TY - JOUR
T1 - Electrochemical Na+ and Ca2+gradients drive coupled-clock regulation of automaticity of isolated rabbit sinoatrial nodal pacemaker cells
AU - Sirenko, Syevda G.
AU - Maltsev, Victor A.
AU - Yaniv, Yael
AU - Bychkov, Rostislav
AU - Yaeger, Daniel
AU - Vinogradova, Tatiana
AU - Spurgeon, Harold A.
AU - Lakatta, Edward G.
N1 - Funding Information:
This work was supported by the Intramural Research Program of the NIH, National Institute on Aging.
Publisher Copyright:
© 2016 the American Physiological Society.
PY - 2016/7
Y1 - 2016/7
N2 - 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.
AB - 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.
KW - Calcium
KW - Cardiac automaticity
KW - Electrochemical driving forces
KW - Sodium
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U2 - 10.1152/ajpheart.00667.2015
DO - 10.1152/ajpheart.00667.2015
M3 - Article
C2 - 27208164
AN - SCOPUS:84983761192
SN - 0363-6135
VL - 311
SP - H251-H267
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 1
ER -