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Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model.

ABSTRACT: Recent experimental studies have demonstrated that sinoatrial node cells (SANC) generate spontaneous, rhythmic, local subsarcolemmal Ca(2+) releases (Ca(2+) clock), which occur during late diastolic depolarization (DD) and interact with the classic sarcolemmal voltage oscillator (membrane clock) by activating Na(+)-Ca(2+) exchanger current (I(NCX)). This and other interactions between clocks, however, are not captured by existing essentially membrane-delimited cardiac pacemaker cell numerical models. Using wide-scale parametric analysis of classic formulations of membrane clock and Ca(2+) cycling, we have constructed and initially explored a prototype rabbit SANC model featuring both clocks. Our coupled oscillator system exhibits greater robustness and flexibility than membrane clock operating alone. Rhythmic spontaneous Ca(2+) releases of sarcoplasmic reticulum (SR)-based Ca(2+) clock ignite rhythmic action potentials via late DD I(NCX) over much broader ranges of membrane clock parameters [e.g., L-type Ca(2+) current (I(CaL)) and/or hyperpolarization-activated ("funny") current (I(f)) conductances]. The system Ca(2+) clock includes SR and sarcolemmal Ca(2+) fluxes, which optimize cell Ca(2+) balance to increase amplitudes of both SR Ca(2+) release and late DD I(NCX) as SR Ca(2+) pumping rate increases, resulting in a broad pacemaker rate modulation (1.8-4.6 Hz). In contrast, the rate modulation range via membrane clock parameters is substantially smaller when Ca(2+) clock is unchanged or lacking. When Ca(2+) clock is disabled, the system parametric space for fail-safe SANC operation considerably shrinks: without rhythmic late DD I(NCX) ignition signals membrane clock substantially slows, becomes dysrhythmic, or halts. In conclusion, the Ca(2+) clock is a new critical dimension in SANC function. A synergism of the coupled function of Ca(2+) and membrane clocks confers fail-safe SANC operation at greatly varying rates.

SUBMITTER: Maltsev VA

PROVIDER: S-EPMC2660239 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model.

Maltsev Victor A VA Lakatta Edward G EG

American journal of physiology. Heart and circulatory physiology 20090109 3

Recent experimental studies have demonstrated that sinoatrial node cells (SANC) generate spontaneous, rhythmic, local subsarcolemmal Ca(2+) releases (Ca(2+) clock), which occur during late diastolic depolarization (DD) and interact with the classic sarcolemmal voltage oscillator (membrane clock) by activating Na(+)-Ca(2+) exchanger current (I(NCX)). This and other interactions between clocks, however, are not captured by existing essentially membrane-delimited cardiac pacemaker cell numerical mo ...[more]

PMID: 19136600

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Project description:Zebrafish (Danio rerio) have become a popular model in cardiovascular research mainly due to identification of a large number of mutants with structural defects. In recent years, cardiomyopathies and other diseases influencing contractility of the heart have been studied in zebrafish mutants. However, little is known about the regulation of contractility of the zebrafish heart on a tissue level. The aim of the present study was to elucidate the role of trans-sarcolemmal Ca(2+)-flux and sarcoplasmic reticulum Ca(2+)-release in zebrafish myocardium. Using isometric force measurements of fresh heart slices, we characterised the effects of changes of the extracellular Ca(2+)-concentration, trans-sarcolemmal Ca(2+)-flux via L-type Ca(2+)-channels and Na(+)-Ca(2+)-exchanger, and Ca(2+)-release from the sarcoplasmic reticulum as well as beating frequency and ?-adrenergic stimulation on contractility of adult zebrafish myocardium. We found an overall negative force-frequency relationship (FFR). Inhibition of L-type Ca(2+)-channels by verapamil (1 ?M) decreased force of contraction to 22 ± 7% compared to baseline (n=4, p<0.05). Ni(2+) was the only substance to prolong relaxation (5 mM, time after peak to 50% relaxation: 73 ± 3 ms vs. 101 ± 8 ms, n=5, p<0.05). Surprisingly though, inhibition of the sarcoplasmic Ca(2+)-release decreased force development to 54 ± 3% in ventricular (n=13, p<0.05) and to 52 ± 8% in atrial myocardium (n=5, p<0.05) suggesting a substantial role of SR Ca(2+)-release in force generation. In line with this finding, we observed significant post pause potentiation after pauses of 5 s (169 ± 7% force compared to baseline, n=8, p<0.05) and 10 s (198 ± 9% force compared to baseline, n=5, p<0.05) and mildly positive lusitropy after ?-adrenergic stimulation. In conclusion, force development in adult zebrafish ventricular myocardium requires not only trans-sarcolemmal Ca2+-flux, but also intact sarcoplasmic reticulum Ca(2+)-cycling. In contrast to mammals, FFR is strongly negative in the zebrafish heart. These aspects need to be considered when using zebrafish to model human diseases of myocardial contractility.

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Dataset Information

Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model.

Publications

Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model.

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