Skip to main content
SpringerLink
Log in

The Funny Current

Cellular Basis for the Control of Heart Rate

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

The ‘funny’ (pacemaker, If) current, first described almost 30 years ago in sinoatrial node (SAN) myocytes, is a mixed sodium/potassium inward current, activated on hyperpolarisation in the diastolic range of voltages. ‘Funny’ (f) channels are activated by intracellular cyclic adenosine monophosphate (cAMP) concentrations according to a mechanism mediating regulation of heart rate by the autonomic nervous system, as well as by voltage hyperpolarisation. Structural subunits of native f-channels are the hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels; of the four HCN isoforms known, HCN4 is the most highly expressed in SAN tissue.

The If current is a natural target in the search for drugs aimed specifically at affecting heart rate, given its function in pacemaking. Increased heart rate has a negative influence on clinical outcome in patients with cardiovascular disease, and indeed is also an established risk factor for cardiovascular and all-cause mortality in the general population. Clearly, therefore, independent reduction of heart rate, through inhibition of the If current, appears to be a suitable therapeutic option for patients with ischaemic heart disease.

β-Adrenoceptor antagonists (β-blockers) reduce intracellular cAMP levels, and a substantial part of their negative chronotropic effect is therefore attributable to a reduction of the If current. However, neither β-blockers nor Ca2+ channel antagonists, both of which have traditionally been used to reduce myocardial ischaemia, are ‘pure’ heart rate-lowering drugs. These agents may, in fact, have adverse cardiovascular and noncardiovascular effects.

Conversely, the novel heart rate-reducing agent ivabradine is a specific blocker of f-channels, hence a selective inhibitor of the pacemaker If current in the SAN. Ivabradine slows heart rate by reducing the If current-regulated steepness of the diastolic depolarisation in SAN myocytes, thereby increasing diastolic duration, without altering action potential duration or causing negative inotropy. As such, ivabradine is particularly useful in patients with chronic stable angina pectoris.Further clinical studies are ongoing to evaluate the efficacy of ivabradine in patients with coronary heart disease, left ventricular dysfunction and heart failure.

This short article reviews the current state of knowledge of the properties of the ‘funny’ current in relation to exploitation of the If function in pacemaking generation and modulation for the pharmacological control of heart rate.

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
Table I
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 1993; 55: 455–72

    Article  PubMed  CAS  Google Scholar 

  2. Barbuti A, Baruscotti M, DiFrancesco D. The pacemaker current: from basics to the clinics. J Cardiovasc Electrophysiol 2007; 18(3): 342–7

    Article  PubMed  Google Scholar 

  3. Benetos A, Rudnichi A, Thomas F, et al. Influence of heart rate on mortality in a French population: role of age, gender, and blood pressure. Hypertension 1999; 33(1): 44–52

    Article  PubMed  CAS  Google Scholar 

  4. Chang M, Havlik RJ, Corti MC, et al. Relation of heart rate at rest and mortality in the Women's Health and Aging Study. Am J Cardiol 2003; 92(11): 1294–9

    Article  PubMed  Google Scholar 

  5. Goldberg RJ, Larson M, Levy D. Factors associated with survival to 75 years of age in middle-aged men and women: the Framingham Study. Arch Intern Med 1996; 156(5): 505–9

    Article  PubMed  CAS  Google Scholar 

  6. Jouven X, Empana JP, Schwartz PJ, et al. Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med 2005; 352(19): 1951–8

    Article  PubMed  CAS  Google Scholar 

  7. Shattock M, Camm JA. Pure heart rate reduction: the If channels from discovery to therapeutic target. Br J Cardiol 2006; 13(1): 27–35

    Google Scholar 

  8. Ferrari R. Selective heart rate reduction: a new approach to the management of angina pectoris. Medicographia 2002; 24: 201–10

    Google Scholar 

  9. Diaz A, Bourassa MG, Guertin MC, et al. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J 2005; 26(10): 967–74

    Article  PubMed  Google Scholar 

  10. Diaz A, Tardif JC. Clinical applications of exclusive heart rate reduction in emergency cardiology. Medicographia 2005; 27: 82–5

    Google Scholar 

  11. Fox K, Ferrari R, Tendera M, et al. Rationale and design of a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction: the morBidity-mortality EvAlUaTion of the I(f) inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) study. Am Heart J 2006; 152(5): 860–6

