Sg. Spence et al., EFFECTS OF THE CLASS-III ANTIARRHYTHMIC, DOFETILIDE (UK-68,798) ON THE HEART-RATE OF MIDGESTATION RAT EMBRYOS, IN-VITRO, Teratology, 49(4), 1994, pp. 282-292
Gestation day 11 (GD11) and 14 (GD14) embryos were cultured for up to
4 hours in the presence of Dofetilide (0.01-0.50 mu g/ml), a potent Cl
ass III Antiarrhythmic which selectively inhibits the rapid component
of the time dependent outward potassium current (IKr). Significant (P
less than or equal to 0.05) reductions in heart rate (HR) as measured
over a 4 hour period were dose dependent and reversible. The sensitivi
ty 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 concentr
ations 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 Isopro
terenol or Theophylline. (C) 1994 Wiley-Liss, Inc.