial pressure and endotheliumderived vasodilator factors in rat aortas. PLoS One. 2011; 6(2): e17117.Fiorim J., Ribeiro R.F., Silveira E.A., Padilha A.S., Vescovi M.V., de Jesus H.C. et al. Low-level lead exposure increases systolic arterial pressure and endotheliumderived vasodilator factors in rat aortas. PLoS One. 2011; 6(2): e17117.World Health Organization. Safety evaluation of certain food additives and contaminants. Geneva: WHO Food Additives Series; 2011: No. 64.World Health Organization. Safety evaluation of certain food additives and contaminants. Geneva: WHO Food Additives Series; 2011: No. 64.Gidlow D.A. Lead toxicity. Occup. Med. 2015; 65(5): 348–356.Gidlow D.A. Lead toxicity. Occup. Med. 2015; 65(5): 348–356.Yang W.Y., Zhang Z.Y., Thijs L., Cauwenberghs N., Wei F.F., Jacobs L. et al. Left Ventricular Structure and Function in Relation to Environmental Exposure to Lead and Cadmium. J. Am. Heart Assoc. 2017; 6(2): pii:e004692.Yang W.Y., Zhang Z.Y., Thijs L., Cauwenberghs N., Wei F.F., Jacobs L. et al. Left Ventricular Structure and Function in Relation to Environmental Exposure to Lead and Cadmium. J. Am. Heart Assoc. 2017; 6(2): pii:e004692.Silveira E.A., Siman F.D., de Oliveira F.T., Vescovi M.V., Furieri L.B., Lizardo J.H. et al. Low-dose chronic lead exposure increases systolic arterial pressure and vascular reactivity of rat aortas. Free Radic. Biol. Med. 2014; 67: 366–376.Silveira E.A., Siman F.D., de Oliveira F.T., Vescovi M.V., Furieri L.B., Lizardo J.H. et al. Low-dose chronic lead exposure increases systolic arterial pressure and vascular reactivity of rat aortas. Free Radic. Biol. Med. 2014; 67: 366–376.Simões M.R., Ribeiro Júnior R.F., Vescovi M.V., de Jesus H.C., Padilha A.S., Stefanon I. et al. Acute lead exposure increases arterial pressure: role of the renin-angiotensin system. PLoS One. 2011; 6: e18730.Simões M.R., Ribeiro Júnior R.F., Vescovi M.V., de Jesus H.C., Padilha A.S., Stefanon I. et al. Acute lead exposure increases arterial pressure: role of the renin-angiotensin system. PLoS One. 2011; 6: e18730.Vaziri N.D., Norris K. Lipid disorders and their relevance to outcomes in chronic kidney disease. Blood Purif. 2011; 31(1-3): 189-196.Vaziri N.D., Norris K. Lipid disorders and their relevance to outcomes in chronic kidney disease. Blood Purif. 2011; 31(1-3): 189-196.Carmignani M., Volpe A.R., Boscolo P., Qiao N., Di Gioacchino M., Grilli A. et al. Catcholamine and nitric oxide systems as targets of chronic lead exposure in inducing selective functional impairment. Life Sci. 2000; 68: 401–415.Carmignani M., Volpe A.R., Boscolo P., Qiao N., Di Gioacchino M., Grilli A. et al. Catcholamine and nitric oxide systems as targets of chronic lead exposure in inducing selective functional impairment. Life Sci. 2000; 68: 401–415.Khalil-Manesh F., Gonick H.C., Weiler E.W., Prins B., Weber M.A., Purdy R.E. Lead-induced hypertension: possible role of endothelial factors. Am. J. Hypertens. 1993; 6: 723–729.Khalil-Manesh F., Gonick H.C., Weiler E.W., Prins B., Weber M.A., Purdy R.E. Lead-induced hypertension: possible role of endothelial factors. Am. J. Hypertens. 1993; 6: 723–729.Трахтенберг И.М., Лубянова И.П., Апыхтина Е.