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Heparin Oligosaccharides Have Antiarrhythmic Effect by Accelerating the Sodium-Calcium Exchanger.

Abstract

Background:

Blockage of the Na+/Ca2+ exchanger (NCX) is used to determine the role of NCX in arrhythmogenesis. Trisulfated heparin disaccharide (TD) and Low Molecular Weight Heparins (LMWHs) can directly interact with the NCX and accelerate its activity.

Objective:

In this work, we investigated the antiarrhythmic effect of heparin oligosaccharides related to the NCX activity.

Methods:

The effects of heparin oligosaccharides were tested on the NCX current (patch clamping) and intracellular calcium transient in rat cardiomyocytes. The effects of heparin oligosaccharides were further investigated in arrhythmia induced in isolated rat atria and rats in vivo.

Results:

The intracellular Ca2+ concentration decreases upon treatment with either enoxaparin or ardeparin. These drugs abolished arrhythmia induction in isolated atria. The NCX antagonist KB-R7943 abolished the enoxaparin or ardeparin antiarrhythmic effects in isolated atria. In the in vivo measurements, injection of TD 15 min both before coronary occlusion or immediately after reperfusion, significantly prevented the occurrence of reperfusion-induced arrhythmias (ventricular arrhythmia and total AV block) and reduced the lethality rate. The patch clamping experiments showed that, mechanistically, TD increases the forward mode NCX current.

Conclusion:

Together, the data shows that heparin oligosaccharides may constitute a new class of antiarrhythmic drug that acts by accelerating the forward mode NCX under calcium overload.

Authors+Show Affiliations

Institute of Science and Technology, Universidade Federal de São Paulo, São Paulo, Brazil.Department of Gastroenterology (LIM 37), Medical School, University of São Paulo, São Paulo, Brazil. Núcleo de Pesquisas Tecnológicas, Universidade de Mogi das Cruzes, Mogi das Cruzes, Brazil.Department of Pharmacology, Universidade Federal de São Paulo, São Paulo, Brazil.Department of Pharmacology, Universidade Federal de São Paulo, São Paulo, Brazil.Department of Pharmacology, Universidade Federal de São Paulo, São Paulo, Brazil.Núcleo de Pesquisas Tecnológicas, Universidade de Mogi das Cruzes, Mogi das Cruzes, Brazil.Department of Biochemistry, Universidade Federal de São Paulo, São Paulo, Brazil.Department of Biochemistry, Universidade Federal de São Paulo, São Paulo, Brazil.Department of Biochemistry, Universidade Federal de São Paulo, São Paulo, Brazil.Department of Biochemistry, Universidade Federal de São Paulo, São Paulo, Brazil. Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi das Cruzes, Mogi das Cruzes, Brazil.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29930947

Citation

de Godoy, Carlos M G., et al. "Heparin Oligosaccharides Have Antiarrhythmic Effect By Accelerating the Sodium-Calcium Exchanger." Frontiers in Cardiovascular Medicine, vol. 5, 2018, p. 67.
de Godoy CMG, Vasques ÊR, Caricati-Neto A, et al. Heparin Oligosaccharides Have Antiarrhythmic Effect by Accelerating the Sodium-Calcium Exchanger. Front Cardiovasc Med. 2018;5:67.
de Godoy, C. M. G., Vasques, Ê. R., Caricati-Neto, A., Tavares, J. G. P., Alves, B. J., Duarte, J., ... Tersariol, I. L. D. S. (2018). Heparin Oligosaccharides Have Antiarrhythmic Effect by Accelerating the Sodium-Calcium Exchanger. Frontiers in Cardiovascular Medicine, 5, p. 67. doi:10.3389/fcvm.2018.00067.
de Godoy CMG, et al. Heparin Oligosaccharides Have Antiarrhythmic Effect By Accelerating the Sodium-Calcium Exchanger. Front Cardiovasc Med. 2018;5:67. PubMed PMID: 29930947.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Heparin Oligosaccharides Have Antiarrhythmic Effect by Accelerating the Sodium-Calcium Exchanger. AU - de Godoy,Carlos M G, AU - Vasques,Ênio R, AU - Caricati-Neto,Afonso, AU - Tavares,José G P, AU - Alves,Beatriz J, AU - Duarte,Juliana, AU - Miranda-Ferreira,Regiane, AU - Lima,Marcelo A, AU - Nader,Helena B, AU - Tersariol,Ivarne L Dos Santos, Y1 - 2018/06/07/ PY - 2017/12/23/received PY - 2018/05/17/accepted PY - 2018/6/23/entrez PY - 2018/6/23/pubmed PY - 2018/6/23/medline KW - arrhythmia KW - calcium overload KW - low molecular weight heparin KW - sodium-calcium exchanger KW - trisulfated heparin disaccharide SP - 67 EP - 67 JF - Frontiers in cardiovascular medicine JO - Front Cardiovasc Med VL - 5 N2 - Background: Blockage of the Na+/Ca2+ exchanger (NCX) is used to determine the role of NCX in arrhythmogenesis. Trisulfated heparin disaccharide (TD) and Low Molecular Weight Heparins (LMWHs) can directly interact with the NCX and accelerate its activity. Objective: In this work, we investigated the antiarrhythmic effect of heparin oligosaccharides related to the NCX activity. Methods: The effects of heparin oligosaccharides were tested on the NCX current (patch clamping) and intracellular calcium transient in rat cardiomyocytes. The effects of heparin oligosaccharides were further investigated in arrhythmia induced in isolated rat atria and rats in vivo. Results: The intracellular Ca2+ concentration decreases upon treatment with either enoxaparin or ardeparin. These drugs abolished arrhythmia induction in isolated atria. The NCX antagonist KB-R7943 abolished the enoxaparin or ardeparin antiarrhythmic effects in isolated atria. In the in vivo measurements, injection of TD 15 min both before coronary occlusion or immediately after reperfusion, significantly prevented the occurrence of reperfusion-induced arrhythmias (ventricular arrhythmia and total AV block) and reduced the lethality rate. The patch clamping experiments showed that, mechanistically, TD increases the forward mode NCX current. Conclusion: Together, the data shows that heparin oligosaccharides may constitute a new class of antiarrhythmic drug that acts by accelerating the forward mode NCX under calcium overload. SN - 2297-055X UR - https://www.unboundmedicine.com/medline/citation/29930947/Heparin_Oligosaccharides_Have_Antiarrhythmic_Effect_by_Accelerating_the_Sodium-Calcium_Exchanger L2 - https://dx.doi.org/10.3389/fcvm.2018.00067 DB - PRIME DP - Unbound Medicine ER -