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Burst pacemaker activity of the sinoatrial node in sodium–calcium exchanger knockout mice

Abstract : In sinoatrial node (SAN) cells, electrogenic sodium-calcium exchange (NCX) is the dominant calcium (Ca) efflux mechanism. However, the role of NCX in the generation of SAN automaticity is controversial. To investigate the contribution of NCX to pacemaking in the SAN, we performed optical voltage mapping and high-speed 2D laser scanning confocal microscopy (LSCM) of Ca dynamics in an ex vivo intact SAN/atrial tissue preparation from atrial-specific NCX knockout (KO) mice. These mice lack P waves on electrocardiograms, and isolated NCX KO SAN cells are quiescent. Voltage mapping revealed disorganized and arrhythmic depolarizations within the NCX KO SAN that failed to propagate into the atria. LSCM revealed intermittent bursts of Ca transients. Bursts were accompanied by rising diastolic Ca, culminating in long pauses dominated by Ca waves. The L-type Ca channel agonist BayK8644 reduced the rate of Ca transients and inhibited burst generation in the NCX KO SAN whereas the Ca buffer 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (acetoxymethyl ester) (BAPTA AM) did the opposite. These results suggest that cellular Ca accumulation hinders spontaneous depolarization in the NCX KO SAN, possibly by inhibiting L-type Ca currents. The funny current (If) blocker ivabradine also suppressed NCX KO SAN automaticity. We conclude that pacemaker activity is present in the NCX KO SAN, generated by a mechanism that depends upon If. However, the absence of NCX-mediated depolarization in combination with impaired Ca efflux results in intermittent bursts of pacemaker activity, reminiscent of human sinus node dysfunction and "tachy-brady" syndrome.
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https://hal.umontpellier.fr/hal-02477196
Contributeur : Angelo Torrente <>
Soumis le : jeudi 13 février 2020 - 11:28:55
Dernière modification le : jeudi 13 février 2020 - 17:00:11

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Angelo Torrente, Rui Zhang, Audrey Zaini, Jorge Giani, Jeanney Kang, et al.. Burst pacemaker activity of the sinoatrial node in sodium–calcium exchanger knockout mice. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2015, 112 (31), pp.9769-9774. ⟨10.1073/pnas.1505670112⟩. ⟨hal-02477196⟩

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