Effects of the class III antiarrhythmic, dofetilide (UK-68,798) on the heart rate of midgestation rat embryos, in vitro.
Gestation day 11 (GD11) and 14 (GD14) embryos were cultured for up to 4 hours in the presence of Dofetilide (0.01-0.50 microgram/ml), a potent Class III Antiarrhythmic which selectively inhibits the rapid component of the time dependent outward potassium current (IKr). Significant (P < or = 0.05) reductions in heart rate (HR) as measured over a 4 hour period were dose dependent and reversible. The sensitivity of the GD11 embryos was greater than GD14 embryos (14-64% decrease in HR vs. an 11-43% decrease in HR, respectively) at the same concentrations tested. These in vitro results support the hypothesis that the embryo-lethality of Class III Antiarrhythmics observed in vivo may be a class effect of the IKr subtype potassium channel blockers. The data suggest a possible mechanism of embryotoxicity is to lower embryonic HR resulting in subsequent hypoxia and death. Dofetilide's effects on GD11 HR were partially reversible by the sequential addition of Isoproterenol or Theophylline.
Spence
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Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486.
Vetter
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Hoe
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D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D046508:Culture Techniques; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects*; D000860:Hypoxia / Q000139:chemically induced / Q000196:embryology; D010627:Phenethylamines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000633:toxicity*
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide