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Phase 1 repolarization rate defines Ca(2+) dynamics and contractility on intact mouse hearts

In the heart, Ca(2+) influx through L-type Ca(2+) channels triggers Ca(2+) release from the sarcoplasmic reticulum. In most mammals, this influx occurs during the ventricular action potential (AP) plateau phase 2. However, in murine models, the influx through L-type Ca(2+) channels happens in early...

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Detalles Bibliográficos
Autores principales: López Alarcón, María Micaela, Rodríguez de Yurre, Ainhoa, Felice, Juan Ignacio, Medei, Emiliano, Escobar, Ariel L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571993/
https://www.ncbi.nlm.nih.gov/pubmed/31000581
http://dx.doi.org/10.1085/jgp.201812269
Descripción
Sumario:In the heart, Ca(2+) influx through L-type Ca(2+) channels triggers Ca(2+) release from the sarcoplasmic reticulum. In most mammals, this influx occurs during the ventricular action potential (AP) plateau phase 2. However, in murine models, the influx through L-type Ca(2+) channels happens in early repolarizing phase 1. The aim of this work is to assess if changes in the open probability of 4-aminopyridine (4-AP)–sensitive Kv channels defining the outward K(+) current during phase 1 can modulate Ca(2+) currents, Ca(2+) transients, and systolic pressure during the cardiac cycle in intact perfused beating hearts. Pulsed local-field fluorescence microscopy and loose-patch photolysis were used to test the hypothesis that a decrease in a transient K(+) current (I(to)) will enhance Ca(2+) influx and promote a larger Ca(2+) transient. Simultaneous recordings of Ca(2+) transients and APs by pulsed local-field fluorescence microscopy and loose-patch photolysis showed that a reduction in the phase 1 repolarization rate increases the amplitude of Ca(2+) transients due to an increase in Ca(2+) influx through L-type Ca(2+) channels. Moreover, 4-AP induced an increase in the time required for AP to reach 30% repolarization, and the amplitude of Ca(2+) transients was larger in epicardium than endocardium. On the other hand, the activation of I(to) with NS5806 resulted in a reduction of Ca(2+) current amplitude that led to a reduction of the amplitude of Ca(2+) transients. Finally, the 4-AP effect on AP phase 1 was significantly smaller when the L-type Ca(2+) current was partially blocked with nifedipine, indicating that the phase 1 rate of repolarization is defined by the competition between an outward K(+) current and an inward Ca(2+) current.