Long-term programming effects on blood pressure
following gestational exposure to the I
Louise Prestipino*, Jaimie W. Polson*, Elisabeth Brolin & Helen E. Ritchie
School of Medical Sciences and Bosch Institute, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
embryonic bradycardia, programmed
Jaimie Polson, Discipline of Biomedical
Science, School of Medical Sciences, Sydney
Medical School, The University of Sydney,
Cumberland Campus, C42, PO Box 170,
Lidcombe, NSW 1825, Australia.
Tel: +612 93519353
Fax: +612 93519520
No funding information provided.
Received: 7 November 2017; Revised: 2
January 2018; Accepted: 3 January 2018
Physiol. Rep., 6 (5), 2018, e13621,
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 ges-
tational days 11–14. Embryonic heart rate and rhythm were determined using
embryo culture. Cardiovascular function was assessed in surviving adult off-
spring 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 Æ 3.9 vs. 111.2 Æ 3.0 mmHg, P = 0.01). While the pressor response to
AJS was similar in both groups (control 17.7 Æ 3.4; Dof 18.9 Æ 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 Æ 1.7 mmHg, P = 0.05). The results indicate that embryonic bradycar-
dia programs hypertension and impaired stress adaptation, and have implica-
tions for the maternal use of cardioactive drugs during pregnancy.
There is now 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). Traditionally, these insults include maternal
dietary manipulations, maternal psychological stress, or
compromises to fetal perfusion. While reductions in uter-
ine and placental blood ﬂow have been well studied in
programming models of preeclampsia, placental insufﬁ-
ciency, and uterine artery ligation (Hutter et al. 2010),
potential consequences of reduced postplacental perfu-
sion, for example, following fetal bradycardia (Olgan
et al. 2014) are largely unknown. Fetal bradycardia may
manifest as a result of congenital channelopathies, mater-
nal autoantibodies, or following exposure to cardioactive
drugs (Strasburger and Wakai 2010; Nilsson et al. 2013;
Nilsson and Webster 2014).
A number of studies have shown that fetal bradycardia
is associated with a high risk of ﬁrst trimester sponta-
neous abortion (Doubilet and Benson 2005; Arleo and
Troiano 2011) and birth defects (Webster et al. 2014).
Thus, pharmaceutical medications that have the capacity
to alter cardiac ion channel activity, including class III
antiarrhythmics, antidepressants, antipsychotics, macro-
lide antibiotics, certain antihistamines, and anticonvul-
sants, are tested for safe use in pregnancy (Webster et al.
2014). However, the endpoints for these studies are
structural malformations or embryonic death. No studies
are routinely performed to evaluate the long-term
ª 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of
The Physiological Society and the American Physiological Society.
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2018 | Vol. 6 | Iss. 5 | e13621
Physiological Reports ISSN 2051-817X