Pace-maker f-channels of sinus node myocytеs as a new therapeutic target for heart rate reduction
Abstract
Heart pace-maker activity is controlled by highly specialized sinus node (SN) myocytes. This control is linked to functional activity of f-channels providing Na+ and К+ If current. F-channels are activated by plasmatic membrane hyperpolarization in pace-maker cells, at diastolic values of membrane potential. Recent experiments have demonstrated that If current activates slow diastolic depolarization (DD) and regulates the rate of this process, together with endogenous neuromediators and exogenous chemical agents. Decrease in the quantity of open f-channels reduces If current, DD rate and increases threshold membrane potential time. As the result, heart rate (HR) decreases. If current is also controlled by cAMP binding to f-channel proteins. cAMP level in SN myocyte cytoplasma is influenced by autonomous nervous system (ANS) neuromediators. This is the mechanism for ANS regulation of HR in physiological settings. Search for chemical agents selectively targeting f-channels resulted in the development of a new medication, ivabradine (Coraxan®), which is used for angina treatment in patients with sinus rhythm. The medication decreases HR by If current reduction and DD time increase. Importantly, ivabradine does not affect other ion channels.
About the Authors
E. I. Astashkin
I.M. Sechenov Moscow Medical Academy, Moscow
Russian Federation
Russian Federation
M. G. Glezer
I.M. Sechenov Moscow Medical Academy, Moscow
Russian Federation
Russian Federation
References
1. Brown HF, DiFrancesco D, Nooble SJ. How does adrenaline accelerate the heart? Nature 1979; 280: 235-6.
2. DiFrancesco D. Sinoatrial If current: a target for specific heart rate reduction. Medicographia 2002; 24(3): 218-24.
3. Irisawa H, Brown HF, Giles W. Cardiac pacemaking in sinoatrial node. Physiol Rev 1993; 73: 197-227.
4. Zhang H, Holden AV, Kodama I, et al. Mathematical models of action potentials in the periphery and center of the rabbit sinoa trial node. Am J Physiol 2000; 279: H397-421.
5. Lipsius SL, Husser J, Blatter LA. Intracellular Ca2+ release sparks atrial pacemaker activity. New Physiol Sci 2001; 16: 101-6.
6. DiFrancesco D. If current: state of the art. In “Selective & Specific If Inhibition in Cardiovascular Disease” Eds. By Singh B.N., Vanhoutte P.M., 2003, pp. 3-10, Lippincott Williams & Wilkins.
7. Zaza A, Rocchetti M. Regulation of the sinoatrial pacemaker: selective If inhibition by ivabradine// In: Fox K, Ferrari R. (Eds) Heart Rate Management in Stable Angina. Taylor& Francis Group, London and New York 2005; 51-67.
8. Shattock MJ, Curtis MJ. The role of If in the regulation of heart rate. Medicographia 2006; 28(3): 224-31.
9. Lakatta EG, Houser SR. Myocyte dysfunction in Heart Failure. Science & Medicine 1999: July/August: 8-17.
10. DiFrancesco D. If inhibition: a novel mechanism of action. Eur Heart J 2003; 5 (Suppl G): G19-25.
11. DiFrancesco D. Funny channels in control of cardiac rhythm and mode of action of selective blockers. Pharmacol Res 2006; 53: 399-406.
12. Thollon C, Bedut S, Villeneuve N, Coge F. Use-dependent inhi bition of hHCN4 by ivabradine and relationship with reduction in pacemaker activity. Br J Pharmacol 2007; 150: 37 46.
13. Barbuti A, Gravante B, Riolfo M, et al. Localization of pacemaker channels in lipid rafts regulates channel kinetics. Circ Res 2004; 94: 1325-31.
14. Ludwig A, Zong X, Jeglitsch M, et al. A family of hyperpolarization activated mammalian cation channels. Nature 1998; 393: 587-91.
