EMBRYOTOXIC EFFECTS OF L-691,121, A CLASS-III ANTIARRHYTHMIC AGENT, IN RATS

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 qestational 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. In GD 11 embryos cultured for 24 h with the drug, then were gross abnormalities that consisted of altered yolk sac and embryonic circulation. and enlargement of cardiac tube and pericardium similar to those seen in the preceding in vivo study. These results suggest that decreased heart rates, reduced yolk sac circulation and the associated morphological abnormalities induced by L-691,121 are related to the embryolethality in rats.