    Article  PubMed  CAS  Google Scholar 

  12. DiFrancesco D. The pacemaker current (I(f)) plays an important role in regulating SA node pacemaker activity. Cardiovasc Res 1995; 30(2): 307–8

    PubMed  CAS  Google Scholar 

  13. DiFrancesco D. The onset and autonomic regulation of cardiac pacemaker activity: relevance of the f current. Cardiovasc Res 1995; 29(4): 449–56

    PubMed  CAS  Google Scholar 

  14. Brown HF, DiFrancesco D, Noble SJ. How does adrenaline accelerate the heart? Nature 1979; 280(5719): 235–6

    Article  PubMed  CAS  Google Scholar 

  15. Baruscotti M, Bucchi A, DiFrancesco D. Physiology and pharmacology of the cardiac pacemaker (“funny”) current. Pharmacol Ther 2005; 107(1): 59–79

    Article  PubMed  CAS  Google Scholar 

  16. Dobrzynski H, Nikolski VP, Sambelashvilli AT, et al. Site of origin and molecular substrate of atrioventricular junctional rhythm in the rabbit heart. Circ Res 2003; 93(11): 1102–10

    Article  PubMed  CAS  Google Scholar 

  17. Munk AA, Adjemian RA, Zhao J, et al. Electrophysiological properties of morphologically distinct cells isolated from the rabbit atrioventricular node. J Physiol 1996; 493: 801–18

    PubMed  CAS  Google Scholar 

  18. Shi W, Wymore R, Yu H, et al. Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ Res 1999; 85: e1–6

    Article  PubMed  CAS  Google Scholar 

  19. Bucchi A, Baruscotti M, Robinson RB, et al. Modulation of rate by autonomic agonists in SAN cells involves changes in diastolic depolarization and the pacemaker current. J Mol Cell Cardiol 2007; 43: 39–48

    Article  PubMed  CAS  Google Scholar 

  20. Lipsius SL, Huser J, Blatter LA. Intracellular Ca2+ release sparks atrial pacemaker activity. News Physiol Sci 2001; 16: 101–6

    PubMed  CAS  Google Scholar 

  21. DiFrancesco D, Noble D. A model of cardiac electrical activity incorporating ionic pumps and concentration changes. Phil Trans R Soc Lond 1985; 307: 353–98

    Article  CAS  Google Scholar 

  22. Robinson RB, Siegelbaum SA. Hyperpolarization-activated cation current: form molecules to physiological function. Annu Rev Physiol 2003; 65: 453–80

    Article  PubMed  CAS  Google Scholar 

  23. Altomare C, Terragni B, Brioschi C, et al. Heteromeric HCN1-HCN4 channels: a comparison with native pacemaker channels form the rabbit sinoatrial node. J Physiol 2003; 549(2): 347–59

    Article  PubMed  CAS  Google Scholar 

  24. Moroni A, Gorza L, Beltrame M, et al. Hyperpolarization-activated cyclic nucleotide-gated channel 1 is a molecular determinant of the cardiac pacemaker current I(f). J Biol Chem 2001; 276(31): 29233–41

    Article  PubMed  CAS  Google Scholar 

  25. Santoro B, Liu DT, Yao H, et al. Identification of a gene encoding a hyperpolarization-activated pacemaker channels of brain. Cell 1998; 93: 717–29

    Article  PubMed  CAS  Google Scholar 

  26. DiFrancesco D, Ducouret P, Robinson RB. Muscarinic modulation of cardiac rate at low acetylcholine concentrations. Science 1989; 243: 669–71

    Article  PubMed  CAS  Google Scholar 

  27. DiFrancesco D, Tortora P. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature 1991; 351(6322): 145–7

    Article  PubMed  CAS  Google Scholar 

  28. DiFrancesco D. Sinoatrial If current: a target for specific heart rate reduction. Medicographia 2002; 24: 218–24

    Google Scholar 

  29. Ishii T, Takano M, Xie LH, et al. Molecular characterization of the hyperpolarization-activated cation channel in rabbit heart sinoatrial node. J Biol Chem 1999; 274: 12835–9

