Teratogenicity of the class III antiarrhythmic drug almokalant. Role of hypoxia and reactive oxygen species.
The class III antiarrhythmic drug almokalant (ALM) was given to pregnant rats on Gestation Day 11 (125 micromol/kg) or 13 (25 micromol/kg). Other groups were pretreated with alpha-phenyl-N-t-butylnitrone, (PBN; 850 micromol/kg intraperitoneally) 1 h before administration of ALM or given (-)-2-oxo-4-thiazolidine carboxylic acid (OTC; 250 micromol/kg subcutaneously) 4 h before administration of ALM. PBN is a spin-trapping agent that can capture reactive oxygen species (ROS), and OTC is an antioxidant. Controls received tap water only. All groups (eight in total) consisted of 7 to 10 pregnant rats. ALM induced cardiovascular defects, orofacial clefts, and tail defects after administration on Day 11, and reduced the size of digits on Day 13. Pretreatment with PBN prevented induction of all the above-mentioned malformations by ALM. The results also indicated that OTC may have some protective effect against ALM-induced teratogenicity but not to the same extent as PBN. The results support the hypothesis that almokalant induces malformations via induction of episodes of embryonic arrhythmia/cardiac arrest, which result in hypoxia followed by reoxygenation and generation of ROS.
Wellfelt
K
K
Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
Sköld
A C
AC
Wallin
A
A
Danielsson
B R
BR
D000014:Abnormalities, Drug-Induced / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D018376:Cardiovascular Abnormalities / Q000139:chemically induced; D003497:Cyclic N-Oxides; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D009589:Nitrogen Oxides / Q000494:pharmacology; D011247:Pregnancy; D011412:Propanolamines / Q000378:metabolism / Q000633:toxicity*; D011761:Pyrrolidonecarboxylic Acid; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013113:Spin Labels; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines
D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; D003497:Cyclic N-Oxides; D009589:Nitrogen Oxides; D011412:Propanolamines; D017382:Reactive Oxygen Species; D013113:Spin Labels; D013844:Thiazoles; D053778:Thiazolidines; C029217:phenyl-N-tert-butylnitrone; C074334:almokalant; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid