Long‐term programming effects on blood pressure following gestational exposure to the IKr blocker Dofetilide

• Published in: Physiological reports Vol. 6; no. 5
• Main Authors: Prestipino, Louise, Polson, Jaimie W., Brolin, Elisabeth, Ritchie, Helen E.
• Format: Journal Article
• Language: English
• Published: 01.03.2018
• Subjects: embryonic bradycardia; programmed hypertension; stress
• ISSN: 2051-817X
• DOI: 10.14814/phy2.13621

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. Gestational bradycardia produces adverse fetal outcomes but long‐term consequences remain unknown. In this study, we show that gestational exposure to the antiarrhythmic drug dofetilide (2.5 mg/kg), which produces embryo‐specific bradycardia, evoked high blood pressure and reduced habituation of cardiovascular responses to repeated stress in the adult offspring. These results highlight the need to consider both the short‐ and long‐term consequence to the developing fetus of drug use during pregnancy.