15. Ludwig A, Zong X, Hofmann F, Biel M. Stucture and function of cardiac pacemaker channels. Cell Physiol Biochem 1999; 9: 179-86.
16. Ishii TM, Takano M, Xie LH, et al. Molecular characterization of the hyperpolarization activated cation channek in rabbit heart sinoatrial node. J Biol Chem 1999; 274: 12835-9.
17. Baruscotti M, DiFrancesco D. Pacemeker channels. Ann NY Acad Sci 2004; 1015: 111-21.
18. Shi W, Wymore R, Yu H, et al. Distribution and prevalence of HCN mRNA expression in cardic tissues. Circ Res 1999; 85: e1-6.
19. Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco M. Familial sinus bradicardia associated with a mutated cardiac pacemaker channel. N Engl J Med 2006; 354(2): 151-7.
20. Moosmang S, Steiber J, Zong X, et al. Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. Eur J Biochem 2001; 268: 1646-52.
21. Zicha S, Fernandez-Velasco M, Lonardo G, et al. Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in canine heart failure model. Cardiovasc Res 2005; 66: 472-81.
22. Stieber J, Herrmann S, Fiel S, et al. The hyperpolarization activated channel HCN4 is required for the generation of pacemaker action potentials in the embrionic heart. Proc Natl Acad Sci USA 2003; 100: 15235-40.
23. Ludwig A, Budde T, Stieber J, et al. Absence epilepsy and sinus dysrthythmia in mice lacking the pacemaker channel HCN2. EMBO J 2003; 22: 216-24.
24. Colin P, Ghaleh B, Hittinger L, et al. Differential effects of heart rate reduction and beta-blockade on left ventricular relaxation during exercise. Am J Physiol 2002; 282: H672-9.
25. Vilaine JP, Bidouard J P, Lesage L, et al. Anti-ischemic effects of ivabradine, a selective heart rate reducing agent, in exercise induced myocardial ischemia in pigs. J Cardiovasc Pharmacol 2003; 42: 688-96.
26. Bois P, Bescond J, Renaudon B, Lenfant J. Mode of action of bradycardic agent, S-16257, on ionic currents of rabbit sinoatrial node cells. Br J Pharmacol 1996; 118: 1051-7.
27. 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.
28. Fox K. Selective and specific If inhibition: new perspectives fore the treatment of stable angina. Expert Opin Pharmacother 2006; 7(9): 1211-20.
29. Borer JS. Drug insight: If inhibitors as specific heart-rate-reducing agents. Nature clinical practice Cardiovasc med 2004; 1(2): 103-9.
30. Mugelli A. The role of the pacemaker current If in cardiovascular pharmacology. Pharmacol Res 2006; 53: 397-8.
31. Sulfi S, Timmis AD. Ivabradine – the first selective sinus node If channel inhibitor in the treatment of stable angina. Int J Clin Pract 2006; 60(2): 222-8.
32. Bucchi A, Baruscotti M, DiFrancesco D. Current-dependent block of rabbit sino-atrial node If channels by ivabradine. J Gen Physiol 2002; 120: 1-13.
33. Mangoni ME, Marger L, Nargeof J. If current inhibition: cellular basis and physiology In Camm J., Tendera M. (Eds); Heart Rate Slowing by If Current Inhibition. Adv Cardiol Basel Karger 2006; 43: 17-30.
34. Thollon C, Cambarrat C, Vian J, et al. Electrophysiological effects of S-16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardic preparations; comparison with UL-FS 49. Br J Pharmacol 1994; 112: 37-42.
35. Ragueneau I, Laveille C, Jochemsen R, et al. Pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers. Clin Pharmacol Ther 1998; 64: 192-203.
Review
For citations:
Astashkin E.I., Glezer M.G. Pace-maker f-channels of sinus node myocytеs as a new therapeutic target for heart rate reduction. Cardiovascular Therapy and Prevention. 2007;6(8):106-115. (In Russ.)
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