Effects of the class III Antiarrhythmic, Dofetilide (UK‐68,798) on the heart rate of midgestation rat embryos, in vitro

Abstract

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.

Developmental Toxicity in the Pregnant Rabbit by theClass III Antiarrhythmic Drug Sotalol

“…Developmental toxicity occurred at doses causing no adverse effects in the mothers, with the exception of the two deaths that will be discussed later in this section. The observed sotalol-induced embryonic death in this study is in accordance with what has been shown for other Ikr blockers in studies in rats (Ban et al 1994;Spence et al 1994;Marks & Terry 1996;Webster et al 1996) and in mice (Skö ld & Danielsson, 2000). Single-dose administration during Day 9, 10, 11, 12, 13, or 14 of the selective Ikr blockers dofetilide and almokalant in rats (Spence et al 1994;Webster et al 1996) resulted in embryonic death.…”

“…These data suggest that Ikr channels are expressed and functional when the embryonic heart starts beating, which occurs on Day 9.6 in the rat (Ban et al 1994). The results also suggest that the rabbit is a sensitive species for induction of developmental toxicity of Ikr blockers in the same way as has previously been shown for the mouse and the rat (see above) (Spence et al 1994;Webster et al 1996). However, in contrast to the rat where the Ikr channel is most likely suppressed in favour of other repolarisation ion channels on Days 14-15, developmental toxicity was also observed on Days 15-16 in the rabbit.…”

“…In rodent embryos cultured in vitro during the susceptible period, a dose-dependent occurrence of embryonic bradycardia, arrhythmia and cardiac arrest has been noticed for almokalant and dofetilide (Spence et al 1994;Webster et al 1996) and L-691,121 (Ban et al 1994). The results in these in vivo and in vitro studies show a very good correlation between maternal concentrations, which were related with embryonic death, and concentrations that caused severe dysrhythmia.…”

“…In rat embryo, a susceptible period seems to exist between Days 9-14. Embryos cultured in vitro during this period show dose-dependent bradycardia, arrhythmia and cardiac arrest after exposure to almokalant, dofetilide and L-691,121 (Spence et al 1994;Webster et al 1996). Pharmacologically induced embryonic bradycardia and arrhythmia have been proposed to be the underlying mechanism for developmental toxicity observed after administration of these agents in vivo in rodents (Abrahamsson et al 1994;Webster et al 1996;Skö ld & Danielsson 2000).…”

Expression of the IKr components KCNH2 (rERG) and KCNE2 (rMiRP1) during late rat heart development

“…This idea has been supported by the observation of embryotoxic effects in pregnant rats, where application of IKr specific channel blocker, dofetilide, has been described to strongly impair the rhythm of embryonic hearts with lethal effects (Spence et al,1994;Webster et al, 1996). To explore the expression pattern of the IKr forming components KCNH2 (hERG) and KCNE2 (MiRP1), we analysed, by means of in situ hybridization, sagittal and transversal sections in late rat embryonic development.…”