Induction of rhythm abnormalities in the fetal rat heart. A tentative mechanism for the embryotoxic effect of the class III antiarrhythmic agent almokalant.
OBJECTIVE
The aim was to test the hypothesis that the recently reported embryotoxic effect of class III antiarrhythmic agents may be a result of electrophysiological disturbances induced by these agents.


METHODS
Comparative studies of drug effects in the adult and fetal rat were performed using three experimental models: (1) effects of almokalant upon pregnancy and fetal mortality in rats given daily doses of 0, 10, 50, 100, or 400 mumol.kg-1 orally in the diet on days 6-15 of pregnancy; (2) effects of d-sotalol (1-1000 microM), almokalant (0.1-100 microM) and dofetilide (0.01-10 microM) on the adult and fetal cardiac action potential in vitro; (3) voltage clamp recordings in single fetal and adult ventricular myocytes superfused with almokalant (0.5 microM).


RESULTS
In the groups of rats treated with 100 and 400 mumol.kg-1, respectively, the body weight gain was decreased from day 12 of gestation, and there were no viable fetuses at termination of pregnancy. In atrial as well as ventricular tissue, the class III agents induced a concentration dependent prolongation of the fetal action potential duration, accompanied by a reduction in heart rate and eventually the appearance of rhythm abnormalities and/or early afterdepolarisations. The adult action potential duration remained unaffected. An almokalant sensitive current (probably the delayed rectifier, IK) could be evoked both in the fetal and in the adult ventricular cells.


CONCLUSIONS
Class III antiarrhythmic agents were shown to induce fetal mortality and rhythm abnormalities in the rat heart. Although they do not prove a causal relationship between these effects, our observations may have implications for the clinical use of class III antiarrhythmic agents in women of childbearing potential.
Abrahamsson
C
C
Astra Hässle AB, Preclinical Research and Development, Cardiovascular Pharmacology, Mölndal, Sweden.
Palmer
M
M
Ljung
B
B
Duker
G
G
Bäärnhielm
C
C
Carlsson
L
L
Danielsson
B
B
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D002478:Cells, Cultured; D046508:Culture Techniques; D005260:Female; D005313:Fetal Death / Q000139:chemically induced*; D005318:Fetal Heart / Q000187:drug effects*; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D010627:Phenethylamines / Q000494:pharmacology; D011247:Pregnancy; D011412:Propanolamines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D011412:Propanolamines; D013449:Sulfonamides; D013015:Sotalol; C074334:almokalant; C063533:dofetilide