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In vivo arrhythmogenicity of the marine biotoxin azaspiracid-2 in rats

Abstract

Azaspiracids (AZAs) are marine biotoxins produced by the dinoflagellate Azadinium spinosum that accumulate in several shellfish species. Azaspiracid poisoning episodes have been described in humans due to ingestion of AZA-contaminated seafood. Therefore, the contents of AZA-1, AZA-2 and AZA-3, the best-known analogs of the group, in shellfish destined to human consumption have been regulated by food safety authorities of many countries to protect human health. In vivo and in vitro toxicological studies have described effects of AZAs at different cellular levels and on several organs, however, AZA target remains unknown. Very recently, AZAs have been demonstrated to block the hERG cardiac potassium channel. In this study, we explored the potential cardiotoxicity of AZA-2 in vivo. The effects of AZA-2 on rat electrocardiogram (ECG) and cardiac biomarkers were evaluated for cardiotoxicity signs besides corroborating the hERG-blocking activity of AZA-2. Our results demonstrated that AZA-2 does not induce QT interval prolongation on rat ECGs in vivo, in spite of being an in vitro blocker of the hERG cardiac potassium channel. However, AZA-2 alters the heart electrical activity causing prolongation of PR intervals and the appearance of arrhythmias. More studies will be needed to clarify the mechanism by which AZA-2 causes these ECG alterations; however, the potential cardiotoxicity of AZAs demonstrated in this in vivo study should be taken into consideration when evaluating the possible threat that these toxins pose to human health, mainly for individuals with pre-existing cardiovascular disease when regulated toxin limits are exceeded.

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Acknowledgments

This work was funded with the following FEDER cofunded-grants: From Ministerio de Ciencia y Tecnología, Spain: SAF2009-12581 (subprograma NEF), AGL2009 13581-CO2-01, TRA2009-0189, AGL2010-17875. From Xunta de Galicia, Spain: GRC 2010/10, and PGDIT 07MMA006261PR, PGIDIT (INCITE) 09MMA003261PR, PGDIT (INCITE) 09261080PR, 2009/XA044 and 10PXIB261254 PR. From EU VIIth Frame Program: 211326-CP (CONffIDENCE), 265896 BAMMBO, 265409 μAQUA, and 262649 BEADS, 312184 PharmaSea, 315285 Ciguatools. From the Atlantic Area Programme (Interreg IVB Trans-national): 2009-1/117 Pharmatlantic. From the National Institutes of Health (USA) (Grant ES013314, to K.C.N.). No competing financial interests.

Conflict of interest

The authors declare that they have no conflict of interest.

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Correspondence to Natalia Vilariño or Luis M. Botana.

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Ferreiro, S.F., Vilariño, N., Carrera, C. et al. In vivo arrhythmogenicity of the marine biotoxin azaspiracid-2 in rats. Arch Toxicol 88, 425–434 (2014). https://doi.org/10.1007/s00204-013-1115-4

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Keywords

  • Azaspiracid
  • Cardiotoxicity
  • hERG
  • ECG
  • Cardiac biomarkers