Л. Роль свинца и железа, как техногенных химических загрязнителей, в патогенезе сердечно-сосудистых заболеваний. Therapia. 2010; 07-08(49): 36-39. / Trakhtenberg I.M., Lubyanova I.P., Apykhtina E.L. Lead and iron as man-made chemical pollutants in the pathogenesis of cardiovascular diseases. Therapia. 2010; 07-08(49): 36-39 (in Russian).Трахтенберг И.М., Лубянова И.П., Апыхтина Е.Л. Роль свинца и железа, как техногенных химических загрязнителей, в патогенезе сердечно-сосудистых заболеваний. Therapia. 2010; 07-08(49): 36-39. / Trakhtenberg I.M., Lubyanova I.P., Apykhtina E.L. Lead and iron as man-made chemical pollutants in the pathogenesis of cardiovascular diseases. Therapia. 2010; 07-08(49): 36-39 (in Russian).Carmignani M., Boscolo P., Poma A., Volpe A.R. Kininergic system and arterial hypertension following chronic exposure to inorganic lead. Immunopharmacol. 1999; 44: 105–110.Carmignani M., Boscolo P., Poma A., Volpe A.R. Kininergic system and arterial hypertension following chronic exposure to inorganic lead. Immunopharmacol. 1999; 44: 105–110.Staessen J.A., Roels H., Fagard R. Lead exposure and conventional and ambulatory blood pressure: a prospective population study. Phee Cad. Investigators. JAMA. 1996; 275: 1563–1570.Staessen J.A., Roels H., Fagard R. Lead exposure and conventional and ambulatory blood pressure: a prospective population study. Phee Cad. Investigators. JAMA. 1996; 275: 1563–1570.Nawrot T.S., Thijs L., Den Hond E.M., Roels H.A., Staessen J.A. An epidemiological re-appraisal of the association between blood pressure and lead: a metaanalysis. J. Hum. Hypertens. 2002; 16: 123–131.Nawrot T.S., Thijs L., Den Hond E.M., Roels H.A., Staessen J.A. An epidemiological re-appraisal of the association between blood pressure and lead: a metaanalysis. J. Hum. Hypertens. 2002; 16: 123–131.Staessen J.A., Lauwerys R.R., Buchet J.P., Bulpitt C.J., Rondia D., Vanrenterghem Y. 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: 151–156.Staessen J.A., Lauwerys R.R., Buchet J.P., Bulpitt C.J., Rondia D., Vanrenterghem Y. 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: 151–156.Chao S.H., Suzuki Y., Zysk J.R., Cheung W.Y. Activation of calmodulin by various metal cations as a function of ionic radius. Mol. Pharmacol. 1984; 26(1): 75-82.Chao S.H., Suzuki Y., Zysk J.R., Cheung W.Y. Activation of calmodulin by various metal cations as a function of ionic radius. Mol. Pharmacol. 1984; 26(1): 75-82.Chao S.H., Bu C.-H., Cheung W.Y. Activation of troponin C by Cd2+ and Pb2+. Arch. Toxicol. 1990; 64: 490-496.Chao S.H., Bu C.-H., Cheung W.Y. Activation of troponin C by Cd2+ and Pb2+. Arch. Toxicol. 1990; 64: 490-496.Richardt G., Federolf G., Habermann E. Affinity of heavy metal ions to intracellular Ca2+-binding proteins. Biochem. Pharmacol. 1986; 35(8): 1331-1335.Richardt G., Federolf G., Habermann E. Affinity of heavy metal ions to intracellular Ca2+-binding proteins. Biochem. Pharmacol. 1986; 35(8): 1331-1335.Markovac J., Goldstein G.W. Picomolar concentrations of lead stimulate brain protein kinase C. Nature. 1988; 334: 71 -73.Markovac J., Goldstein G.W. Picomolar concentrations of lead stimulate brain protein kinase C. Nature. 