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Chronic atrial ionic remodeling by aldosterone: potentiation of L-type Ca2+ channels and its arrhythmogenic significance

  • Erick B. Ríos-Pérez
  • Maricela García-Castañeda
  • Adrián Monsalvo-Villegas
  • Guillermo AvilaEmail author
Ion channels, receptors and transporters

Abstract

It is widely accepted that aldosterone induces atrial fibrillation (AF) by promoting structural changes, but its effects on the function of primary atrial myocytes remain unknown. We have investigated this point in adult rat atrial myocytes, chronically exposed to the hormone. This treatment produced larger amplitude of Ca2+ transients, longer action potential (AP) duration, and higher incidence of unsynchronized Ca2+ oscillations. Moreover, it also gave rise to increases in both cell membrane capacitance (Cm, 30 %) and activity of L-type Ca2+ channels (LTCCs, 100 %). Concerning K+ currents, a twofold increase was also observed, but only in a delayed rectifier component (IKsus). Interestingly, the maximal conductance (Gmax) of Na+ channels was also enhanced, but it occurred in the face of a negative shift in the voltage dependence of inactivation. Thus, at physiological potentials, a decreased fraction of available channels neutralized the effect on GNa-max. With regard to the effects on both Cm and LTCCs, they involved activation of mineralocorticoid receptors (MRs), were dose-dependent (EC50 ∼20–130 nM), and developed and recovered in days. Neither gating currents nor protein levels of LTCCs were altered. Instead, the effect on LTCCs was mimicked by cAMP, reverted by a PKA inhibitor, and attenuated by a nitric oxide donor (short-term exposures). Both EGTA and the antioxidant NAC prevented the increase in Cm, without significantly interfering with the upregulation of LTCCs. Overall, these results show that chronic exposures to aldosterone result in dire functional changes at the single myocyte level, which may explain the link between aldosteronism and AF.

Keywords

Intracellular calcium Ion channels Cardiac myocyte EC coupling Mineralocorticoid receptor 

Notes

Acknowledgments

We would like to thank Marcelino Flores Flores for excellent technical assistance.

Compliance with ethical standards

Funding

This work was supported by a Conacyt grant to GA (no. 151540).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

424_2016_1876_MOESM1_ESM.docx (213 kb)
ESM 1 (DOCX 212 kb)

