In vivo arrhythmogenicity of the marine biotoxin azaspiracid-2 in rats.
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.
Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002, Lugo, Spain.
Sara F
SF
Ferreiro
Natalia
N
Vilariño
Cristina
C
Carrera
M Carmen
MC
Louzao
Germán
G
Santamarina
Antonio G
AG
Cantalapiedra
Laura P
LP
Rodríguez
J Manuel
JM
Cifuentes
Andrés C
AC
Vieira
K C
KC
Nicolaou
Michael O
MO
Frederick
Luis M
LM
Botana
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D015415:Biomarkers / Q000097:blood; D016466:CHO Cells / Q000187:drug effects; D003412:Cricetulus; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism; D005260:Female; D005663:Furans / Q000633:toxicity*; D009206:Myocardium / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011714:Pyrans / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000095702:Polyether Toxins
D015415:Biomarkers; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005663:Furans; D026902:Potassium Channel Blockers; D011714:Pyrans; C000606913:KCNH2 protein, human; C520447:azaspiracid-2; D000095702:Polyether Toxins