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.
Raised gestational glucocorticoid may program hypertension in the offspring, although the data are inconsistent. The pathophysiological mechanisms may be due to altered autonomic responses to stress. We compared the cardiovascular and autonomic responses to air jet stress in rats programed by maternal injection of dexamethasone (DEX, 0.2 mg/kg) at gestational days E15 and E16 with control rats. At 6 months, offspring were implanted with a telemetry blood pressure (BP) transmitter. BP, heart rate (HR), and spontaneous baroreflex gain (sBRG) were recorded at rest and during exposure to a series of puffs of air directed at the face. There was a trend towards a higher resting mean BP in DEX rats than controls (97.6±4.9 v 84.1±2.5 mmHg, n=6, P=0.06), although there was no difference in systolic BP (109.7±5.5 v 104.7±1.3 mmHg, P=0.45). This was accompanied by a lower heart rate (260±9 v 302±13 bpm, P<0.05) and sBRG (1.5±0.2 v 2.3±0.2 ms/mmHg, P<0.05) in DEX rats. Air jet stress increased BP and HR in both groups, however the BP increase was greater in DEX (initial increase 22.2±3.7 vs 8.3±3.9 mmHg, P<0.05). Stress reduced sBRG in control but not DEX rats (by 0.86±0.14 vs 0.01±0.3 ms/mmHg). Our results show that DEX programmed rats have altered cardiovascular and baroreflex responses to airjet stress.
Numerous studies in both humans and animal models highlight intrauterine hypoxia as a potential stressor capable of programing hypertension in the offspring. The underlying causative mechanisms are unclear, but may be due to altered cardiovascular responses to chronic stress. In this study in the rat, we used dofetilide (dof), a class III antiarrhythmic agent reported to reduce fetal heart rate, without affecting the dam, and thereby induce hypoxia specific to the fetus. Blood pressure (BP), heart rate (HR), HR variability (HRV) and BP variability (BPV) were compared in dof programed and control offspring at 3–6 months of age. Pregnant rats were dosed daily with dof (2.5 mg/kg orally) or saline from gestational days 11–14. Embryonic HR was determined using an ex vivo embryonic culture preparation, which confirmed a period of ~6h embryonic bradycardia after dosing. The absence of an effect of dof on adult HR was confirmed in a separate cohort of control adult rats following surgical implantation of radiotelemetry BP transmitters. Dof and control offspring were telemetered and cardiovascular variables were measured at rest and following an air jet stress (AJS) protocol, repeated twice daily for 7 days. Dof rats were hypertensive at rest before AJS (day1 mean BP: dof, 92±2.3 mmHg; control, 83±1.9 mmHg, P=0.03). The increase in BP in response to the first AJS was similar between groups (dof, 23.8 mmHg; control 22.8 mmHg), as were the increases in HRV and BPV. However, after 7 days, there was a significant attenuation of the AJS pressor response in control (51.2%, P=0.04), but not dof (28.9%, P=0.48) rats. This pattern was also reflected in the total power component of BPV, with control rats displaying significantly greater attenuation (72%, P=0.02) than dof (41%, P= 0.06). The 7 days of repeated AJS did not affect resting blood pressure in either group (day 7 mean BP: dof, 95±2.2 mmHg, P=0.31 compared to day 1; control, 85±2.3 mmHg, P=0.46). The results indicate that fetal hypoxia programs for hypertension and altered responses to repeated psychological stress. Although repeated stress showed reduced adaptation of the pressor response, more than 7 days of chronic stress may be required before an effect on resting BP may be observed.
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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