Skip to main content

Advertisement

Log in

Age-related down-regulation of HCN channels in rat sinoatrial node

  • ORIGINAL CONTRIBUTION
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Aging is associated with deteriorated sinoatrial (SA) node function. The pacemaker current (If) carried by hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels plays a key role in the generation of spontaneous activity of the SA node cells. In the present study, the SA node cells were identified and isolated using the laser capture microdissection (LCM) technique for quantitative analysis of the HCN channel isoforms HCN1-HCN4 transcripts. Using real-time quantitative reverse transcription- polymerase chain reaction (RT-PCR), marked down-regulated transcriptions of HCN2 and HCN4 were observed in the SA node from young (1-month-old) to adult (4-month-old) and further to aged (30- month-old) rats. However, neither the HCN1 nor HCN3 transcript was detectable throughout the lifespan of the rat. Consistently, the effect of 2 mM Cs+ to selectively block the HCN channels, on pacemaking was also lessened with age. Our findings raise the possibility that the down-regulated transcription and relative function of HCN channels may contribute to the decline of the SA node function in aged rats.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Accili EA, Proenza C, Baruscotti M, DiFrancesco D (2002) From funny current to HCN channels: 20 years of excitation. News Physiol Sci 17:2–7

    Google Scholar 

  2. Alings AM, Bouman LN (1993) Electrophysiology of the ageing rabbit and cat sinoatrial node – a comparative study. Eur Heart J 14:1278–1288

    PubMed  CAS  Google Scholar 

  3. Bonner RF, Emmert-Buck M, Cole K, Pohida T,Chuaqui R,Goldstein S,Liotta LA (1997) Laser capture microdissection: molecular analysis of tissue. Science 278:1481–1483

    Article  PubMed  CAS  Google Scholar 

  4. Clapham DE (1998) Not so funny anymore: pacing channels are cloned. Neuron 21:5–7

    Article  PubMed  CAS  Google Scholar 

  5. Curran S,McKay JA,McLeod HL,Murray GI (2000) Laser capture microscopy. Mol Pathol 53:64–68

    Article  PubMed  CAS  Google Scholar 

  6. DiFrancesco D (1993) Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 55:455–472

    Article  PubMed  CAS  Google Scholar 

  7. Di Gennaro M, Bernabei R, Sgadari A, Carosella L, Carbonin PU (1987) Agerelated differences in isolated rat sinus node function. Basic Res Cardiol 82:530–536

    Article  PubMed  CAS  Google Scholar 

  8. Emmert-Buck MR, Bonner RF, Smith PD, Chuaqui RF, Zhuang Z, Goldstein SR, Weiss RA, Liotta LA (1996) Laser capture microdissection. Science 274:998–1001

    Article  PubMed  CAS  Google Scholar 

  9. Fend F, Emmert-Buck MR, Chuaqui R, Cole K, Lee J, Liotta LA, Raffeld M (1999) Immuno-LCM: laser capture microdissection of immunostained frozen sections for mRNA analysis. Am J Pathol 154:61–66

    PubMed  CAS  Google Scholar 

  10. Gregoratos G (1999) Permanent pacemakers in older persons. J Am Geriatr Soc 47:1125–1135

    PubMed  CAS  Google Scholar 

  11. Ishii TM, Takano M, Xie LH, Noma A, Ohmori H (1999) Molecular characterization of the hyperpolarization-activated cation channel in rabbit heart sinoatrial node. J Biol Chem 274:12835–12839

    Article  PubMed  CAS  Google Scholar 

  12. Josephson ME (1993) Clinical cardiac electrophysiology: techniques and interpretations, 2nd ed. Lea and Febeger, Philadelphia

    Google Scholar 

  13. Lei M, Brown HF (1996) Two components of the delayed rectifier potassium current, IK, in rabbit sino-atrial node cells. Exp Physiol 81:725–741

    PubMed  CAS  Google Scholar 

  14. Livak K, Schmittgen T (2001) Analysis of relative gene expression data using real-time quantitative pcr and the 2–ΔΔCt method. Methods 25:402–440

    Article  PubMed  CAS  Google Scholar 

  15. Ludwig A, Zong X, Jeglitsch M, Hofmann F, Biel M (1998) A family of hyperpolarization- activated mammalian cation channels. Nature 393:587–591

    Article  PubMed  CAS  Google Scholar 

  16. Ludwig A, Zong X, Stieber J, Hullin R, Hofmann F, Biel M (1999) Two pacemaker channels from human heart with profoundly different activation kinetics. EMBO J 18:2323–2329