1988; 334: 71 -73.Williams B.J., Griffith W.H. 3rd, Albrecht C.M., Pirch J.H., Hejtmancik M.R.Jr. Effects of chronic lead treatment on some cardiovascular responses to norepinephrine in the rat. Toxicol. Appl. Pharmacol. 1977; 40: 407-413.Williams B.J., Griffith W.H. 3rd, Albrecht C.M., Pirch J.H., Hejtmancik M.R.Jr. Effects of chronic lead treatment on some cardiovascular responses to norepinephrine in the rat. Toxicol. Appl. Pharmacol. 1977; 40: 407-413.Kopp S.J., Barany M., Erlanger M., Perry E.F., Perry H.M. 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: 48–56.Kopp S.J., Barany M., Erlanger M., Perry E.F., Perry H.M. 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: 48–56.Kopp S.J., Perry H.M.Jr., Glonek T., Erlanger M., Perry E.F., Barany M. et al. Cardiac physiologic-metabolic changes after chronic low-level heavy metal feeding. Am. J. Physiol. 1980; 239: H22–30.Kopp S.J., Perry H.M.Jr., Glonek T., Erlanger M., Perry E.F., Barany M. et al. Cardiac physiologic-metabolic changes after chronic low-level heavy metal feeding. Am. J. Physiol. 1980; 239: H22–30.Prentice R.C., Kopp S.J. Cardiotoxicity of lead at various perfusate calcium concentrations: functional and metabolic responses of the perfused rat heart. Toxicol. Appl. Pharmacol. 1985; 81: 491–501.Prentice R.C., Kopp S.J. Cardiotoxicity of lead at various perfusate calcium concentrations: functional and metabolic responses of the perfused rat heart. Toxicol. Appl. Pharmacol. 1985; 81: 491–501.Vassallo D.V., Lebarch E.C., Moreira C.M., Wiggers G.A., Stefanon I. Lead reduces tension development and the myosin ATPase activity of the rat right ventricular myocardium. Braz. J. Med. Biol. Res. 2008; 41: 789–795.Vassallo D.V., Lebarch E.C., Moreira C.M., Wiggers G.A., Stefanon I. Lead reduces tension development and the myosin ATPase activity of the rat right ventricular myocardium. Braz. J. Med. Biol. Res. 2008; 41: 789–795.Fioresi M., Furieri L.B., Simões M.R., Ribeiro R.F.Jr., Meira E.F., Fernandes A.A. et al. Acute exposure to lead increases myocardial contractility independent of hypertension development. Braz. J. Med. Biol. Res. 2013; 46: 178–185.Fioresi M., Furieri L.B., Simões M.R., Ribeiro R.F.Jr., Meira E.F., Fernandes A.A. et al. Acute exposure to lead increases myocardial contractility independent of hypertension development. Braz. J. Med. Biol. Res. 2013; 46: 178–185.Fioresi M., Simões M.R., Furieri L.B., Broseghini-Filho G.B., Vescovi M.V., Stefanon I. et al. Chronic lead exposure increases blood pressure and myocardial contractility in rats. PLoS One. 2014; 9(5): e96900.Fioresi M., Simões M.R., Furieri L.B., Broseghini-Filho G.B., Vescovi M.V., Stefanon I. et al. Chronic lead exposure increases blood pressure and myocardial contractility in rats. PLoS One. 2014; 9(5): e96900.Silva M.A., de Oliveira T.F., Almenara C.C., Broseghini-Filho G.B., Vassallo D.V., Padilha A.S. et al. Exposure to a Low Lead Concentration Impairs Contractile Machinery in Rat Cardiac Muscle. Biol. Trace Elem. Res. 2015; 167: 280–287.Silva M.A., de Oliveira T.F., Almenara C.C., Broseghini-Filho G.B., Vassallo D.V., Padilha A.S. et al. Exposure to a Low Lead Concentration Impairs Contractile