Ulyanovsk Medico-biological Journal

PHYSIOLOGY

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DOI 10.34014/2227-1848-2022-3-106-119

ACUTE PHASE OF MYOCARDIAL INFARCTION: EFFECT OF IF-CURRENT BLOCKADE ON ISOLATED RAT HEART

A.M. Kuptsova, R.K. Bugrov, N.I. Ziyatdinova, T.L. Zefirov

Kazan Federal University, Kazan, Russia

 

If-current density in cardiomyocytes changes not only with age, but also with pathophysiological hypertrophy. Thus, studies of pathological conditions in experimental animal models allow us to study If-current role in pathophysiological processes occurring in the heart after myocardial infarction (MI).

The objective of the study is to examine the effect of If-currents blockade on the isolated heart of rats with modelled acute myocardial infarction (AMI) and sham-operated (SO) rats.

Materials and Methods. MI was reproduced by the left coronary artery ligation. The study was conducted on a Langendorff-isolated heart (ADInstruments). During AMI, the authors studied chronotropy, inotropy and its temporal characteristics, and blood supply of the rat heart.

Results. It was found that the initial values of contractile force and coronary flow were significantly lower in the group with an experimental AMI model. There were no differences in heart rate and temporal characteristics of contractile force. If-current blockade (ZD7288, 10-9 M, 10-5 M) reduced the contractile force and coronary flow of the isolated heart in both experimental groups, the changes were more pronounced in the SO group. If-current blockade (10-9 M) in the SO group led to tachycardia, and in the AMI group - to bradycardia. ZD7288 (10-5 M) reduced heart rate in both groups, but in the AMI group, bradycardia was more pronounced. It is possible that the obtained dynamics is associated with a change in the if-current density in the dyscrasic myocardium. Thus, it is obvious that If-currents are not only involved in the regulation of various MI heart functions, but their role changes at different stages of experimental myocardial infarction.

Key words: hyperpolarization-activated currents, experimental myocardial infarction, isolated heart, rat.

 

References

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  2. DiFrancesco D. Funny channels in the control of cardiac rhythm and mode of action of selective blocker. Pharmacol. Res. 2006; 53: 399–406.

  3. Sartiani L., Mannaioni G., Masi A., Romanelli M.N., Cerbai E. The Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: from Biophysics to Pharmacology of a Unique Family of Ion Channels. Pharmacol. Rev. 2017; 69: 354–395. DOI: https://doi.org/10.1124/pr.117.014035.

  4. Zefirov T.L., Ziyatdinova N.I., Zefirov A.L. Autonomic control of cardiac function involves modulation of hyperpolarization activated channels in vitro. Russ. J. Physiol. 2003; 89 (2): 154–160.

  5. Zefirov T.L., Gibina A.E., Sergejeva A.M., Ziyatdinova N.I., Zefirov A.L. Age-Related Peculiarities of Contractile Activity of Rat Myocardium during Blockade of Hyperpolarization-Activated Currents. Bull. Exp. Biol. Med. 2007; 144 (3): 273–275.

  6. Bugrov R.K., Kuptsova A.M., Khabibrakhmanov I.I., Ziyatdinova N.I., Zefirov T.L. Influence of If-current blockade on rat heart contractility with a model of myocardial infarction. Archivos Venezolanos de Farmacología y Terapéutica. 2020; 37 (7): 817–821.

  7. Rivolta I., Binda A., Masi A., DiFrancesco J.C. Cardiac and neuronal HCN channelopathies. Pflugers Arch. 2020; 472 (7): 931–951. DOI: 10.1007/s00424-020-02384-3.

  8. Cerbai E., Pino R., Sartiani L., Mugelli A. Influence of postnatal-development on If occurrence and properties in neonatal rat ventricular myocytes. Cardiovascular Research. 1999; 42: 416–423.

  9. Boateng S., Sanborn T. Acute myocardial infarction. Dis. Mon. 2013; 59: 83–96.

  10. Ide T., Ohtani K., Higo T. Ivabradine for the Treatment of Cardiovascular Diseases. Circ. J. 2019; 83: 252–260.

  11. Sharashova E., Wilsgaard T., Mathiesen E.B. Resting heart rate predicts incident myocardial infarction, atrial fibrillation, ischaemic stroke and death in the general population: the Tromsø Study. J. Epidemiol. Community Health. 2016; 70: 902–909.

