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- W2318590074 abstract "A major postulate of a modern coupled-clock pacemaker-cell theory is based upon electrochemical driving force for sodium and calcium (ENa and ECa). However, [sodium] gradients and their changes induced by glycosides (inhibiting sodium/potassium-ATPase) have never been measured. We measured time-dependent changes in intracellular [sodium](Nai), [calcium](Cai), and action-potentials (AP) [using Sodium-Binding-Benzofuran-Isophthalate (SBFI), Indo-1, and perforated patch-clamp, respectively] induced by cardiac glycosides (digoxegenin, 10μM) in single, isolated rabbit sinoatrial node cells. During 5 minutes of drug application spontaneous AP firing rate underwent biphasic changes, i.e. an increase followed by a decrease. During this time Nai monotonically increased from 8.5±0.6 mM to 13.1±1.1 mM (n=7 cells). The diastolic Cai also monotonically increased 124±6 nM to 149±11 nM (n=5). This Cai increase and biphasic drug effect on AP firing rate were closely reproduced by a coupled-clock Maltsev-Lakatta model simulations when the experimentally measured Nai time course was included in the model as an independent parameter. Model simulations also reproduced the initial AP rate increase via a moderate Cai increase (predicted by the model and validated by our Cai measurements). Specifically, when more cell calcium is available for pumping and release, it boosts the calcium clock, driving membrane clocks and the entire coupled-clock system. According to model predictions, subsequent marked increases in Nai and Cai collapse ENa and ECa and lead to AP rate decrease and dysrhythmic beating as sodium/calcium-exchanger current decreases, resulting in clock uncoupling. Thus, our results not only explain the complex glycoside effects on pacemaker cell AP-firing rate, but also provide new evidence supporting the idea that the normal automaticity of SANC emerges from coupled-clock functions, i.e. Cai and membrane ionic currents, that are controlled by sodium and calcium gradients to regulate sodium/calcium-exchanger current." @default.
- W2318590074 created "2016-06-24" @default.
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- W2318590074 date "2015-01-01" @default.
- W2318590074 modified "2023-09-29" @default.
- W2318590074 title "Glycoside-Induced Collapse of the Sodium and Calcium Gradients Leads to a Biphasic Effect on Cardiac Cell Pacemaker Function" @default.
- W2318590074 doi "https://doi.org/10.1016/j.bpj.2014.11.3115" @default.
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