Embryotoxic effects of L-691,121, a class III antiarrhythmic agent, in rats.

Abstract

L-691,121 is a class III antiarrhythmic agent which blocks potassium currents, leading to prolongation of cardiac potential and prevention of cardiac arrhythmia. In a developmental toxicity study in rats, there was a dose-dependent decrease in embryonic/fetal survival, and death of the entire litter was seen at an oral dose of 0.8 mg/kg per day. The critical period for embryolethality was determined as gestational days (GD) 10-13. In a study where females received 1 mg/kg on a critical day (GD 10 or 12) and were killed at 24-h intervals, a high embryonic mortality was seen at 72 h (GD 10 treatment) or 48 h (GD 12 treatment) after dosing. The surviving embryos had morphological abnormalities such as enlarged cardiac tube and pericardium, generalized edema, and hematoma. In order to investigate a possible mechanism for the embryolethality, GD 11 embryos were dissected from females at 4 h after dosing of 1 mg/kg and incubated for 5 h in vitro. The embryonic heart rates were decreased for the first 2 h after incubation but tended to recover to control levels thereafter. When GD 11 embryos were incubated for 4 h with the drug, there were decreases in the heart rates during the entire observation period. In a washout study where the embryos were transferred to drug-free medium after 1-h exposure, decreased heart rates recovered to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: Y Ban, R Konishi, K Kawana, T Nakatsuka, T Fujii, J M Manson
• Journal: Archives of toxicology (Arch Toxicol) Vol. 69 Issue 1 Pg. 65-71 ( 1994) ISSN: 0340-5761 [Print] Germany
• PMID: 7717857 (Publication Type: Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• Piperidones
• Spiro Compounds
• L 691121

Topics

• Administration, Oral
• Animals
• Anti-Arrhythmia Agents (administration & dosage, toxicity)
• Cardiomegaly (chemically induced)
• Dose-Response Relationship, Drug
• Edema (chemically induced)
• Embryo, Mammalian (abnormalities, drug effects, pathology)
• Embryonic and Fetal Development (drug effects)
• Female
• Fetal Diseases (chemically induced, mortality)
• Gestational Age
• Heart Rate, Fetal (drug effects)
• Hematoma (chemically induced)
• Male
• Pericardium (drug effects, pathology)
• Piperidones (administration & dosage, toxicity)
• Pregnancy
• Rats
• Rats, Sprague-Dawley
• Spiro Compounds (administration & dosage, toxicity)