Machinery in Rat Cardiac Muscle. Biol. Trace Elem. Res. 2015; 167: 280–287.Linke W.A., Rudy D.E., Centner T., Gautel, M., Witt C., Labeit S. et al. I-band titin in cardiac muscle is a three-element molecular spring and is critical for maintaining thin filament structure. J. Cell Biol. 1999; 146: 631–644.Linke W.A., Rudy D.E., Centner T., Gautel, M., Witt C., Labeit S. et al. I-band titin in cardiac muscle is a three-element molecular spring and is critical for maintaining thin filament structure. J. Cell Biol. 1999; 146: 631–644.Freiburg A., Trombitas K., Hell W., Cazorla O., Fougerousse F., Centner T. et al. Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity. Circ Res. 2000; 86: 1114–1121.Freiburg A., Trombitas K., Hell W., Cazorla O., Fougerousse F., Centner T. et al. Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity. Circ Res. 2000; 86: 1114–1121.Fujita H., Labeit D., Gerull B., Labeit S., Granzier H.L. Titin isoform-dependent effect of calcium on passive myocardial tension. Am. J. Physiol. Heart Irc. Physiol. 2004; 287: H2528–H2534.Fujita H., Labeit D., Gerull B., Labeit S., Granzier H.L. Titin isoform-dependent effect of calcium on passive myocardial tension. Am. J. Physiol. Heart Irc. Physiol. 2004; 287: H2528–H2534.Sarantitis I., Papanastasopoulos P., Manousi M., Baikoussis N.G., Apostolakis E. The cytoskeleton of the cardiac muscle cell. Hellenic J. Cardiol. 2012; 53(5): 367-79.Sarantitis I., Papanastasopoulos P., Manousi M., Baikoussis N.G., Apostolakis E. The cytoskeleton of the cardiac muscle cell. Hellenic J. Cardiol. 2012; 53(5): 367-79.Reiser P.J., Kline W.O. Electrophoretic separation and quantitation of cardiac myosin heavy chain isoforms in eight mammalian species. Am. J. Physiol. 1998; 284 (3 Pt 2): H1048-H1053.Reiser P.J., Kline W.O. Electrophoretic separation and quantitation of cardiac myosin heavy chain isoforms in eight mammalian species. Am. J. Physiol. 1998; 284 (3 Pt 2): H1048-H1053.Farkhondeh T., Boskabady M.H., Kohi M.K., Sadeghi-Hashjin G., Moin M. Lead exposure affects inflammatory mediators, total and differential white blood cells in sensitized guinea pigs during and after sensitization. Drug Chem. Toxicol. 2014; 37(3): 329-335.Farkhondeh T., Boskabady M.H., Kohi M.K., Sadeghi-Hashjin G., Moin M. Lead exposure affects inflammatory mediators, total and differential white blood cells in sensitized guinea pigs during and after sensitization. Drug Chem. Toxicol. 2014; 37(3): 329-335.Al Momen A. Thrombocytosis secondary to chronic lead poisoning. Platelets. 2010; 21(4): 297-299.Al Momen A. Thrombocytosis secondary to chronic lead poisoning. Platelets. 2010; 21(4): 297-299.Rius R.A., Govoni S., Trabucchi M. Regional modification of brain calcium antagonist binding after in vivo chronic lead exposure. Toxicol. 1986; 40(2): 191-197.Rius R.A., Govoni S., Trabucchi M. Regional modification of brain calcium antagonist binding after in vivo chronic lead exposure. Toxicol. 1986; 40(2): 191-197.Bressler J.P., Goldstein G.W. Mechanisms of lead neurotoxicity. Biochem. Pharmacol. 1991; 41: 479-484.Bressler J.P., Goldstein G.W. Mechanisms of lead neurotoxicity. Biochem. Pharmacol. 