Skip to main content

Advertisement

SpringerLink
Log in

TNF-α provokes electrical abnormalities in rat atrial myocardium via a NO-dependent mechanism

  • Ion channels, receptors and transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Stretch-induced depolarizations of cardiomyocytes, which are related to activity of mechano-gated cation channels (MGCs), can lead to serious arrhythmias. However, signaling pathways leading to activation of mechano-gated channels by stretch remain almost unexplored. Using standard sharp microelectrodes, the present study addresses the hypothesis that tumor necrosis factor-alpha (TNF-α) modulates stretch-induced electrophysiological abnormalities in rat atrial myocardium by a mechanism involving nitric oxide (NO)-dependent pathways. TNF-α (50 ng/ml) produced a marked prolongation of action potential, subsequently transforming into humplike depolarizations and, finally, leading to occurrence of arrhythmias. These effects developed slowly during 25 min of TNF-α application. Similar electrical effects were induced by stretching the preparations. A blocker of MGCs, Gd3+ (40 μM), completely abolished action potential (AP) prolongations and electrical abnormalities caused by TNF-α or stretch. Further, a donor of exogenous NO, S-nitroso-N-acetylpenicillamine SNAP (300 μM), evoked the same electrical abnormalities as TNF-α and tissue stretch. Both TNF-α and stretch failed to produce their typical effects after pretreatment of the preparations with the NO-synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME) (100 μM). Thus, the present study shows (i) that TNF-α and the NO-donor SNAP evoke MGC-mediated electrical abnormalities in rat atrial myocardium in the absence of stretch that is very similar to stretch-evoked electrical events and (ii) that the TNF-α-induced electrical abnormalities are mediated by NO synthase. In conclusion, our data suggest that NO is an endogenous modulator of MGCs and mediates proarrhythmic effects of TNF-α in mammalian organism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Alloatti G, Pennaa C, DeMartinoa A (1999) Role of nitric oxide and platelet-activating factor in cardiac alterations induced by tumor necrosis factor-a in the guinea-pig papillary muscle. Cardiovasc Res 41:611–619

    Article  PubMed  CAS  Google Scholar 

  2. Burchfield JS, Dong JW, Sakata Y, Gao F, Tzeng HP, Topkara VK, Entman ML, Sivasubramanian N, Mann DL (2010) The cytoprotective effects of tumor necrosis factor are conveyed through tumor necrosis factor receptor-associated factor 2 in the heart. Circ Heart Fail 3(1):157–164

    Article  PubMed  CAS  Google Scholar 

  3. Calabrese V, Cornelius C, Rizzarelli E, Owen JB, Dinkova-Kostova AT, Butterfield DA (2009) Nitric oxide in cell survival: a janus molecule. Antioxid Redox Signal 11:2717–2739

    Article  PubMed  CAS  Google Scholar 

  4. Casadei B, Sears CE (2003) Nitric-oxide-mediated regulation of cardiac contractility and stretch responses. Prog Biophys Mol Biol 82(1–3):67–80

    Article  PubMed  CAS  Google Scholar 

  5. Chen Y, Pat B, Zheng J, Cain L, Powell P, Shi K, Sabri A, Husain A, Dell'italia LJ (2010) Tumor necrosis factor-alpha produced in cardiomyocytes mediates a predominant myocardial inflammatory response to stretch in early volume overload. J Mol Cell Cardiol 49(1):70–78

    Article  PubMed  CAS  Google Scholar 

  6. Dean JW, Lab MJ (1989) Arrhythmia in heart failure: role of mechanically induced changes in electrophysiology. Lancet 1:1309–1312

    Article  PubMed  CAS  Google Scholar 

  7. Defer N, Azroyan A, Pecker F, Pavoine C (2007) TNFR1 and TNFR2 signaling interplay in cardiac myocytes. J Biol Chem 282(49):35564–35573

    Article  PubMed  CAS  Google Scholar 

  8. Dyachenko V, Rueckschloss U, Isenberg G (2009) Modulation of cardiac mechanosensitive ion channels involves superoxide, nitric oxide and peroxynitrite. Cell Calcium 45(1):55–64

    Article  PubMed  CAS  Google Scholar 

  9. Fan HC, Zhang X, McNaughton PA (2009) Activation of the TRPV4 ion channel is enhanced by phosphorylation. J Biol Chem 284(41):27884–27891