  12. Wang B., Zhang X., Chen J., Chen S., Chen Q., Yang S., Wang Q. Effectiveness and safety of ivabradine in the treatment of acute myocardial infarction: a systematic review and meta-analysis. Ann. Palliat. Med. 2021; 10 (4): 4523–4531. DOI: 10.21037/apm-21-563.

  13. Swedberg K., Komajda M., Böhm M., Borer J.S., Ford I., Dubost-Brama A., Lerebours G., Tavazzi L. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized placebo-controlled study. Lancet. 2010; 376: 875–885.

  14. Fang Y., Debunne M., Vercauteren M., Brakenhielm E., Richard V., Lallemand F., Henry J-P., Mulder P., Thuillez C. Heart rate reduction induced by the if current inhibitor ivabradine improves diastolic function and attenuates cardiac tissue hypoxia. J. Cardiovasc. Pharmacol. 2012; 59: 260–267.

  15. Li C., Jiang D. Study and progress of ivabradine in cardiovascular diseases. Advances in Cardiovascular Diseases. 2019; 40: 143–145.

  16. Ramirez-Carracedo R., Tesoro L., Hernandez I., Diez-Mata J., Botana L., Saura M., Sanmartin M., Zamorano J.L., Zaragoza C. Ivabradine-stimulated microvesicle release induces cardiac protection against acute myocardial infarction. Int. J. Mol. Sci. 2020; 21: 6566.

  17. Brown H., Dfirancesco D., Noble S. How does adrenaline accelerate the heart? Nature. 1979; 280: 235–236.

  18. Nikulina N.A., Dotsenko E.A., Nerovnya A.M., Salivonchik D.P., Platoshkin E.N., Nikolaeva N.V., Tishkov S.P. Experimental myocardial infarction in rats: features of modeling and course within the first 48 hours after coronary artery ligation. Problems of health and ecology. 2020; 2 (64): 91–96.

  19. Kuptsova A.M., Ziyatdinova N.I., Faskhutdinov L.I., Biktemirova R.G., Zefirov T.L. Vliyanie HCN-kanalov na rabotu izolirovannogo serdtsa vzroslykh krys [Influence of HCN channels on the isolated heart functions in adult rats]. Uchenye zapiski Kazanskogo universiteta. Ser. Estestvennye nauki. 2018; 160 (4): 568–578 (in Russian).

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  21. Abramochkin D.V., Faskhutdinov L.I., Filatova T.S., Ziyatdinova N.I. Changes in Electrical Activity of Working Myocardium Under Condition of I-f Current Inhibition. Bull. Exp. Biol. Med. 2015; 158 (5): 600–603.

Received 20 June 2022; accepted 22 July 2022.

 

Information about the authors

Kuptsova Anna Mikhaylovna, Candidate of Sciences (Biology), Associate Professor, Chair of Human Health Protection, Kazan Federal University. 420008, Russia, Kazan, Kremlevskaya St., 18, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0002-3592-6589

Bugrov Roman Kutdusovich, Post-graduate Student, Chair of Human Health Protection, Kazan Federal University. 420008, Russia, Kazan, Kremlevskaya St., 18, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0001-6801-8547

Ziyatdinova Nafisa Il'gizovna, Doctor of Sciences (Biology), Professor, Chair of Human Health Protection, Kazan Federal University. 420008, Russia, Kazan, Kremlevskaya St., 18, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0002-4503-7451

Zefirov Timur L'vovich, Doctor of Sciences (Medicine), Professor, Head of the Chair of Human Health Protection, Kazan Federal University. 420008, Russia, Kazan, Kremlevskaya St., 18, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0001-9557-1639

 

For citation

Kuptsova A.M., Bugrov R.K., Ziyatdinova N.I., Zefirov T.L. Ostreyshaya stadiya infarkta miokarda: vliyanie blokady If na izolirovannoe serdtse krys [Acute phase of myocardial infarction: Effect of If-current blockade on the isolated rat heart]. Ul'yanovskiy mediko-biologicheskiy zhurnal. 2022; 3: 106–119. DOI: 10.34014/2227-1848-2022-3-106-119 (in Russian).

