The Effect of Fetal Hypoxia on Programing Cardiovascular Function

Abstract

Chronic prenatal hypoxia is associated with intrauterine growth retardation and programs hypertension in the offspring. However, previous methods for inducing fetal hypoxia used either maternal hypoxia or placental insufficiency, both of which may confound the interpretation because of side effects. We have developed a model in which hypoxia is restricted to the fetus. Dofetilide (Dof) is a class III antiarrhythmic agent that specifically blocks the IKr channel. This channel is expressed in the rat fetus but not adult and its blockade induces fetal bradycardia. In this study, we confirmed the effects of Dof on the fetal heart rate (HR) and determined its effects on the adult offspring. Dams were dosed with Dof (2.5 mg/kg) or saline at gestational days E11‐E14. In the first series of experiments dams were sacrificed after two hours and 8 embryos were collected from each rat and placed in culture for 15 min. Embryos were then videoed for HR analysis, the results confirming that Dof induced a 35‐45% drop in HR in Dof embryos compared to controls. In the second series of experiments, litters were born and at 3‐4 months of age, blood pressure (BP), HR and spontaneous baroreflex gain (sBRG) were recorded using radiotelemetry. At 3 days of age, Dof pups were 6% lighter than control rats, and remained ~8% lighter at 3‐4 months. Mean BP was ~10 mmHg higher in the adult Dof rat than controls during both the night (active phase) and day (night: controls, 81.7±1.8 mmHg; Dof, 91.8±2.3 mmHg, P<0.01). There were no differences in HR or sBRG. Our results show that Dof produces a large fall in HR in the fetus at E11‐E14, producing small birth weight pups and programing for hypertension in later life. We found no evidence of altered baroreflex function.