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

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) -tetrakis(-ethylpyridinium-2-yl)porphyrin, AEOL10113, BMX-010 (MnTE-2-PyP), on rat heart as an entry to new strategies to circumvent cardiomyopathies.

Methods: 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.

Results: 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.

Conclusion: 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.