1991; 41: 479-484.Adonaylo V.N., Oteiza P.I. Lead intoxication: antioxidant defenses and oxidative damage in rat brain. Toxicol. 1999; 135(2-3): 77-85.Adonaylo V.N., Oteiza P.I. Lead intoxication: antioxidant defenses and oxidative damage in rat brain. Toxicol. 1999; 135(2-3): 77-85.Ma T., Chen H.H., Ho I.K. Effects of chronic lead (Pb) exposure on neurobehavioral function and dopaminergic neurotransmitter receptors in rats. Toxicol. Lett. 1999; 105(2): 111-21.Ma T., Chen H.H., Ho I.K. Effects of chronic lead (Pb) exposure on neurobehavioral function and dopaminergic neurotransmitter receptors in rats. Toxicol. Lett. 1999; 105(2): 111-21.Nehru B., Sidhu P. Behavior and neurotoxic consequences of lead on rat brain followed by recovery. Biol. Trace Elem. Res. 2001; 84(1-3): 113-121.Nehru B., Sidhu P. Behavior and neurotoxic consequences of lead on rat brain followed by recovery. Biol. Trace Elem. Res. 2001; 84(1-3): 113-121.NourEddine D., Miloud S., Abdelkader A. Effect of lead exposure on dopaminergic transmission in the rat brain. Toxicol. 2005; 207(3): 363-368.NourEddine D., Miloud S., Abdelkader A. Effect of lead exposure on dopaminergic transmission in the rat brain. Toxicol. 2005; 207(3): 363-368.Deveci E. Ultrastructural effects of lead acetate on brain of rats. Toxicol. Ind. Health. 2006; 22(10): 419-22.Deveci E. Ultrastructural effects of lead acetate on brain of rats. Toxicol. Ind. Health. 2006; 22(10): 419-22.Sanders T., Liu Yi., Buchner V., Tchounwou P.B. Neurotoxic Effects and Biomarkers of Lead Exposure: A Review. Rev. Environ. Health. 2009; 24(1): 15–45.Sanders T., Liu Yi., Buchner V., Tchounwou P.B. Neurotoxic Effects and Biomarkers of Lead Exposure: A Review. Rev. Environ. Health. 2009; 24(1): 15–45.Mason L.H., Harp J.P., Han D.Y. Pb Neurotoxicity: Neuropsychological Effects of Lead Toxicity. BioMed. Res. Int. 2014; 2014: 840547, 8 pages.Mason L.H., Harp J.P., Han D.Y. Pb Neurotoxicity: Neuropsychological Effects of Lead Toxicity. BioMed. Res. Int. 2014; 2014: 840547, 8 pages.Kusumoto F., Bernath P. ECG interpretation for everyone: an on-the-spot guide. Wiley-Blackwell. 2012; https://doi.org/10.1002/9781119962168Kusumoto F., Bernath P. ECG interpretation for everyone: an on-the-spot guide. Wiley-Blackwell. 2012; https://doi.org/10.1002/9781119962168Sharma P., Purohit P. Lead Exposure Exacerbates Cardiovascular Risk. Ind. J. Clin. Biochem. 2014; 29(2): 117–118.Sharma P., Purohit P. Lead Exposure Exacerbates Cardiovascular Risk. Ind. J. Clin. Biochem. 2014; 29(2): 117–118.Allouche L., Hamadouche M., Touabti A., Khennouf S. Effect of Long-term Exposure to Low or Moderate Lead Concentrations on Growth, Lipid Profile and Liver Function in Albino Rats. Advan. Biol. Res. 2011; 5(6): 339-347.Allouche L., Hamadouche M., Touabti A., Khennouf S. Effect of Long-term Exposure to Low or Moderate Lead Concentrations on Growth, Lipid Profile and Liver Function in Albino Rats. Advan. Biol. Res. 2011; 5(6): 339-347.Tarugi P., Calandra S., Borella P., Vivoli G.F. Heavy metals and experimental atherosclerosis. Effect of lead intoxication on rabbit plasma lipoproteins. Atherosclerosis. 1982; 45(2): 221- 234.Tarugi P., Calandra S., Borella P., Vivoli G.F. Heavy metals and experimental atherosclerosis. Effect of lead intoxication on rabbit plasma lipoproteins. Atherosclerosis. 1982; 45(2): 221- 234.Skoczyńska A., Smolik R., Jeleń M. Lipid abnormalities in rats given small doses of lead. Arc. Toxicol. 1993; 67(3): 200–204.Skoczyńska A., Smolik R., Jeleń M. Lipid abnormalities in rats given small doses of lead. Arc. Toxicol. 1993; 67(3): 200–204.Barton J.C., Conrad M.E., Harrison L., Nuby S. Effects of calcium on the absorption and retention of lead. J. Lab. Clin. Med. 1978; 91(3): 366-376.Barton J.C., Conrad M.E., Harrison L., Nuby S. Effects of calcium on the absorption and retention of lead. J. Lab. Clin. Med. 1978; 91(3): 366-376.Bogden J.D., Gertner S.B., Christakos S., Kemp F.W., Yang Z., Katz S.R. et al. Dietary calcium modifies concentrations of lead and other metals and renal calbindin in rats. J. Nutr. 1992; 122(7): 1351-1360.Bogden J.D., Gertner S.B., Christakos S., Kemp F.W., Yang Z., Katz S.R. et al. Dietary calcium modifies concentrations of lead and other metals and renal calbindin in rats. J. Nutr. 1992; 122(7): 1351-1360.Varnai V.M., Piasek M., Blanusa M., Sarić M.M., Simić D., Kostial K. Calcium supplementation efficiently reduces lead absorption in suckling rats. Pharmacol. Toxicol. 2001; 89(6): 326-30.Varnai V.M., Piasek M., Blanusa M., Sarić M.M., Simić D., Kostial K. Calcium supplementation efficiently reduces lead absorption in suckling rats. Pharmacol. Toxicol. 2001; 89(6): 326-30.Привалова Л.И. Свинец и его соединения. В кн.: Филов В.А., Мусийчук Ю.И., Москвин А.В., Ивин Б.А., ред. Вредные вещества в окружающей среде. Элементы I-IV групп периодической системы и их неорганические соединения. СПб.: Профессионал; 2005: 400-27 / Privalova, L.I. Lead and its compounds, in: Philov, V.A., Musiychuk, Yu.I., Moskvin, A.V., Ivin, B.A. (Eds.), Harmful substances in the environment. Elements of groups I-IV of the periodic table and their inorganic compounds. St. Petersburg: Professional; 2005: 400-27 (in Russian).Привалова Л.И. Свинец и его соединения. В кн.: Филов В.А., Мусийчук Ю.И., Москвин А.В., Ивин Б.А., ред. Вредные вещества в окружающей среде. Элементы I-IV групп периодической системы и их неорганические соединения. СПб.: Профессионал; 2005: 400-27 / Privalova, L.I. Lead and its compounds, in: Philov, V.A., Musiychuk, Yu.I., Moskvin, A.V., Ivin, B.A. (Eds.), Harmful substances in the environment. Elements of groups I-IV of the periodic table and their inorganic compounds. St. Petersburg: Professional; 2005: 400-27 (in Russian).Katsnelson B. A., Makeev O. H., Kochneva N. I., Privalova L. I., Degtyareva T.D., Minin V.V. et al. Testing a set of bioprotectors against the genotoxic effect of a combination of ecotoxicants. Cent. Eur. J. Occup. Environ. Med. 2007; 13(3-4): 251-264.Katsnelson B. A., Makeev O. H., Kochneva N. I., Privalova L. I., Degtyareva T.D., Minin V.V. et al. Testing a set of bioprotectors against the genotoxic effect of a combination of ecotoxicants. Cent. Eur. J. Occup. Environ. Med. 2007; 13(3-4): 251-264.Katsnelson B.A., Privalova L.I., Kuzmin S. V., Malykh O.L., Gurvitch V.B., Voronin S.A. et al. Lead and Childhood: Risks and their Management (The Middle Urals