References

  1. 1.
    Avila G, Aguilar CI, Ramos-Mondragón R (2007) Sustained CGRP1 receptor stimulation modulates development of EC coupling by cAMP/PKA signalling pathway in mouse skeletal myotubes. J Physiol 584:47–57. doi: 10.1113/jphysiol.2007.137687 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Bell DC, Butcher AJ, Berrow NS, Page KM, Brust PF, Nesterova A, Stauderman KA, Seabrook GR, Nürnberg B, Dolphin AC (2001) Biophysical properties, pharmacology, and modulation of human, neuronal l-type (a1d, cav1.3) voltage-dependent calcium currents. J Neurophysiol 85:816–827PubMedGoogle Scholar
  3. 3.
    Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415:198–205. doi: 10.1038/415198a CrossRefPubMedGoogle Scholar
  4. 4.
    Burstein B, Nattel S (2008) Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol 51:802–809. doi: 10.1016/j.jacc.2007.09.064 CrossRefPubMedGoogle Scholar
  5. 5.
    Claycomb WC, Lanson NA, Stallworth BS, Egeland DB, Delcarpio JB, Bahinski A, Izzo NJ (1998) HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc Natl Acad Sci U S A 95:2979–2984CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Dartsch T, Fischer R, Gapelyuk A, Weiergraeber M, Ladage D, Schneider T, Schirdewan A, Reuter H, Mueller-Ehmsen J, Zobel C (2013) Aldosterone induces electrical remodeling independent of hypertension. Int J Cardiol 164:170–178. doi: 10.1016/j.ijcard.2011.06.100 CrossRefPubMedGoogle Scholar
  7. 7.
    Ferreiro M, Petrosky AD, Escobar AL (2012) Intracellular Ca2+ release underlies the development of phase 2 in mouse ventricular action potentials. Am J Physiol Heart Circ Physiol 302:H1160–H1172. doi: 10.1152/ajpheart.00524.2011 CrossRefPubMedGoogle Scholar
  8. 8.
    Fuller MD, Emrick MA, Sadilek M, Scheuer T, Catterall WA (2010) Molecular mechanism of calcium channel regulation in the fight-or-flight response. Sci Signal 3:ra70. doi: 10.1126/scisignal.2001152 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Fuller PJ, Young MJ (2005) Mechanisms of mineralocorticoid action. Hypertension 46:1227–1235. doi: 10.1161/01.HYP.0000193502.77417.17 CrossRefPubMedGoogle Scholar
  10. 10.
    Gómez AM, Ruiz-Hurtado G, Benitah JP, Domínguez-Rodríguez A (2013) Ca(2+) fluxes involvement in gene expression during cardiac hypertrophy. Curr Vasc Pharmacol 11:497–506. doi: 10.2174/1570161111311040013 CrossRefPubMedGoogle Scholar
  11. 11.
    Goette A, Hoffmanns P, Enayati W, Meltendorf U, Geller JC, Klein HU (2001) Effect of successful electrical cardioversion on serum aldosterone in patients with persistent atrial fibrillation. Am J Cardiol 88(906–909):A8Google Scholar
  12. 12.
    He BJ, Anderson ME (2013) Aldosterone and cardiovascular disease: the heart of the matter. Trends Endocrinol Metab TEM 24:21–30. doi: 10.1016/j.tem.2012.09.004 CrossRefPubMedGoogle Scholar
  13. 13.
    Kar R, Kellogg DL, Roman LJ (2015) Oxidative stress induces phosphorylation of neuronal NOS in cardiomyocytes through AMP-activated protein kinase (AMPK). Biochem Biophys Res Commun 459:393–397. doi: 10.1016/j.bbrc.2015.02.113 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kass RS, Lederer WJ, Tsien RW, Weingart R (1978) Role of calcium ions in transient inward currents and aftercontractions induced by strophanthidin in cardiac Purkinje fibres. J Physiol 281:187–208CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kass RS, Tsien RW, Weingart R (1978) Ionic basis of transient inward current induced by strophanthidin in cardiac Purkinje fibres. J Physiol 281:209–226CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Lalevée N, Rebsamen MC, Barrère-Lemaire S, Perrier E, Nargeot J, Bénitah J-P, Rossier MF (2005) Aldosterone increases T-type calcium channel expression and in vitro beating frequency in neonatal rat cardiomyocytes. Cardiovasc Res 67:216–224. doi: 10.1016/j.cardiores.2005.05.009 CrossRefPubMedGoogle Scholar
  17. 17.