 

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УДК 612.17

DOI 10.34014/2227-1848-2022-3-106-119

ОСТРЕЙШАЯ СТАДИЯ ИНФАРКТА МИОКАРДА: ВЛИЯНИЕ БЛОКАДЫ If НА ИЗОЛИРОВАННОЕ СЕРДЦЕ КРЫС

А.М. Купцова, Р.К. Бугров, Н.И. Зиятдинова, Т.Л. Зефиров

ФГАОУ ВО «Казанский (Приволжский) федеральный университет», г. Казань, Россия

 

Плотность If в кардиомиоцитах изменяется не только с возрастом, но и при патофизиологической гипертрофии, поэтому исследования патологических состояний на моделях экспериментальных животных позволяют детально изучить роль If в патофизиологических процессах, происходящих в сердце после инфаркта миокарда (ИМ).

Цель – изучить влияние блокады If-токов на изолированное сердце крыс с моделью острейшего инфаркта миокарда (ОИМ) и ложнооперированных (ЛО) крыс.

Материалы и методы. ИМ воспроизводили путем лигирования левой коронарной артерии. Исследование проводилось на изолированном по Лангендорфу сердце (ADInstruments). В период ОИМ изучали хронотропию, инотропию и ее временные характеристики, кровоснабжение сердца крыс.

Результаты. Выявлено, что исходные значения силы сокращения и коронарного потока были достоверно ниже в группе с экспериментальной моделью ОИМ, различий в ЧСС и временных характеристиках силы сокращения не обнаружено. Блокада If (ZD7288, 10-9 М, 10-5 М) уменьшает силу сокращения и коронарный поток изолированного сердца в обеих экспериментальных группах, изменения более выражены в группе ЛО крыс. Блокада If (10-9 M) в группе ЛО крыс приводит к тахикардии, а в группе ОИМ – к брадикардии. ZD7288 (10-5 М) снижает ЧСС в обеих исследуемых группах, но в группе с ОИМ брадикардия была более выраженной. Возможно, полученная динамика выраженности эффектов связана с изменением плотности If в патологическом миокарде. Таким образом, очевидно, что токи If не только участвуют в регуляции различных функций сердца после ИМ, но и меняют свою роль на разных стадиях экспериментального инфаркта миокарда.

Ключевые слова: токи, активируемые при гиперполяризации, экспериментальный инфаркт миокарда, изолированное сердце, крыса.

 

Литература

  1. Shi S., Wu X. Clinical research progress of ivabradine in cardiovascular disease. Chinese Circulation Journal. 2015; 30: 613–616.

  2. DiFrancesco D. Funny channels in the control of cardiac rhythm and mode of action of selective blocker. Pharmacol. Res. 2006; 53: 399–406.

  3. Sartiani L., Mannaioni G., Masi A., Romanelli M.N., Cerbai E. The Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: from Biophysics to Pharmacology of a Unique Family of Ion Channels. Pharmacol. Rev. 2017; 69: 354–395. DOI: https://doi.org/10.1124/pr.117.014035.

  4. Zefirov T.L., Ziyatdinova N.I., Zefirov A.L. Autonomic control of cardiac function involves modulation of hyperpolarization activated channels in vitro. Russ. J. Physiol. 2003; 89 (2): 154–160.

  5. Zefirov T.L., Gibina A.E., Sergejeva A.M., Ziyatdinova N.I., Zefirov A.L. Age-Related Peculiarities of Contractile Activity of Rat Myocardium during Blockade of Hyperpolarization-Activated Currents. Bull. Exp. Biol. Med. 2007; 144 (3): 273–275.

  6. Bugrov R.K., Kuptsova A.M., Khabibrakhmanov I.I., Ziyatdinova N.I., Zefirov T.L. Influence of If-current blockade on rat heart contractility with a model of myocardial infarction. Archivos Venezolanos de Farmacología y Terapéutica. 2020; 37 (7): 817–821.

  7. Rivolta I., Binda A., Masi A., DiFrancesco J.C. Cardiac and neuronal HCN channelopathies. Pflugers Arch. 2020; 472 (7): 931–951. DOI: 10.1007/s00424-020-02384-3.

  8. Cerbai E., Pino R., Sartiani L., Mugelli A. Influence of postnatal-development on If occurrence and properties in neonatal rat ventricular myocytes. Cardiovascular Research. 1999; 42: 416–423.

  9. Boateng S., Sanborn T. Acute myocardial infarction. Dis. Mon. 2013; 59: 83–96.

  10. Ide T., Ohtani K., Higo T. Ivabradine for the Treatment of Cardiovascular Diseases. Circ. J. 2019; 83: 252–260.

  11. Sharashova E., Wilsgaard T., Mathiesen E.B. Resting heart rate predicts incident myocardial infarction, atrial fibrillation, ischaemic stroke and death in the general population: the Tromsø Study. J. Epidemiol. Community Health. 2016; 70: 902–909.

