title: Noninvasive high-resolution ultrasound reveals structural and functional deficits in dimethadione-exposed fetal rat hearts in utero.
abstract: BACKGROUND
  We previously showed dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant trimethadione, induces ventricular septation defects (VSD) and other heart anomalies in rat (Weston et al., 2011). Because of the relationship between cardiac structure and function, we hypothesized that DMO-induced structural defects of the heart are associated with in utero functional deficits. To test the hypothesis, the goals were (1) define the parameters for ultrasound in the rat conceptus, and; (2) use ultrasound to identify structural and functional deficits following DMO treatment.
  
  
  METHODS
  Different ultrasound modes (B-mode, M-mode, and Pulse-wave Doppler) using four high-resolution ultrasound transducer heads of varying frequency (25-40 MHz) were tested on gestational day (GD) 14, 15, 16, 17, and 21. Having identified the optimal conditions, pregnant Sprague-Dawley rats were administered six 300 mg/kg doses of DMO every 12 hr beginning at 19:00 hr on GD 8 to generate conceptuses with a high incidence of VSD.
  
  
  RESULTS
  The three ultrasound modalities were used to identify VSD and several novel and rare structural heart anomalies (cardiac effusions and bifurcated septum) in live rat fetuses. DMO-treated hearts had an array of functional deficits including a decrease in mean heart rate, ejection fraction, and cardiac output and increased incidence of bradycardia and dysrhythmia.
  
  
  CONCLUSIONS
  The ultrasound biomicroscope is an effective tool for the real-time characterization of the structure and function of embryo/fetal rat hearts. DMO causes significant deficits to in utero heart function for up to ten days (GD 21) following its final administration, suggesting long-term or possible permanent changes cardiac function.
authors: Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
authors: Elizabeth
authors: E
authors: Purssell
authors: Andrea D
authors: AD
authors: Weston
authors: Jason J
authors: JJ
authors: Thomson
authors: Terri A
authors: TA
authors: Swanson
authors: Nigel A
authors: NA
authors: Brown
authors: Terence R S
authors: TR
authors: Ozolinš
mesh_terms: D000818:Animals; D004114:Dimethadione / Q000009:adverse effects*; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000503:physiopathology*; D006321:Heart / Q000187:drug effects / Q000196:embryology* / Q000503:physiopathology*; D006334:Heart Function Tests; D006339:Heart Rate / Q000187:drug effects; D006345:Heart Septal Defects, Ventricular / Q000000981:diagnostic imaging; D007530:Isoflurane / Q000009:adverse effects; D009200:Myocardial Contraction / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014465:Ultrasonics; D014463:Ultrasonography
chemical_list: D004114:Dimethadione; D007530:Isoflurane