    Laszlo R, Bentz K, Konior A, Eick C, Schreiner B, Kettering K, Schreieck J (2010) Effects of selective mineralocorticoid receptor antagonism on atrial ion currents and early ionic tachycardia-induced electrical remodelling in rabbits. Naunyn Schmiedebergs Arch Pharmacol 382:347–356. doi: 10.1007/s00210-010-0553-2 CrossRefPubMedGoogle Scholar
  18. 18.
    Laszlo R, Bentz K, Schreieck J (2011) Effects of aldosterone and mineralocorticoid receptor antagonism on cardiac ion channels in the view of upstream therapy of atrial fibrillation. Gen Physiol Biophys 30:11–19. doi: 10.4149/gpb_2011_01_11 CrossRefPubMedGoogle Scholar
  19. 19.
    Lendeckel U, Dobrev D, Goette A (2010) Aldosterone-receptor antagonism as a potential therapeutic option for atrial fibrillation. Br J Pharmacol 159:1581–1583. doi: 10.1111/j.1476-5381.2010.00675.x CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Li GR, Feng J, Wang Z, Fermini B, Nattel S (1996) Adrenergic modulation of ultrarapid delayed rectifier K+ current in human atrial myocytes. Circ Res 78:903–915. doi: 10.1161/01.RES.78.5.903 CrossRefPubMedGoogle Scholar
  21. 21.
    López-Domínguez AM, Espinosa JL, Navarrete A, Avila G, Cota G (2006) Nerve growth factor affects Ca2+ currents via the p75 receptor to enhance prolactin mRNA levels in GH3 rat pituitary cells. J Physiol 574:349–365. doi: 10.1113/jphysiol.2006.110791 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mahapatra S, Marcantoni A, Zuccotti A, Carabelli V, Carbone E (2012) Equal sensitivity of Cav1.2 and Cav1.3 channels to the opposing modulations of PKA and PKG in mouse chromaffin cells. J Physiol 590:5053–5073. doi: 10.1113/jphysiol.2012.236729 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Milliez P, Girerd X, Plouin P-F, Blacher J, Safar ME, Mourad J-J (2005) Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 45:1243–1248. doi: 10.1016/j.jacc.2005.01.015 CrossRefPubMedGoogle Scholar
  24. 24.
    Odermatt A, Atanasov AG (2009) Mineralocorticoid receptors: emerging complexity and functional diversity. Steroids 74:163–171. doi: 10.1016/j.steroids.2008.10.010 CrossRefPubMedGoogle Scholar
  25. 25.
    Qu Y, Baroudi G, Yue Y, El-Sherif N, Boutjdir M (2005) Localization and modulation of {alpha}1D (Cav1.3) L-type Ca channel by protein kinase A. Am J Physiol Heart Circ Physiol 288:H2123–H2130. doi: 10.1152/ajpheart.01023.2004 CrossRefPubMedGoogle Scholar
  26. 26.
    Ramos-Mondragón R, Galindo CA, García-Castañeda M, Sánchez-Vargas JL, Vega AV, Gómez-Viquez NL, Avila G (2012) Chronic potentiation of cardiac L-type Ca(2+) channels by pirfenidone. Cardiovasc Res 96:244–254. doi: 10.1093/cvr/cvs248 CrossRefPubMedGoogle Scholar
  27. 27.
    Ramos-Mondragón R, Vega AV, Avila G (2011) Long-term modulation of Na + and K+ channels by TGF-β1 in neonatal rat cardiac myocytes. Pflüg Arch Eur J Physiol 461:235–247. doi: 10.1007/s00424-010-0912-3 CrossRefGoogle Scholar
  28. 28.
    Reil J-C, Hohl M, Selejan S, Lipp P, Drautz F, Kazakow A, Münz BM, Müller P, Steendijk P, Reil G-H, Allessie MA, Böhm M, Neuberger H-R (2012) Aldosterone promotes atrial fibrillation. Eur Heart J 33:2098–2108. doi: 10.1093/eurheartj/ehr266 CrossRefPubMedGoogle Scholar
  29. 29.
    Reuter H (1983) Calcium channel modulation by neurotransmitters, enzymes and drugs. Nature 301:569–574CrossRefPubMedGoogle Scholar
  30. 30.
    Rogerson FM, Yao Y-Z, Smith BJ, Dimopoulos N, Fuller PJ (2003) Determinants of spironolactone binding specificity in the mineralocorticoid receptor. J Mol Endocrinol 31:573–582CrossRefPubMedGoogle Scholar
  31. 31.
    Rook MB, Evers MM, Vos MA, Bierhuizen MF (2012) Biology of cardiac sodium channel Nav1.5 expression. Cardiovasc Res 93:12–23. doi: 10.1093/cvr/cvr252 CrossRefPubMedGoogle Scholar
  32. 32.
    Rousseau MF, Gurné O, Duprez D, Van Mieghem W, Robert A, Ahn S, Galanti L, Ketelslegers JM, Belgian RALES Investigators (2002) Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: results from the RALES neurohormonal substudy. J Am Coll Cardiol 40:1596–1601. doi: 10.1016/S0735-1097(02)02382-3 CrossRefPubMedGoogle Scholar
  33. 33.
