Redox-Active Drug, MnTE-2-PyP⁵⁺, Prevents and Treats Cardiac Arrhythmias Preserving Heart Contractile Function

Abstract

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.

Thiol regulation by Mn porphyrins, commonly known as SOD mimics

“…Ferrari’s team showed MnPs act as a suppressor of sclerotic events in aortic valves [38]. Another cardiac application of MnPs, demonstrated by Gomes’s team, is based on their ability to suppress arrhythmias thereby preserving heart contractile function [39]. MnPs are excellent suppressors of tumor growth particularly in the presence of chemotherapy, radiotherapy and ascorbate.…”

Can a Nonorganometallic Ruthenium(II) Polypyridylamine Complex Catalyze Hydride Transfer? Mechanistic Insight from Solution Kinetics on the Reduction of Coenzyme NAD+ by Formate

“…According to the latest reports, many serious diseases plaguing contemporary society are caused by redox imbalance in cells. − Elucidation of the relationship between oxidative/reductive stress and cellular inflammation, and the development of a so-called redox therapy, is one of the main tasks of the upcoming new discipline of redox biology. − It deals with the redox imbalance in cells, involves electron transfer of free radicals and nitrogen and oxygen metabolites (O 2 – , H 2 O 2 , OH • , 1 O 2 , NO • , ONOO – , NO 2 , and N 2 O 3 ), and focuses on an important sector of fundamental processes in biology. Reductive stress is defined as a relative shortage of reactive oxygen species (ROS) compared to the reducing equivalents in the form of redox couples such as NAD + /NADH (where NAD + and NADH are nicotinamide adenine dinucleotide and its reduced form, respectively).…”

Thermal Stability Kinetics and Shelf Life Estimation of the Redox‐Active Therapeutic and Mimic of Superoxide Dismutase Enzyme, Mn(III) meso‐Tetrakis(N‐ethylpyridinium‐2‐yl)porphyrin Chloride (MnTE‐2‐PyPCl5, BMX‐010)

“…MnTE-2-PyPCl 5 has an established reputation of being the Mn(III) 2-N-alkylpyridylporphyin-based prototype for the design of bioavailable SOD mimics, the development of catalytic antioxidants, and mechanistic studies [1,3,12,[15][16][17]. Given its safe toxicity profile in animal models and humans [1,9,10,13], MnTE-2-PyPCl 5 is usually the compound of choice in most exploratory preclinical studies [12,[17][18][19][20][21][22][23][24][25], being forwarded to translational medicine and clinical trials [1,9,10], and is now recognized as an excellent redox-active therapeutic [1], with well-defined pharmacokinetics [26,27]. Despite the large number of studies dedicated to unravelling the biological and clinical aspects of MnTE-2-PyPCl 5 both in vitro and in vivo [1,[16][17][18]22], studies on the stability of this class of compounds are still somewhat limited [28][29][30].…”