Background. 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. Methods. 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. Results. 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. Conclusion. 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.
Background
. 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-PyP
5+
), on rat heart as an entry to new strategies to circumvent cardiomyopathies.
Methods
. Wistar rats weighing 250-300 g were used in both
in vitro
and
in vivo
experiments, to analyze intracellular Ca
2+
dynamics, L-type Ca
2+
currents, Ca
2+
spark frequency, intracellular reactive oxygen species (ROS) levels, and cardiomyocyte and cardiac contractility, in control and MnTE-2-PyP
5+
-treated cells, hearts, or animals. Cells and hearts were treated with 20
μ
M MnTE-2-PyP
5+
and animals with 1 mg/kg, i.p. daily. Additionally, we performed electrocardiographic and echocardiographic analysis.
Results
. Using isolated rat cardiomyocytes, we observed that MnTE-2-PyP
5+
reduced intracellular Ca
2+
transient amplitude, without altering cell contractility. Whereas MnTE-2-PyP
5+
did not alter basal ROS levels, it was efficient in modulating cardiomyocyte redox state under stress conditions; MnTE-2-PyP
5+
reduced Ca
2+
spark frequency and increased sarcoplasmic reticulum (SR) Ca
2+
load. Accordingly, analysis of isolated perfused rat hearts showed that MnTE-2-PyP
5+
preserves cardiac function, increases SR Ca
2+
load, and reduces arrhythmia index, indicating an antiarrhythmic effect.
In vivo
experiments showed that MnTE-2-PyP
5+
treatment increased Ca
2+
transient, preserved cardiac ejection fraction, and reduced arrhythmia index and duration. MnTE-2-PyP
5+
was effective both to prevent and to treat cardiac arrhythmias.
Conclusion
. MnTE-2-PyP
5+
prevents and treats cardiac arrhythmias in rats. In contrast to most antiarrhythmic drugs, MnTE-2-PyP
5+
preserves cardiac contractile function, arising, thus, as a prospective therapeutic for improvement of cardiac arrhythmia treatment.
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)
-tetrakis(
-ethylpyridinium-2-yl)porphyrin, AEOL10113, BMX-010 (MnTE-2-PyP
), on rat heart as an entry to new strategies to circumvent cardiomyopathies.
Wistar rats weighing 250-300 g were used in both
and
experiments, to analyze intracellular Ca
dynamics, L-type Ca
currents, Ca
spark frequency, intracellular reactive oxygen species (ROS) levels, and cardiomyocyte and cardiac contractility, in control and MnTE-2-PyP
-treated cells, hearts, or animals. Cells and hearts were treated with 20
M MnTE-2-PyP
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-PyP
reduced intracellular Ca
transient amplitude, without altering cell contractility. Whereas MnTE-2-PyP
did not alter basal ROS levels, it was efficient in modulating cardiomyocyte redox state under stress conditions; MnTE-2-PyP
reduced Ca
spark frequency and increased sarcoplasmic reticulum (SR) Ca
load. Accordingly, analysis of isolated perfused rat hearts showed that MnTE-2-PyP
preserves cardiac function, increases SR Ca
load, and reduces arrhythmia index, indicating an antiarrhythmic effect.
experiments showed that MnTE-2-PyP
treatment increased Ca
transient, preserved cardiac ejection fraction, and reduced arrhythmia index and duration. MnTE-2-PyP
was effective both to prevent and to treat cardiac arrhythmias.
MnTE-2-PyP
prevents and treats cardiac arrhythmias in rats. In contrast to most antiarrhythmic drugs, MnTE-2-PyP
preserves cardiac contractile function, arising, thus, as a prospective therapeutic for improvement of cardiac arrhythmia treatment.
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