Experience). Cent. Eur. J. Occup. Environ. Med. 2008; 14(3): 3-25.Katsnelson B.A., Privalova L.I., Kuzmin S. V., Malykh O.L., Gurvitch V.B., Voronin S.A. et al. Lead and Childhood: Risks and their Management (The Middle Urals Experience). Cent. Eur. J. Occup. Environ. Med. 2008; 14(3): 3-25.Katsnelson B.A., Privalova L.I., Kuzmin S.V., Degtyareva T.D., Soloboyeva J.I. Biological prophylaxis of adverse health effects caused by environmental and occupational impacts – theoretical premises, experimental and field testing, practical realization. Cent. Eur. J. Occup. Environ. Med. 2009; 15(1-2): 35-51.Katsnelson B.A., Privalova L.I., Kuzmin S.V., Degtyareva T.D., Soloboyeva J.I. Biological prophylaxis of adverse health effects caused by environmental and occupational impacts – theoretical premises, experimental and field testing, practical realization. Cent. Eur. J. Occup. Environ. Med. 2009; 15(1-2): 35-51.Katsnelson B.A., Privalova L.I., Kireyeva Ye.P, Yeremenko O.S., Sutunkova M.P., Valamina I.E. et al. Combined subchronic fluoride-lead intoxication and its attenuation with the help of a complex of bioprotectors. Med. Lav. 2012; 103(2): 146-159.Katsnelson B.A., Privalova L.I., Kireyeva Ye.P, Yeremenko O.S., Sutunkova M.P., Valamina I.E. et al. Combined subchronic fluoride-lead intoxication and its attenuation with the help of a complex of bioprotectors. Med. Lav. 2012; 103(2): 146-159.Savchenko O.V., Sgrebneva M.N., Kiselev V.I., Khotimchenko Y.S. Lead removal in rats using calcium alginate. Environ. Sci. Pollut. Res. Int. 2015; 22(1): 293-304.Savchenko O.V., Sgrebneva M.N., Kiselev V.I., Khotimchenko Y.S. Lead removal in rats using calcium alginate. Environ. Sci. Pollut. Res. Int. 2015; 22(1): 293-304.Gorza L., Mercadier J.J., Schwartz K., Thornell L.E., 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: 694-702.Gorza L., Mercadier J.J., Schwartz K., Thornell L.E., 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: 694-702.Hirzel H.O., Tuchschmid C.R., Schneider J., Krayenbuehl H.P., Schaub M.C. Relationship between myosin isoenzyme composition, hemodynamics, and myocardial structure in various forms of human cardiac hypertrophy. Circ. Res. 1985; 57: 729-740.Hirzel H.O., Tuchschmid C.R., Schneider J., Krayenbuehl H.P., Schaub M.C. Relationship between myosin isoenzyme composition, hemodynamics, and myocardial structure in various forms of human cardiac hypertrophy. Circ. Res. 1985; 57: 729-740.DeTombe P.P., Mateja R.D., Tachampa K., AitMou Y., Farman G.P., Irving T.C. Myofilament length dependent activation. J. Mol. Cell. Cardiol. 2010; 48: 851–858.DeTombe P.P., Mateja R.D., Tachampa K., AitMou Y., Farman G.P., Irving T.C. Myofilament length dependent activation. J. Mol. Cell. Cardiol. 2010; 48: 851–858.Allen D.G., Kentish J.C. The cellular basis of the length-tension relation in cardiac muscle. J. Mol. Cell. Cardiol. 1985; 17: 821–840.Allen D.G., Kentish J.C. The cellular basis of the length-tension relation in cardiac muscle. J. Mol. Cell. Cardiol. 