Abstract
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.
Highlights
There is robust evidence from human and animal studies that a range of gestational insults impact on fetal growth and increase the risk of cardiovascular diseases in the adult offspring in a process known as developmental programming (Barker 1995; Yeung et al 2014; Burton et al 2016)
Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society
We have previously shown that Dof induces embryonic bradycardia and/or arrhythmia both in vivo and in vitro (Ritchie et al 2013, 2015) but the possible long-term effects on the offspring have not been studied
Summary
There is robust evidence from human and animal studies that a range of gestational insults impact on fetal growth and increase the risk of cardiovascular diseases in the adult offspring in a process known as developmental programming (Barker 1995; Yeung et al 2014; Burton et al 2016). These insults include maternal dietary manipulations, maternal psychological stress, or compromises to fetal perfusion.
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