A slow embryonic heart rate in early‐mid gestation is associated with increased risk of embryonic death and malformation, however, the long‐term consequences remain unknown. We administered Dofetilide (Dof, 2.5 mg/kg), a drug that produces embryo‐specific bradycardia, to pregnant rats from gestational days 11–14. Embryonic heart rate and rhythm were determined using embryo culture. Cardiovascular function was assessed in surviving adult offspring at rest, during acute psychological stress (air jet stress, AJS), and after 7 days of repeated AJS. Dof reduced embryonic HR by 40% for ~8 h on each of the treatment days. On postnatal day 3, Dof offspring were ~10% smaller. Blood pressure was elevated in adult Dof rats (systolic blood pressure, night: 103.8 ± 3.9 vs. 111.2 ± 3.0 mmHg, P = 0.01). While the pressor response to AJS was similar in both groups (control 17.7 ± 3.4; Dof 18.9 ± 0.9 mmHg, P = 0.74), after 7 days repeated AJS, clear habituation was present in control (P = 0.0001) but not Dof offspring (P = 0.48). Only Dof offspring showed a small increase in resting blood pressure after 7 days repeated stress (+3.9 ± 1.7 mmHg, P = 0.05). The results indicate that embryonic bradycardia programs hypertension and impaired stress adaptation, and have implications for the maternal use of cardioactive drugs during pregnancy.
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.
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