    Santamaria-Herrera MA, Ríos-Pérez EB, de la Rosa JA, García-Castañeda M, Osornio-Garduño DS, Ramos-Mondragón R, Mancilla-Percino T, Avila G (2016) MDIMP, a novel cardiac Ca2+ channel blocker with atrial selectivity. Eur J Pharmacol 781:218–228. doi: 10.1016/j.ejphar.2016.04.027 CrossRefPubMedGoogle Scholar
  34. 34.
    Sun Y, Ramires FJA, Weber KT (1997) Fibrosis of atria and great vessels in response to angiotensin II or aldosterone infusion. Cardiovasc Res 35:138–147. doi: 10.1016/S0008-6363(97)00097-7 CrossRefPubMedGoogle Scholar
  35. 35.
    Takimoto K, Li D, Nerbonne JM, Levitan ES (1997) Distribution, splicing and glucocorticoid-induced expression of cardiac alpha 1C and alpha 1D voltage-gated Ca2+ channel mRNAs. J Mol Cell Cardiol 29:3035–3042. doi: 10.1006/jmcc.1997.0532 CrossRefPubMedGoogle Scholar
  36. 36.
    Tsai C-T, Chiang F-T, Tseng C-D, Hwang J-J, Kuo K-T, Wu C-K, Yu C-C, Wang Y-C, Lai L-P, Lin J-L (2010) Increased expression of mineralocorticoid receptor in human atrial fibrillation and a cellular model of atrial fibrillation. J Am Coll Cardiol 55:758–770. doi: 10.1016/j.jacc.2009.09.045 CrossRefPubMedGoogle Scholar
  37. 37.
    Tsien RW, Bean BP, Hess P, Lansman JB, Nilius B, Nowycky MC (1986) Mechanisms of calcium channel modulation by beta-adrenergic agents and dihydropyridine calcium agonists. J Mol Cell Cardiol 18:691–710CrossRefPubMedGoogle Scholar
  38. 38.
    Voigt N, Li N, Wang Q, Wang W, Trafford AW, Abu-Taha I, Sun Q, Wieland T, Ravens U, Nattel S, Wehrens XHT, Dobrev D (2012) Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na + −Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation. Circulation 125:2059–2070. doi: 10.1161/CIRCULATIONAHA.111.067306 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Voigt N, Nattel S, Dobrev D (2012) Proarrhythmic atrial calcium cycling in the diseased heart. Adv Exp Med Biol 740:1175–1191. doi: 10.1007/978-94-007-2888-2_53 CrossRefPubMedGoogle Scholar
  40. 40.
    Wagner S, Dybkova N, Rasenack EC, Jacobshagen C, Fabritz L, Kirchhof P, Maier SK, Zhang T, Hasenfuss G, Brown JH, Bers DM, Maier LS (2006) Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. J Clin Invest 116(12):3127–3138. doi: 10.1172/JCI26620 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    White SM, Constantin PE, Claycomb WC (2004) Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function. Am J Physiol Heart Circ Physiol 286:H823–H829. doi: 10.1152/ajpheart.00986.2003 CrossRefPubMedGoogle Scholar
  42. 42.
    Williams RS, deLemos JA, Dimas V, Reisch J, Hill JA, Naseem RH (2011) Effect of spironolactone on patients with atrial fibrillation and structural heart disease. Clin Cardiol 34:415–419. doi: 10.1002/clc.20914 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Xu X, Best PM (1992) Postnatal changes in T-type calcium current density in rat atrial myocytes. J Physiol 454:657–672CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Xu W, Lipscombe D (2001) Neuronal Ca(V)1.3alpha(1) L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines. J Neurosci 21:5944–5951PubMedGoogle Scholar
  45. 45.
    Zakon HH (1998) The effects of steroid hormones on electrical activity of excitable cells. Trends Neurosci 21:202–207. doi: 10.1016/S0166-2236(97)01209-5 CrossRefPubMedGoogle Scholar
  46. 46.
    Zhang Z, He Y, Tuteja D, Xu D, Timofeyev V, Zhang Q, Glatter KA, Xu Y, Shin HS, Low R, Chiamvimonvat N (2005) Functional roles of Cav1.3(alpha1D) calcium channels in atria: insights gained from gene-targeted null mutant mice. Circulation 112:1936–1944. doi: 10.1161/CIRCULATIONAHA.105.540070 CrossRefPubMedGoogle Scholar
  47. 47.
    Zhao J, Li J, Li W, Li Y, Shan H, Gong Y, Yang B (2010) Effects of spironolactone on atrial structural remodelling in a canine model of atrial fibrillation produced by prolonged atrial pacing. Br J Pharmacol 159:1584–1594. doi: 10.1111/j.1476-5381.2009.00551.x CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of BiochemistryCinvestav-IPNMéxico CityMéxico

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