    Article  PubMed  CAS  Google Scholar 

  10. Fernández-Velasco M, Ruiz-Hurtado G, Hurtado O, Moro MA, Delgado C (2007) TNF-alpha downregulates transient outward potassium current in rat ventricular myocytes through iNOS overexpression and oxidant species generation. Am J Physiol Heart Circ Physiol 293(1):H238–H245

    Article  PubMed  Google Scholar 

  11. Feron O, Belhassen L, Kobzik L, Smith TW, Kelly RA, Michel T (1996) Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells. J Biol Chem 271:22810–22814

    Article  PubMed  CAS  Google Scholar 

  12. Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL (1992) Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 257(5068):387–389

    Article  PubMed  CAS  Google Scholar 

  13. Franz MR (1996) Mechano-electrical feedback in ventricular myocardium. Cardiovasc Res 32:15–24

    PubMed  CAS  Google Scholar 

  14. Goldhaber JI, Kim KH, Natterson PD, Lawrence T, Yang P, Weiss JN (1996) Effects of TNF-alpha on [Ca2+]i and contractility in isolated adult rabbit ventricular myocytes. Am J Physiol 271:H1449–H1455

    PubMed  CAS  Google Scholar 

  15. Hamill OP, Martinac B (2001) Molecular basis of mechanotransduction in living cells. Physiol Rev 81:685–740

    PubMed  CAS  Google Scholar 

  16. Hu H, Sachs F (1997) Stretch-activated ion channels in the heart. J Mol Cell Cardiol 29:1511–1523

    Article  PubMed  CAS  Google Scholar 

  17. Isenberg G, Kazanski V, Kondratev D, Gallitelli MF, Kiseleva I, Kamkin A (2003) Differential effects of stretch and compression on membrane currents and [Na+]c in ventricular myocytes. Prog Biophys Mol Biol 82(13):43–56

    Article  PubMed  CAS  Google Scholar 

  18. Kamkin A, Kiseleva I, Isenberg G (2000) Stretch-activated currents in ventricular myocytes: amplitude and arrhythmogenic effects increase with hypertrophy. Cardiovasc Res 48(3):409–420

    Article  PubMed  CAS  Google Scholar 

  19. Kamkin A, Kiseleva I, Isenberg G (2003) Ion selectivity of stretch-activated cation currents in mouse ventricular myocytes. Pflügers Arch 446(2):220–231

    PubMed  CAS  Google Scholar 

  20. Kamkin A, Kiseleva I, Wagner KD, Bohm J, Theres H, Günther J, Scholz H (2003) Characterization of stretch-activated ion currents in isolated atrial myocytes from human hearts. Pflügers Arch 446(3):339–346

    PubMed  CAS  Google Scholar 

  21. Kamkin A, Kiseleva I, Wagner KD, Leiterer KP, Theres H, Scholz H, Günther J, Lab MJ (2000) Mechano-electric feedback in right atrium after left ventricular infarction in rats. J Mol Cell Cardiol 32(3):465–477

    Article  PubMed  CAS  Google Scholar 

  22. Kamkin A, Kiseleva I, Wagner KD, Scholz H (2005) Mechano-electric feedback in the heart: evidence from intracellular microelectrode recordings on multicellular preparations and single cells from healthy and diseased tissue. In: Kamkin A, Kiseleva I (eds) Mechanosensitivity in cells and tissues. Academia, Moscow, pp 165–202

    Google Scholar 

  23. Kapadia SR, Oral H, Lee J, Nakano M, Taffet GE, Mann DL (1997) Hemodynamic regulation of tumor necrosis factor-alpha gene and protein expression in adult feline myocardium. Circ Res 81(2):187–195

    Article  PubMed  CAS  Google Scholar 

  24. Kazanski V, Kamkin A, Makarenko E, Lysenko N, Lapina N, Kiseleva I (2011) The role of nitric oxide in the regulation of mechanically gated channels in the heart. In: Kamkin A, Kiseleva I (eds) Mechanosensitivity in cells and tissues 4. Mechanosensitivity and mechanotransduction. Springer, Berlin, pp 109–140

    Google Scholar 

  25. Kazanski V, Kamkin A, Makarenko E, Lysenko N, Sutyagin PV, Bo T, Kiseleva IS (2010) Role of nitric oxide in activity control of mechanically gated ionic channels in cardiomyocytes: NO-donor study. Bull Exp Biol Med 150(1):1–5

