Effect of phenytoin on maternal heart rate in A/J mice: possible role in teratogenesis.
Phenytoin (diphenylhydantoin, Dilantin, PHT), an anticonvulsant and antiarrhythmic drug, is teratogenic to A/J mice, producing an increased incidence of cleft lip with or without cleft palate [CL(P)] and cardiac defects. Although its mechanism of teratogenic action remains unclear, one possibility may involve uterine ischemia resulting from an exaggerated depressant effect on maternal cardiovascular function. To test this hypothesis, the heart rate response of susceptible A/J and resistant C57Bl/6J mice was monitored following intraperitoneal injection of doses of PHT of known teratogenic potential. Heart rate (HR) was obtained electrocardiographically from unanesthetized, pregnant mice on day 10 of gestation via previously implanted subcutaneous electrodes. The HR of A/J mice was significantly depressed relative to vehicle-injected controls following doses of 40, 60, and 75 mg/kg, with the greatest effect occurring in the high-dose group. In C57Bl/6J mice, the HR response of the group treated with 75 mg/kg was not different from that of the vehicle-treated controls. At the same dose level, the depression of HR of A/J mice was significantly greater in magnitude and duration than that of C57Bl/6J mice. A proposed maternally mediated mechanism of CL(P) in A/J mice involving low placental/embryonic oxygen delivery is discussed. The results of the present study indicate the potential significance that changes in maternal physiology may have on embryonic development.
D000014:Abnormalities, Drug-Induced / Q000503:physiopathology*; D000818:Animals; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D010672:Phenytoin / Q000633:toxicity*; D011247:Pregnancy; D013723:Teratogens
D013723:Teratogens; D010672:Phenytoin