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Redox-Active Drug, MnTE-2-PyP 5+ , Prevents and Treats Cardiac Arrhythmias Preserving Heart Contractile Function

2020; Hindawi Publishing Corporation; Volume: 2020; Linguagem: Inglês

10.1155/2020/4850697

ISSN

1942-0900

Autores

Andrezza Miná Barbosa, José F. Sarmento-Neto, José Evaldo Rodrigues de Menezes‐Filho, Itamar Couto Guedes de Jesus, Diego Santos Souza, Valério M. N. Vasconcelos, Fagner D. L. Gomes, Aline Lara, Juliana Sousa Soares de Araújo, Sandra da Silva Mattos, Carla Maria Lins de Vasconcelos, Sílvia Guatimosim, Jáder Santos Cruz, Ines Batinic̈‐Haberle, Demétrius A. M. Araújo, Júlio S. Rebouças, Enéas Ricardo de Morais Gomes,

Tópico(s)

Cardiac Imaging and Diagnostics

Resumo

Cardiomyopathies remain among the leading causes of death worldwide, despite all efforts and important advances in the development of cardiovascular therapeutics, demonstrating the need for new solutions. Herein, we describe the effects of the redox-active therapeutic Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, AEOL10113, BMX-010 (MnTE-2-PyP5+), on rat heart as an entry to new strategies to circumvent cardiomyopathies.Wistar rats weighing 250-300 g were used in both in vitro and in vivo experiments, to analyze intracellular Ca2+ dynamics, L-type Ca2+ currents, Ca2+ spark frequency, intracellular reactive oxygen species (ROS) levels, and cardiomyocyte and cardiac contractility, in control and MnTE-2-PyP5+-treated cells, hearts, or animals. Cells and hearts were treated with 20 μM MnTE-2-PyP5+ and animals with 1 mg/kg, i.p. daily. Additionally, we performed electrocardiographic and echocardiographic analysis.Using isolated rat cardiomyocytes, we observed that MnTE-2-PyP5+ reduced intracellular Ca2+ transient amplitude, without altering cell contractility. Whereas MnTE-2-PyP5+ did not alter basal ROS levels, it was efficient in modulating cardiomyocyte redox state under stress conditions; MnTE-2-PyP5+ reduced Ca2+ spark frequency and increased sarcoplasmic reticulum (SR) Ca2+ load. Accordingly, analysis of isolated perfused rat hearts showed that MnTE-2-PyP5+ preserves cardiac function, increases SR Ca2+ load, and reduces arrhythmia index, indicating an antiarrhythmic effect. In vivo experiments showed that MnTE-2-PyP5+ treatment increased Ca2+ transient, preserved cardiac ejection fraction, and reduced arrhythmia index and duration. MnTE-2-PyP5+ was effective both to prevent and to treat cardiac arrhythmias.MnTE-2-PyP5+ prevents and treats cardiac arrhythmias in rats. In contrast to most antiarrhythmic drugs, MnTE-2-PyP5+ preserves cardiac contractile function, arising, thus, as a prospective therapeutic for improvement of cardiac arrhythmia treatment.

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