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Mechanism of pacemaking in I(K1)-downregulated myocytes.

ABSTRACT: Biological pacemakers were recently created by genetic suppression of inward rectifier potassium current, I(K1), in guinea pig ventricular cells. We simulated these cells by adjusting I(K1) conductance in the Luo-Rudy model of the guinea pig ventricular myocyte. After 81% I(K1) suppression, the simulated cell reached steady state with pacemaker period of 594 ms. Pacemaking current is carried by the Na+-Ca2+ exchanger, I(NaCa), which depends on the intracellular calcium concentration [Ca2+]i. This [Ca2+]i dependence suggests responsiveness (increase in rate) to beta-adrenergic stimulation (betaAS), as observed experimentally. Simulations of betaAS demonstrate such responsiveness, which depends on I(NaCa) expression. However, a simultaneous betaAS-mediated increase in the slow delayed rectifier, I(Ks), limits betaAS sensitivity.

SUBMITTER: Silva J

PROVIDER: S-EPMC1890031 | biostudies-literature | 2003 Feb

REPOSITORIES: biostudies-literature

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Mechanism of pacemaking in I(K1)-downregulated myocytes.

Silva Jonathan J Rudy Yoram Y

Circulation research 20030201 3

Biological pacemakers were recently created by genetic suppression of inward rectifier potassium current, I(K1), in guinea pig ventricular cells. We simulated these cells by adjusting I(K1) conductance in the Luo-Rudy model of the guinea pig ventricular myocyte. After 81% I(K1) suppression, the simulated cell reached steady state with pacemaker period of 594 ms. Pacemaking current is carried by the Na+-Ca2+ exchanger, I(NaCa), which depends on the intracellular calcium concentration [Ca2+]i. Thi ...[more]

PMID: 12595336

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Project description:Cardiac repolarization alternans is an arrhythmogenic rhythm disturbance, manifested in individual myocytes as a beat-to-beat alternation of action potential durations and intracellular calcium transient magnitudes. Recent experimental studies have reported "subcellular alternans," in which distinct regions of an individual cell are seen to have counterphase calcium alternations, but the mechanism by which this occurs is not well understood. Although previous theoretical work has proposed a possible dynamical mechanism for subcellular alternans formation, no direct evidence for this mechanism has been reported in vitro. Rather, experimental studies have generally invoked fixed subcellular heterogeneities in calcium-cycling characteristics as the mechanism of subcellular alternans formation.In this study, we have generalized the previously proposed dynamical mechanism to predict a simple pacing algorithm by which subcellular alternans can be induced in isolated cardiac myocytes in the presence or absence of fixed subcellular heterogeneity. We aimed to verify this hypothesis using computational modeling and to confirm it experimentally in isolated cardiac myocytes. Furthermore, we hypothesized that this dynamical mechanism may account for previous reports of subcellular alternans seen in statically paced, intact tissue.Using a physiologically realistic computational model of a cardiac myocyte, we show that our predicted pacing algorithm induces subcellular alternans in a manner consistent with theoretical predictions. We then use a combination of real-time electrophysiology and fluorescent calcium imaging to implement this protocol experimentally and show that it robustly induces subcellular alternans in isolated guinea pig ventricular myocytes. Finally, we use computational modeling to demonstrate that subcellular alternans can indeed be dynamically induced during static pacing of 1D fibers of myocytes during tissue-level spatially discordant alternans.Here we provide the first direct experimental evidence that subcellular alternans can be dynamically induced in cardiac myocytes. This proposed mechanism may contribute to subcellular alternans formation in the intact heart.

Dataset Information

Mechanism of pacemaking in I(K1)-downregulated myocytes.

Publications

Mechanism of pacemaking in I(K1)-downregulated myocytes.

Similar Datasets

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