    Article  PubMed  CAS  Google Scholar 

  26. Kazanski V, Kamkin A, Makarenko E, Lysenko N, Sutyagin PV, Kiseleva IS (2010) Role of nitric oxide in the regulation of mechanosensitive ionic channels in cardiomyocytes: contribution of NO-synthases. Bull Exp Biol Med 150(2):263–267

    Article  PubMed  CAS  Google Scholar 

  27. Kiseleva I, Kamkin A, Wagner KD, Theres H, Ladhoff A, Scholz H, Günther J, Lab MJ (2000) Mechanoelectric feedback after left ventricular infarction in rats. Cardiovasc Res 45(2):370–378

    Article  PubMed  CAS  Google Scholar 

  28. Kondratev D, Gallitelli MF (2003) Increments in the concentration of sodium and calcium in cell compartments of stretched mouse ventricular myocytes. Cell Calcium 34:193–203

    Article  PubMed  CAS  Google Scholar 

  29. Lab MJ (1969) The effect on the left ventricular action potential of clamping the aorta. J Physiol 202(2):73P–74P

    PubMed  CAS  Google Scholar 

  30. Lab MJ (1996) Mechanoelectric feedback (transduction) in heart: concepts and implications. Cardiovasc Res 32:3–14

    PubMed  CAS  Google Scholar 

  31. Lal H, Verma SK, Golden HB, Foster DM, Holt AM, Dostal DE (2010) Molecular signaling mechanisms of myocardial stretch: implications for heart disease. In: Kamkin A, Kiseleva I (eds) Mechanosensitivity in cells and tissues 3. Mechanosensitivity of the heart. Springer, Berlin, pp 55–81

    Google Scholar 

  32. Lammerding J, Kamm PD, Lee RT (2004) Mechanotransduction in cardiac myocytes. Ann N Y Acad Sci 1015:53–70

    Article  PubMed  Google Scholar 

  33. Lozinsky I, Kamkin A (2010) Mechanosensitive alterations of action potentials and membrane currents in healthy and diseased cardiomyocytes: cardiac tissue and isolated cell. In: Kamkin A, Kiseleva I (eds) Mechanosensitivity in cells and tissues 3. Mechanosensitivity of the heart. Springer, Berlin, pp 185–238

    Google Scholar 

  34. Nakayama H, Bodi I, Correll RN, Chen X, Lorenz J, Houser SR, Robbins J, Schwartz A, Molkentin JD (2009) alpha1G-dependent T-type Ca2+ current antagonizes cardiac hypertrophy through a NOS3-dependent mechanism in mice. J Clin Invest 119(12):3787–3796

    Article  PubMed  CAS  Google Scholar 

  35. Nazir SA, Lab MJ (1996) Mechanoelectric feedback and atrial arrhythmias. Cardiovasc Res 32:52–61

    PubMed  CAS  Google Scholar 

  36. Nieto-Posadas A, Jara-Oseguera A, Rosenbaum T (2011) TRP channel gating physiology. Curr Top Med Chem 11(17):2131–2150

    Article  PubMed  CAS  Google Scholar 

  37. Petkova-Kirova PS, Gursoy E, Mehdi H, McTiernan CF, London B, Salama G (2006) Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-alpha. Am J Physiol Heart Circ Physiol 290(5):H2098–H2107

    Article  PubMed  CAS  Google Scholar 

  38. Ravens U (2003) Mechano-electric feedback and arrhythmias. Prog Biophys Mol Biol 82(1–3):255–266

    Article  PubMed  Google Scholar 

  39. Sato H, Watanabe A, Tanaka T, Koitabashi N, Arai M, Kurabayashi M, Yokoyama T (2003) Regulation of the human tumor necrosis factor-alpha promoter by angiotensin II and lipopolysaccharide in cardiac fibroblasts: different cis-acting promoter sequences and transcriptional factors. J Mol Cell Cardiol 35(10):1197–1205

    Article  PubMed  CAS  Google Scholar 

  40. Seddon M, Shah AM, Casadei B (2007) Cardiomyocytes as effectors of nitric oxide signalling. Cardiovasc Res 75(2):315–326

    Article  PubMed  CAS  Google Scholar 

  41. Shah AM, MacCarthy PA (2000) Paracrine and autocrine effects of nitric oxide on myocardial function. Pharmacol Ther 86(1):49–86