  12. Wang B., Zhang X., Chen J., Chen S., Chen Q., Yang S., Wang Q. Effectiveness and safety of ivabradine in the treatment of acute myocardial infarction: a systematic review and meta-analysis. Ann. Palliat. Med. 2021; 10 (4): 4523–4531. DOI: 10.21037/apm-21-563.

  13. Swedberg K., Komajda M., Böhm M., Borer J.S., Ford I., Dubost-Brama A., Lerebours G., Tavazzi L. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized placebo-controlled study. Lancet. 2010; 376: 875–885.

  14. Fang Y., Debunne M., Vercauteren M., Brakenhielm E., Richard V., Lallemand F., Henry J-P., Mulder P., Thuillez C. Heart rate reduction induced by the if current inhibitor ivabradine improves diastolic function and attenuates cardiac tissue hypoxia. J. Cardiovasc. Pharmacol. 2012; 59: 260–267.

  15. Li C., Jiang D. Study and progress of ivabradine in cardiovascular diseases. Advances in Cardiovascular Diseases. 2019; 40: 143–145.

  16. Ramirez-Carracedo R., Tesoro L., Hernandez I., Diez-Mata J., Botana L., Saura M., Sanmartin M., Zamorano J.L., Zaragoza C. Ivabradine-stimulated microvesicle release induces cardiac protection against acute myocardial infarction. Int. J. Mol. Sci. 2020; 21: 6566.

  17. Brown H., Dfirancesco D., Noble S. How does adrenaline accelerate the heart? Nature. 1979; 280: 235–236.

  18. Nikulina N.A., Dotsenko E.A., Nerovnya A.M., Salivonchik D.P., Platoshkin E.N., Nikolaeva N.V., Tishkov S.P. Experimental myocardial infarction in rats: features of modeling and course within the first 48 hours after coronary artery ligation. Problems of health and ecology. 2020; 2 (64): 91–96.

  19. Купцова А.М., Зиятдинова Н.И., Фасхутдинов Л.И., Биктемирова Р.Г., Зефиров Т.Л. Влияние HCN-каналов на работу изолированного сердца взрослых крыс. Ученые записки Казанского университета. Сер. Естественные науки. 2018; 160 (4): 568–578.

  20. Катруха И.А. Тропониновый комплекс сердца человека. Структура и функции. Успехи биол. химии. 2013; 53: 149–194.

  21. Abramochkin D.V., Faskhutdinov L.I., Filatova T.S., Ziyatdinova N.I. Changes in Electrical Activity of Working Myocardium Under Condition of I-f Current Inhibition. Bull. Exp. Biol. Med. 2015; 158 (5): 600–603.

Поступила в редакцию 20.06.2022; принята 22.07.2022.

 

Авторский коллектив

Купцова Анна Михайловна – кандидат биологических наук, доцент кафедры охраны здоровья человека, ФГАОУ ВО «Казанский (Приволжский) федеральный университет». 420008, Россия, г. Казань, ул. Кремлевская, 18; е-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0002-3592-6589

Бугров Роман Кутдусович – аспирант кафедры охраны здоровья человека, ФГАОУ ВО «Казанский (Приволжский) федеральный университет». 420008, Россия, г. Казань, ул. Кремлевская, 18; е-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0001-6801-8547

Зиятдинова Нафиса Ильгизовна – доктор биологических наук, профессор кафедры охраны здоровья человека, ФГАОУ ВО «Казанский (Приволжский) федеральный университет». 420008, Россия, г. Казань, ул. Кремлевская, 18; е-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0002-4503-7451

Зефиров Тимур Львович – доктор медицинских наук, профессор, заведующий кафедрой охраны здоровья человека, ФГАОУ ВО «Казанский (Приволжский) федеральный университет». 420008, Россия, г. Казань, ул. Кремлевская, 18; е-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0001-9557-1639

 

Образец цитирования

Купцова А.М., Бугров Р.К., Зиятдинова Н.И., Зефиров Т.Л. Острейшая стадия инфаркта миокарда: влияние блокады If на изолированное сердце крыс. Ульяновский медико-биологический журнал. 2022; 3: 106–119. DOI: 10.34014/2227-1848-2022-3-106-119.