    Article  PubMed  CAS  Google Scholar 

  17. Ludwig A, Budde T, Stieber J, Moosmang S,Wahl C, Holthoff K, Langebartels A,Wotjak C,Munsch T, Zong X, Feil S, Feil R, Lancel M, Chien KR,Konnerth A, Pape HC, Biel M, Hofmann F (2003) Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2. EMBO J 22:216–224

    Article  PubMed  CAS  Google Scholar 

  18. Moosmang S, Stieber J, Zong X, Biel M, Hofmann F, Ludwig A (2001) Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. Eur J Biochem 268:1646–1652

    Article  PubMed  CAS  Google Scholar 

  19. Nazarian J,Bouri K,Hoffman EP (2005) Intracellular expression profiling by laser capture microdissection: three novel components of the neuromuscular junction. Physiol Genomics 21:70–80

    Article  PubMed  CAS  Google Scholar 

  20. Pucelik, Bartak F (1981) Postnatal development of electrophysiological properties of pacemaker cells in the rabbit. Physiol Bohemoslov 30:41–46

    PubMed  CAS  Google Scholar 

  21. Robinson RB, Siegelbaum SA (2003) Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol 65:453–480

    Article  PubMed  CAS  Google Scholar 

  22. Rosati B, McKinnon D (2004) Regulation of ion channel expression. Circ Res 94:874–883

    Article  PubMed  CAS  Google Scholar 

  23. Safa-Tisseront V, Ponchon P, Laude D, Elghozi JL (1998) Contribution of the autonomic nervous system to blood pressure and heart rate variability changes in early experimental hyperthyroidism. Eur J Pharmacol 352:247–255

    Article  PubMed  CAS  Google Scholar 

  24. Santoro B, Liu DT, Yao H, Bartsch D, Kandel ER, Siegelbaum SA, Tibbs GR (1998) Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. Cell 93:717–729

    Article  PubMed  CAS  Google Scholar 

  25. Schmidlin O, Bharati S,Lev M, Schwartz JB (1992) Effects of physiological aging on cardiac electrophysiology in perfused Fischer 344 rat hearts. Am J Physiol 262:H97–H105

    PubMed  CAS  Google Scholar 

  26. Schulze-Bahr E, Neu A, Friederich P, Kaupp UB, Breithardt G, Pongs O, Isbrandt D (2003) Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Invest 111:1537–1545

    Article  PubMed  CAS  Google Scholar 

  27. Seifert R, Scholten A, Gauss R, Mincheva A,Lichter P,Kaupp UB (1999) Molecular characterization of a slowly gating human hyperpolarizationactivated channel predominantly expressed in thalamus, heart, and testis. Proc Natl Acad Sci USA 96:9391–9396

    Article  PubMed  CAS  Google Scholar 

  28. Shi W, Wymore R, Yu H,Wu J, Wymore RT, Pan Z, Robinson RB, Dixon JE, McKinnon D,Cohen IS (1999) Distribution and prevalence of hyperpolarization- activated cation channel (HCN) mRNA expression in cardiac tissues. Circ Res 85:e1–6

    PubMed  CAS  Google Scholar 

  29. Specht K, Richter T,Muller U,Walch A, Werner M,Hofler H (2001) Quantitative gene expression analysis in microdissected archival formalin-fixed and paraffin-embedded tumor tissue. Am J Pathol 158:419–429

    PubMed  CAS  Google Scholar 

  30. Stieber J, Herrmann S, Feil S, Loster J, Feil R, Biel M, Hofmann F, Ludwig A (2003) The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart. Proc Natl Acad. Sci USA 100:15235–15240

    Article  PubMed  CAS  Google Scholar 

  31. Stieber J, Hofmann F, Ludwig A (2004) Pacemaker channels and sinus node arrhythmia. Trends Cardiovasc Med 14:23–28

    Article  PubMed  CAS  Google Scholar 

  32. Toda N (1980) Age-related changes in the transmembrane potential of isolated rabbit sino-atrial nodes and atria. Cardiovasc Res 14:58–63

    Article  PubMed  CAS  Google Scholar 

  33. Zorn-Pauly K, Schaffer P, Pelzmann B, Bernhart E, Lang P, Zink M,Machler H, Rigler B, Koidl B (2003) A hyperpolarization activated inward current (If) is present in infant ventricular myocytes. Basic Res Cardiol 98:362–366

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A. Ma MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, X., Yang, P., Du, Y. et al. Age-related down-regulation of HCN channels in rat sinoatrial node. Basic Res Cardiol 102, 429–435 (2007). https://doi.org/10.1007/s00395-007-0660-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-007-0660-5

Key words

Navigation