Influence of HCN channels on isolated heart functions in adult rats

A.M. Kuptsova^*, N.I. Ziyatdinova^**, L.I. Faskhutdinov^***, R.G. Biktemirova^****, T.L. Zefirov^*****

Kazan Federal University, Kazan, 420008 Russia

E-mail: ^*anuta0285@mail.ru, ^**nafisaz@mail.ru, ^***f.lenar89@mail.ru, ^****RGBiktemirova@kpfu.ru, ^*****zefirovtl@mail.ru

Received July 10, 2018

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Abstract

Heart pacemaking has triggered a research interest for many decades. Hyperpolarization-activated currents (If) and ion channels (HCN channels) that provide this current are widespread in the central and peripheral nervous system. In atypical cardiomyocytes, HCN channels generate a spontaneous electrical activity. The physiological role of HCN channels in the working myocardium remains a subject of constant research. The expression of HCN channels in cardiomyocytes of the ventricles was shown. It is possible that If participates in the formation of the potential action of working cardiomyocytes and, consequently, in the regulation of the inotropic cardiac function. The study was performed in order to investigate the role of hyperpolarization-activated currents on chronotropy, inotropy, and coronary flow of the Langendorff heart in adult rats. Experiments ex vivo were performed on random-bred albino rats aged 20 weeks. The heart was perfused in the Langendorff System (ADInstruments). The coronary flow, left ventricular pressure, and heart rate were calculated along the curve. 10^–9 – 3?10^–5 М concentrations range of ZD7288 (Sigma) were used for If blockade.

The analysis of the results demonstrated that the left ventricular pressure increased after the blockade of If at the concentration of 10^–9 M and decreased with the blocker concentration of 3?10^–5 M. The ZD7288 caused bradycardia of the isolated heart at the concentrations of 10^–9, 10^–6, 3?10^–5 M. The isolated heart coronary flow decreased with the blockade of If at the concentration of 10^–9 M and 3?10^–5 M.

It was concluded that If blockade changes chronotropy, inotropy, and coronary flow of the isolated heart in adult rats.

Keywords: isolated heart, left ventricular pressure, heart rate, coronary flow, hyperpolarization activated currents

Acknowledgments. The work is performed according to the Russian Government Program of Competitive Growth of Kazan Federal University and supported by the Russian Foundation for Basic Research (projects nos. 17-04-00071 and 18-44-160022).

Figure Captions

Fig. 1. Left ventricular pressure dynamics of the isolated heart in adult rats after If blockade. Y-axis – left ventricular pressure (LVP, %), X-axis – experiment recording time (min). Note: * – significance compared with the initial values: р < 0.05.

Fig. 2. Isolated heart rate dynamics in adult rats after If blockade. Y-axis – heart rate (HR, %), X-axis – experiment recording time (min). Note: significance compared with the initial values: р < 0.05.

Fig. 3. Coronary flow dynamics of the isolated heart in adult rats after If blockade. Y-axis – coronary flow (CF, %), X-axis – experiment recording time (min). Note: ** – significance compared with the initial values: р < 0.01; *** – significance compared with the initial values: р < 0.001.

References

1. DiFrancesco D. The role of the funny current in pacemaker activity. Circ. Res., 2010, vol. 106, no. 3, рр. 434–446. doi: 10.1161/CIRCRESAHA.109.208041.

2. Biel M., Wahl-Schott C., Michalakis S., Zong X. Hyperpolarization-activated cation channels: From genes to function. Physiol Rev., 2009, vol. 89, no. 3, pp. 847–885. doi: 10.1152/physrev.00029.2008.

3. Krieger J., Strobel J., Vogl A., Hanke W., Breer H. Identification of a cyclic nucleotide- and voltage-activated ion channel from insect antennae. Insect Biochem. Mol. Biol., 1999, vol. 29, no. 3, рр. 255–267. doi: 10.1016/S0965-1748(98)00134-9.

4. Altomare C., Bucchi A., Camatini E., Baruscotti M., Viscomi C., Moroni A., DiFrancesco D. Integrated allosteric model of voltage gating of HCN channels. J. Gen. Physiol., 2001, vol. 117, no. 6, рр. 519–532. doi: 10.1085/jgp.117.6.519.

5. Craven K.B., Zagotta W.N. CNG and HCN channels: Two peas, one pod. Annu. Rev. Physiol., 2006, vol. 68, рр. 375–401. doi: 10.1146/annurev.physiol.68.040104.134728.

6. DiFrancesco D. Dual allosteric modulation of pacemaker (f) channels by cAMP and voltage in rabbit SA node. J. Physiol., 1999, vol. 515, pt. 2, рр. 367–376. doi: 10.1111/j.1469-7793.1999.367ac.x.

7. Barbuti A., Crespi A., Capilupo D., Mazzocchi N., Baruscotti M., DiFrancesco D. Molecular composition and functional properties of f-channels in murine embryonic stem cell-derived pacemaker cells. J. Mol. Cell Cardiol., 2009, vol. 46, no. 3, рр. 343–351. doi: 10.1016/j.yjmcc.2008.12.001.

8. Bucchi A., Barbuti A., Difrancesco D., Baruscotti M. Funny current and cardiac rhythm: Insights from HCN knockout and transgenic mouse models. Front. Physiol., 2012, V. 3, art. 240, рр. 1–10. doi: 10.3389/fphys.2012.00240.

9. Notomi T., Shigemoto R. Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain. J. Comp. Neurol., 2004, vol. 471, no. 3, рр. 241–276. doi: 10.1002/cne.11039.

10. Hughes D.I., Boyle K.A., Kinnon C.M., Bilsland C., Quayle J.A., Callister R.J., Graham B.A. HCN4 subunit expression in fast-spiking interneurons of the rat spinal cord and hippocampus. Neuroscience, 2013, vol. 237, рр. 7–18. doi: 10.1016/j.neuroscience.2013.01.028.

11. Fyk-Kolodziej B., Pourcho R.G. Differential distribution of hyperpolarization-activated and cyclic nucleotide-gated channels in cone bipolar cells of the rat retina. J. Comp. Neurol., 2007, vol. 501, no. 6, рр. 891–903. doi:10.1002/cne.21287.

12. Wahl-Schott C., Fenske S., Biel M. HCN channels: New roles in sinoatrial node function. Curr. Opin. Pharmacol., 2014, vol. 15, рр. 83–90. doi: 10.1016/j.coph.2013.12.005.

13. Roubille F., Tardif J.-C. New therapeutic targets in cardiology: Heart failure and arrhythmia: HCN channels. Circulation, 2013, vol. 127, no. 19, рр. 1986–1996. doi: 10.1161/CIRCULATIONAHA.112.000145.

14. Herrmann S., Layh B., Ludwig A. Novel insights in to the distribution of cardiac HCN channels: An expression study in the mouse heart. J. Mol. Cell. Cardiol., 2011, vol. 51, no. 6, рр. 997–1006. doi: 10.1016/j.yjmcc.2011.09.005.

15. Fenske S., Krause S., Biel M., Wahl-Schott C. The role of HCN channels in ventricular repolarization. Trends Cardiovasc. Med., 2011, vol. 21, no. 8, рр. 216–220. doi: 10.1016/j.tcm.2012.05.013.

16. Romanelli M.N., Sartiani L., Masi A., Mannaioni G., Manetti D., Mugelli A., Cerbai E. HCN channels modulators: The need for selectivity. Curr. Top. Med. Chem., 2016, vol. 16, no. 16, рр. 1764–1791. doi: 10.2174 / 1568026616999160315130832.

17. He C., Chen F., Li B., Hu Z. Neurophysiology of HCN channels: From cellular functions to multiple regulations. Prog. Neurobiol., 2014, vol. 112, рр. 1–23. doi: 10.1016/j.pneurobio.2013.10.001.

18. Gao Z., Chen B., Joiner M.-l.A., Wu Y., Guan X., Koval O.M., Chaudhary A.K., Cunha S.R., Mohler P.J., Martins J.B., Song L.-S., Anderson M.E. I_f and SR Ca²⁺ release both contribute to pacemaker activity in canine sinoatrial node cells. J. Mol. Cell. Cardiol., 2010, vol. 49, no. 1, рр. 33–40. doi: 10.1016/j.yjmcc.2010.03.019.

19. Schweizer P.A., Yampolsky P., Malik R., Thomas D., Zehelein J., Katus H.A., Koenen M. Trans­cription profiling of HCN-channel isotypes throughout mouse cardiac development. Basic Res. Cardiol., 2009, vol. 104, рр. 621–629. doi: 10.1007/s00395-009-0031-5.

20. Zefirov T.L., Ziyatdinova N.I., Zefirov A.L. Effects of blockade of hyperpolarization-activated ion currents (Ih) on autonomic control of the heart in rats: Age-related peculiarities. Neurophysiology, 2003, vol. 35, no. 6, рр. 415–421. doi: 10.1023/B:NEPH.0000024602.05250.f1.

21. Zefirov T.L., Svyatova N.V., Ziyatdinova N.I. A new insight into mechanisms of age-related changes in heart rate. Bull. Exp. Biol. Med., 2001, vol. 131, no. 6, рр. 518–522. doi: 10.1023/A:1012329930448.

22. 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, vol. 144, no. 3, рр. 273–275. doi: 10.1007/s10517-007-0308-3.

23. 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, vol. 158, no. 5, рр. 600–603. doi: 10.1007/s10517-015-2815-y.

24. Robinson R.B. Autonomic receptor–effector coupling during postnatal development. Cardiovasc. Res., 1996, vol. 31, рр. E68–E76. doi: 10.1016/0008-6363(95)00151-4.

25. Smirnov V.M. The sympathetic nervous system is not implicated in the development of vagotomy-induced tachycardia. Bull. Exp. Biol. Med., 1995, vol. 120, no. 2, рр. 767–770. doi: 10.1007/BF02445948.

For citation: Kuptsova A.M., Ziyatdinova N.I., Faskhutdinov L.I., Biktemirova R.G., Zefirov T.L. Influence of HCN channels on isolated heart functions in adult rats. Uchenye Zapiski Kazanskogo Universiteta. Seriya Estestvennye Nauki, 2018, vol. 160, no. 4, pp. 568–578. (In Russian)

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