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Protective efficacy of dinitrosyl iron complexes with reduced glutathione in cardioplegia and reperfusion

  • Molecular and cellular mechanisms of disease
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Abstract

Disturbed homeostasis of nitric oxide (NO) is one of the causes of myocardial ischemia/reperfusion (I/R) injury during open-heart surgery. This study was designed to explore mechanisms of action of dinitrosyl iron complexes with reduced glutathione ({(GS−)2Fe+(NO+)2}+, DNIC-GS) added to crystalloid cardioplegia or reperfusion solution in isolated working rat hearts. Hearts of male Wistar rats were subjected to cardioplegic arrest by St. Thomas’ Hospital cardioplegic solution (STH) and normothermic global ischemia followed by reperfusion. DNIC-GS were used with STH or during early reperfusion. Lactate dehydrogenase (LDH) activity in the coronary effluent and myocardial contents of adenine nucleotides, phosphocreatine, and lactate were determined spectrophotometrically. Reactive oxygen species (ROS) formation in the coronary effluent and myocardial DNIC content was assessed by EPR technique. Cardioplegia or reperfusion with DNIC-GS significantly improved recovery of coronary flow and cardiac function compared with control. Carboxy-[2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidozoline-1-oxy-3-oxide] (C-PTIO), a selective NO scavenger, reduced/abolished protective action of DNIC-GS. Enhanced recovery of cardiac function with DNIC-GS reduced LDH release in the coronary effluent, augmented recovery of myocardial energy state, and decreased formation of ROS-generating systems at reperfusion. Beneficial effects of DNIC-GS were related to the transfer of [Fe(NO)2] cores to thiol groups of myocardial proteins to form intracellular DNIC pools. The study concluded that DNIC-GS is a promising adjunct agent for metabolic and antioxidant protection of the heart during cardioplegic arrest and reperfusion.

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Acknowledgements

The authors are grateful to Dr. V. Shulzhenko for conducting experiments on isolated perfused rat hearts.

Funding

This work was supported by the Russian Foundation for Basic Research (grant No. 15-04-00359).

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Authors and Affiliations

  1. Laboratory for Myocardial Metabolism, National Medical Research Center for Cardiology, 3rd Cherepkovskaya Str., 15A, Moscow, Russian Federation, 121552

    Oleg Pisarenko, Irina Studneva, Alexander Timoshin & Oksana Veselova

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  1. Oleg Pisarenko
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  2. Irina Studneva
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  3. Alexander Timoshin
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  4. Oksana Veselova
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Contributions

IS and OP designed and planned the study. AT carried out EPR experiments and EPR spectroscopy analyses. OV determined LDH activity in myocardial effluents and performed the statistical analyses. IS carried out determination of metabolites. OP, IS, and AT wrote the manuscript. All authors read, edited, and approved the final manuscript.

Corresponding author

Correspondence to Oleg Pisarenko.

Ethics declarations

The care and use of the animals were conducted in accordance with the European Convention for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes (no. 123 of March 18, 1986).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures were approved by the Bioethical Committee for Animal Care of the National Medical Research Center for Cardiology (permission no. 10 of April 25, 2017).

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Pisarenko, O., Studneva, I., Timoshin, A. et al. Protective efficacy of dinitrosyl iron complexes with reduced glutathione in cardioplegia and reperfusion. Pflugers Arch - Eur J Physiol 471, 583–593 (2019). https://doi.org/10.1007/s00424-018-02251-2

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  • DOI: https://doi.org/10.1007/s00424-018-02251-2

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