Stage-specific skeletal and visceral defects of the I(Kr)-blocker almokalant: further evidence for teratogenicity via a hypoxia-related mechanism.
BACKGROUND
As a class effect, potent I(Kr)-blockers have been shown to induce stage-specific external malformations. The aim of this study was to investigate whether I(Kr)-blockers also induce stage-specific visceral and skeletal defects and to further elucidate a proposed arrhythmia-hypoxia hypothesis.


METHODS
Single oral doses of the selective I(Kr)-blocker almokalant (ALM) 25-150 micromol/kg, 7-14 dams/group, were given to Sprague-Dawley rats on gestation days (GD) 10-14, and the fetuses were examined for malformations on GD 21. One group was pretreated with the spin-trapping agent, alpha-phenyl-N-t-butylnitrone (PBN), given intraperitoneally 1 hr before ALM on GD 11.


RESULTS
Cardiac ventricular septum defects and vascular malformations were observed after dosing on GD 10-11 and, to a lesser degree, on GD 12-13. Urogenital defects, absence/malposition of the postcaval lung lobe, and attenuated diaphragm were observed mainly on GD 10-11. Skeletal examination showed a high incidence of vertebral abnormalities on thoracic level on GD 10, on lower thoracic to caudal level on GD 11, and sternebral defects were observed all days. On GD 13 brachy-, oligo-, and syndactyly of the forepaw were induced, and of the hindpaw on GD 14. PBN reduced the incidence of both visceral and skeletal defects.


CONCLUSIONS
The stage specificity of observed visceral and skeletal defects correlates well with what has been reported in the literature after temporary interruption of oxygen supply during the same stages of development. The protective effect by PBN present further evidence that the teratogenicity of potent I(Kr)-blockers is related to induction of hypoxia- reoxygenation injury due to embryonic cardiac arrhythmia.
Sköld
A C
AC
Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Box 594, 5751 24 Uppsala, Sweden. anna-carin.skold@astrazeneca.com
Wellfelt
K
K
Danielsson
B R
BR
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000633:toxicity*; D001842:Bone and Bones / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000187:drug effects / Q000196:embryology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D000860:Hypoxia; D007726:Krypton / Q000378:metabolism; D008297:Male; D010100:Oxygen / Q000378:metabolism; D011247:Pregnancy; D011412:Propanolamines / Q000009:adverse effects / Q000633:toxicity*; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D011412:Propanolamines; D013723:Teratogens; D007726:Krypton; C074334:almokalant; D010100:Oxygen