    Article  PubMed  CAS  Google Scholar 

  30. Ludwig A, Zong X, Jeglitsch M, et al. A family of hyperpolarization-activated mammalian cation channels. Nature 1998; 393: 587–91

    Article  PubMed  CAS  Google Scholar 

  31. Scifert R, Scholten A, Gauss R, et al. Molecular characterization of a slowly gating human hyperpolarization-activated channel predominately expressed in thalamus, heart, and testis. PNAS 1999; 96: 9391–6

    Article  Google Scholar 

  32. Vaccari T, Moroni A, Rocchi M, et al. The human gene encoding coding for HCN2, a pacemaker channel of the heart. Biochim Biophys Acta 1999; 1446: 419–25

    Article  PubMed  CAS  Google Scholar 

  33. Fox K. Future perspectives of If inhibition in various cardiac conditions. Eur Heart J 2005; 7 Suppl. H: H33–6

    Article  CAS  Google Scholar 

  34. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective If current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs 2004; 64(16): 1757–65

    Article  PubMed  CAS  Google Scholar 

  35. Rosen MR, Bucchi A, Robinson RB. If modulation: perspectives in clinical medicine. Eur Heart J 2006; 8 Suppl. D: D3–8

    Article  CAS  Google Scholar 

  36. Borer JS. Drug insight: If inhibitors as specific heart-rate-reducing agents. Nat Clin Pract Cardiovasc Med 2004; 1(2): 103–9

    Article  PubMed  CAS  Google Scholar 

  37. Sulfi S, Timmis AD. Ivabradine: the first selective sinus node I(f) channel inhibitor in the treatment of stable angina. Int J Clin Pract 2006; 60(2): 222–8

    Article  PubMed  CAS  Google Scholar 

  38. Eisenberg MJ, Brox A, Bestawros A. Calcium channel blockers: an update. Am J Med 2004; 116(1): 35–43

    Article  PubMed  CAS  Google Scholar 

  39. Ravens U, Wettwer E, Hala O. Pharmacological modulation of ion channels and transporters. Cell Calcium 2004; 35(6): 572–82

    Article  Google Scholar 

  40. DiFrancesco D. Serious workings of the funny current. Prog Biophys Mol Biol 2006; 90(1–3): 13–25

    Article  PubMed  CAS  Google Scholar 

  41. Borer JS. Clinical effect of ‘pure’ heart rate slowing with a prototype If current inhibitor: placebo-controlled experience with ivabradine. Adv Cardiol 2006; 43: 54–64

    Article  PubMed  CAS  Google Scholar 

  42. Kobinger W, Lillie C, Pichler L. Cardiovascular actions of N-allyl-clonidine (ST-567), a substance with specific bradycardic action. Eur J Pharmacol 1979; 58: 141–50

    Article  PubMed  CAS  Google Scholar 

  43. Kobinger W, Lillie C, Pichler L. N-allyl-derivative of clonidine, a substance with specific bradycardic action at a cardiac site. Naunyn Schmiedebergs Arch Pharmacol 1979; 306: 255–62

    Article  PubMed  CAS  Google Scholar 

  44. DiFrancesco D. Some properties of the UL-FS 49 block of the hyperpolarization-activated (If) current in SA node myocytes. Pflugers Arch 1994; 427: 64–70

    Article  PubMed  CAS  Google Scholar 

  45. van Bogaert P, Goethals M, Simoens C. Use- and frequency-dependent blockade by Ul-FS 49 of the If pacemaker current in sheep cardiac Purkinje fibres. Eur J Pharmacol 1990; 187: 241–56

    Article  PubMed  Google Scholar 

  46. Satoh H, Hashimoto K. Electrophysiological study of alinidine in voltage clamped rabbit sino-atrial node cells. Euro J Pharmacol 1986; 121(2): 211–9

    Article  CAS  Google Scholar 

  47. Doerr T, Trautwein W. On the mechanism of the “specific bradycardiac action” of the verapamil derivative UL-FS 49. Naunyn Schmiedebergs Arch Pharmacol 1990; 341(4): 331–40

    Article  PubMed  CAS  Google Scholar 

  48. Millar JS, Williams EM. Pacemaker selectivity: influence on rabbit atria of ionic environment and of alinidine, a possible anion antagonist. Cardiovasc Res 1981; 15(6): 335–50

    Article  PubMed  CAS  Google Scholar 

  49. Aidonidis I, Brachmann J, Rizos I, et al. Electropharmacology of the bradycardic agents alinidine and zatebradine (UL-FS 49) in a conscious canine ventricular arrhythmia model of permanent coronary artery occlusion. Cardiovasc Drugs Ther 1995; 9(4): 555–63

    Article  PubMed  CAS  Google Scholar 

  50. Borer JS. If inhibition as a therapeutic approach in stable angina: experimental and clinical studies. Medicographia 2005; 27: 44–50

    Google Scholar 

  51. Frishman WH, Pepine CJ, Weiss RJ, et al. Addition of zatebradine, a direct sinus node inhibitor, provides no greater exercise tolerance benefit in patients with angina taking extended-release nifedipine: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The Zatebradine Study Group. J Am Coll Cardiol 1995; 26(2): 305–12

    Article  CAS  Google Scholar 

  52. Purcell H, Fox K. Selective and specific If inhibition: new perspectives. Medicographia 2005; 27: 51–4

    Google Scholar 

  53. Vilaine JP. The discovery of the selective If current inhibitor ivabradine: a new therapeutic approach to ischemic heart disease. Pharmacol Res 2006; 53: 424–34

    Article  PubMed  CAS  Google Scholar 

  54. Bucchi A, Baruscotti M, DiFrancesco D. Current-dependent block of rabbit sino-atrial node I(f) channels by ivabradine. J Gen Physiol 2002; 120(1): 1–13

    Article  PubMed  CAS  Google Scholar 

  55. DiFrancesco D. Cardiac pacemaker I(f) current and its inhibition by heart rate-reducing agents. Curr Med Res Opin 2005; 21(7): 1115–22

    Article  PubMed  CAS  Google Scholar 

  56. Bucchi A, Tognati A, Milanesi R, et al. Properties of ivabradine-induced block of HCN1 and HCN4 pacemaker channels. J Physiol 2006; 572 (Pt 2): 335–46

    Article  PubMed  CAS  Google Scholar 

  57. Baruscotti M, DiFrancesco D. Pacemaker channels. Ann N Y Acad Sci 2004; 1015: 111–21

    Article  PubMed  Google Scholar 

  58. Borer JS, Fox K, Jaillon P, et al. Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation 2003; 107(6): 817–23

    Article  PubMed  Google Scholar 

  59. Lopez-Bescos L, Fillpova S, Martoa R. Long-term safety and antianginal efficacy of the If current inhibitor ivabradine in patients with chronic stable angina: a one-year randomised, double-blind, multicentre trial [abstract 876]. Eur Heart J 2004; 25 Suppl.: 138

    Google Scholar 

  60. Ruzyllo W, Ford IF, Tendera MT, et al. Anti-anginal and anti-ischaemic effects of the If current inhibitor ivabradine compared to amlodipine as monotherapies in patients with chronic stable angina. Randomised, controlled, double-blind trial [abstract 878]. Eur Heart J 2004; 25 Suppl.: 138

    Google Scholar 

  61. Tardif JC, Ford I, Tendera M, et al. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005; 26(23): 2529–36

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The preparation of this manuscript was supported by Servier. Professor DiFrancesco wishes to declare that Servier has provided support for research activity in his laboratory. Professor Borer is a paid consultant to Servier Laboratoires, the manufacturer of ivabradine. Editorial support for the preparation of the manuscript was provided by Wolters Kluwer Health Medical Communications.

Author information

Authors and Affiliations

  1. Department of Biomolecular Sciences and Biotechnology, Laboratory of Molecular Physiology and Neurobiology, University of Milan, via Celoria 26, Milan, 20133, Italy

    Dario DiFrancesco

  2. Division of Cardiovascular Pathophysiology, New York Presbyterian Hospital-Weill Cornell Center, New York, New York, USA

    Jeffrey S. Borer

Authors
  1. Dario DiFrancesco
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey S. Borer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dario DiFrancesco.

Rights and permissions

Reprints and permissions

About this article

Cite this article

DiFrancesco, D., Borer, J.S. The Funny Current. Drugs 67 (Suppl 2), 15–24 (2007). https://doi.org/10.2165/00003495-200767002-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-200767002-00003

Keywords

Search

Navigation