Electrochemical Na+ and Ca2+gradients drive coupled-clock regulation of automaticity of isolated rabbit sinoatrial nodal pacemaker cells

Syevda G. Sirenko, Victor A. Maltsev, Yael Yaniv, Rostislav Bychkov, Daniel Yaeger, Tatiana Vinogradova, Harold A. Spurgeon, Edward G. Lakatta

Research output: Contribution to journalArticlepeer-review


Coupling of an intracellular Ca2+ clock to surface membrane ion channels, i.e., a “membrane clock,” via coupling of electrochemical Na+ and Ca2+ gradients (ENa and ECa, respectively) has been theorized to regulate sinoatrial nodal cell (SANC) normal automaticity. To test this hypothesis, we measured responses of [Na+] i, [Ca2+] i, membrane potential, action potential cycle length (APCL), and rhythm in rabbit SANCs to Na+ /K+ pump inhibition by the digitalis glycoside, digoxigenin (DG, 10–20 μmol/l). Initial small but significant increases in [Na+] i and [Ca2+] i and reductions in E Na and E Ca in response to DG led to a small reduction in maximum diastolic potential (MDP), significantly enhanced local diastolic Ca2+ releases (LCRs), and reduced the average APCL. As [Na+] i and [Ca2+] i continued to increase at longer times following DG exposure, further significant reductions in MDP, ENa, and ECa occurred; LCRs became significantly reduced, and APCL became progressively and significantly prolonged. This was accompanied by increased APCL variability. We also employed a coupled-clock numerical model to simulate changes in ENa and ECa simultaneously with ion currents not measured experimentally. Numerical modeling predicted that, as the E Na and E Ca monotonically reduced over time in response to DG, ion currents (ICaL, ICaT, If, IKr, and IbNa) monotonically decreased. In parallel with the biphasic APCL, diastolic INCX manifested biphasic changes; initial INCX increase attributable to enhanced LCR ensemble Ca2+ signal was followed by INCX reduction as ENCX (ENCX = 3ENa-2ECa) decreased. Thus SANC automaticity is tightly regulated by ENa, ECa, and ENCX via a complex interplay of numerous key clock components that regulate SANC clock coupling.

Original languageEnglish (US)
Pages (from-to)H251-H267
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number1
StatePublished - Jul 2016
Externally publishedYes


  • Calcium
  • Cardiac automaticity
  • Electrochemical driving forces
  • Sodium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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