1985; 17: 821–840.Sugiura S., Kobayakawa N., Fujita H., Yamashita H., Momomura S., Chaen S. et al. Comparison of unitary displacements and forces between 2 cardiac myosin isoforms by the optical trap technique. Molecular basis for cardiac adaptation. Circ. Res. 1998; 82: 1029 –1034.Sugiura S., Kobayakawa N., Fujita H., Yamashita H., Momomura S., Chaen S. et al. Comparison of unitary displacements and forces between 2 cardiac myosin isoforms by the optical trap technique. Molecular basis for cardiac adaptation. Circ. Res. 1998; 82: 1029 –1034.Morgan J.P., Chesebro J.H., Pluth J.R., Puga F.J., Schaff H.V. Intracellular calcium transients in human working myocardium as detected with aequorin. J. Am. Coll. Cardiol. 1984; 3: 410–418.Morgan J.P., Chesebro J.H., Pluth J.R., Puga F.J., Schaff H.V. Intracellular calcium transients in human working myocardium as detected with aequorin. J. Am. Coll. Cardiol. 1984; 3: 410–418.Fitzsimons D.P., Patel J.R., Moss R.L. Aging dependent depression in the kinetics of force development in rat skinned myocardium. Am. J. Physiol. 1999; 276: 1511-1519.Fitzsimons D.P., Patel J.R., Moss R.L. Aging dependent depression in the kinetics of force development in rat skinned myocardium. Am. J. Physiol. 1999; 276: 1511-1519.Krüger M., Linke W.A. Titin-based mechanical signalling in normal and failing myocardium. J. Mol. Cell. Cardiology. 2009; 46: 490–498.Krüger M., Linke W.A. Titin-based mechanical signalling in normal and failing myocardium. J. Mol. Cell. Cardiology. 2009; 46: 490–498.Stuyvers B.D., Miura M., Jin J.P., ter Keurs H.E. Ca(2+)-dependence of diastolic properties of cardiac sarcomeres: involvement of titin. Prog. Biophys. Mol. Biol. 1998; 69: 425–443.Stuyvers B.D., Miura M., Jin J.P., ter Keurs H.E. Ca(2+)-dependence of diastolic properties of cardiac sarcomeres: involvement of titin. Prog. Biophys. Mol. Biol. 1998; 69: 425–443.Linke W.A. Titin Gene and Protein Functions in Passive and Active Muscle. Annu. Rev. Physiol. 2018; 80: 389-411.Linke W.A. Titin Gene and Protein Functions in Passive and Active Muscle. Annu. Rev. Physiol. 2018; 80: 389-411.Linke W.A., Hamdani N. Gigantic Business Titin Properties and Function Through Thick and Thin. Circ Res. 2014; 114: 1052-1068.Linke W.A., Hamdani N. Gigantic Business Titin Properties and Function Through Thick and Thin. Circ Res. 2014; 114: 1052-1068.Yamasaki R., Wu Y., McNabb M., Greaser M., Labeit S., Granzier H. Protein Kinase A Phosphorylates Titin’s CardiacSpecific N2B Domain and Reduces Passive Tension in Rat Cardiac Myocytes. Circ Res. 2002; 90: 1181-1188.Yamasaki R., Wu Y., McNabb M., Greaser M., Labeit S., Granzier H. Protein Kinase A Phosphorylates Titin’s CardiacSpecific N2B Domain and Reduces Passive Tension in Rat Cardiac Myocytes. Circ Res. 2002; 90: 1181-1188.Simons T. Cellular interactions between lead and calcium. Br. Med Bull. 1986; 42: 431–434.Simons T. Cellular interactions between lead and calcium. Br. Med Bull. 1986; 42: 431–434.Elzinga G., Westerhof N. How to quantify pump function of the heart. The value of variables derived from, measurements on isolated muscle. Circ. Res. 1979; 44: 303-308.Elzinga G., Westerhof N. How to quantify pump function of the heart. The value of variables derived from, measurements on isolated muscle. Circ. Res. 1979; 44: 303-308.

The authors declare that there are no conflicts of interest present.