    Article  PubMed  CAS  Google Scholar 

  42. Tamargo J, Caballero R, Gomez R, Delpon E (2010) Cardiac electrophysiological effects of nitric oxide. Cardiovasc Res 87:593–600

    Article  PubMed  CAS  Google Scholar 

  43. Wang M, Tsai BM, Crisostomo PR, Meldrum DR (2006) Tumor necrosis factor receptor 1 signaling resistance in the female myocardium during ischemia. Circulation 114(1 Suppl):I282–I289

    PubMed  Google Scholar 

  44. Wang J, Wang H, Zhang Y, Gao H, Nattel S, Wang Z (2004) Impairment of HERG K+channel function by tumor necrosis factor-alpha: role of reactive oxygen species as a mediator. J Biol Chem 279(14):13289–13292

    Article  PubMed  CAS  Google Scholar 

  45. Ward M-L, David G, Allen DG (2010) Stretch-activated channels in the heart: contribution to cardiac performance. In: Kamkin A, Kiseleva I (eds) Mechanosensitivity in cells and tissues 3. Mechanosensitivity of the heart. Springer, Berlin, pp 141–167

    Google Scholar 

  46. Ward H, White E (1994) Reduction in the contraction and intracellular calcium transient of single rat ventricular myocytes by gadolinium and the attenuation of these effects by extracellular NaH2PO4. Exp Physiol 79:107–110

    PubMed  CAS  Google Scholar 

  47. Yokoyama T, Vaca L, Rossen RD, Durante W, Hazarika P, Mann DL (1993) Cellular basis for the negative inotropic effects of tumor necrosis factor-α in the adult mammalian cardiac myocytes. J Clin Invest 92(5):2303–2312

    Article  PubMed  CAS  Google Scholar 

  48. Zeng T, Bett GCL, Sachs F (2000) Stretch-activated whole cell currents in adult rat cardiac myocytes. Am J Physiol 278:H548–H557

    CAS  Google Scholar 

  49. Zhang YH, Youm JB, Sung HK, Lee SH, Ryu SY, Ho WK, Earm YE (2000) Stretch-activated and background non-selective cation channels in rat atrial myocytes. J Physiol 523:607–619

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Russian Foundation for Basic Research (grant no. 12-04-00390-a). The Department of Fundamental and Applied Physiology (Professor and Chairman—Andre Kamkin) was supported by the Ministry of Education and Science of the Russian Federation. The Order of Ministry of Education and Science of the Russian Federation No. 743 from 01 July 2010, Supplement, Event 4.4, the Period of Financing 2010–2019 also supported this work. This study was supported by the German Federal Ministry of Education and Research [01DJ12024 to R.S. and A.G.K.].

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Fundamental and Applied Physiology, Russian National Research Medical University, Ostrovitjanova 1, Moscow, 117997, Russia

    Denis V. Abramochkin, Vladislav S. Kuzmin, Vadim M. Mitrochin, Leonid Kalugin, Anton Dvorzhak, Ekaterina Y. Makarenko & Andre Kamkin

  2. Department of Human and Animal Physiology, Moscow State University, Leninskie gory 1, Building 12, Moscow, 119991, Russia

    Denis V. Abramochkin & Vladislav S. Kuzmin

  3. Synaptic Dysfunction Group, Exzellenzcluster Neurocure, Abt. Exp. Neurologie, Charité–Universitätsmedizin, Robert-Koch-Platz 4, 10115, Berlin, Germany

    Anton Dvorzhak

  4. Centre for Biomedicine and Medical Technology Mannheim (CBTM), Research Division Cardiovascular Physiology, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany

    Rudolf Schubert

  5. Lomonosov Moscow State University, Leninskie Gory, 1, Building 12, 119991, Moscow, Russia

    Denis V. Abramochkin

Authors
  1. Denis V. Abramochkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vladislav S. Kuzmin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vadim M. Mitrochin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leonid Kalugin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anton Dvorzhak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ekaterina Y. Makarenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rudolf Schubert
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andre Kamkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Denis V. Abramochkin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abramochkin, D.V., Kuzmin, V.S., Mitrochin, V.M. et al. TNF-α provokes electrical abnormalities in rat atrial myocardium via a NO-dependent mechanism. Pflugers Arch - Eur J Physiol 465, 1741–1752 (2013). https://doi.org/10.1007/s00424-013-1320-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-013-1320-2

Keywords

Search

Navigation