The effects of nifedipine and ivabradine on the functionality of the early rat embryonic heart. Are these drugs a risk in early human pregnancy?

Abstract

Background: When the human heart begins its earliest contractions from day 21, it lacks a functional autonomic nerve supply. Instead, contractions are generated by regular calcium transients later augmented by the funny current (I_f ) produced by sinoatrial-like cells. This study examined effects of blocking these currents in the early rat embryonic heart.

Methods: Rat embryos were incubated in vitro with either the calcium channel blocker nifedipine and/or the funny current (I_f ) blocker ivabradine for 1 hr to examine the effects of these drugs on the activity of the embryonic heart.

Results: On gestational day (GD) 10, nifedipine (0.45-1.8 μM) caused asystole at high concentrations (8/10 embryos at 1.8 μM and 3/10 embryos at 0.9 μM) and markedly increased embryonic heart rate (EHR) in all surviving embryos but likely reduced blood flow due to weak contractions. Ivabradine (1.5 μM) caused a 29% reduction in EHR in GD 10 embryos and a greater than 50% reduction in EHR for GD 11-14 embryos. Combined exposure to both nifedipine and ivabradine resulted in an additive effect. The increased EHR due to nifedipine was reduced by the ivabradine.

Conclusion: The results suggest that exposure to nifedipine in human pregnancy 3-4 weeks postfertilization may cause a direct effect on the embryonic heart resulting in reduced blood flow leading to abnormal heart and/or blood vessel development and/or embryonic death. Accidental exposure to ivabradine in the organogenic period would be expected to cause embryonic bradycardia, hypoxia, malformations, and embryonic death. This drug is currently contraindicated in pregnancy.

Keywords: early pregnancy; embryonic death; embryonic heart rate; ivabradine; nifedipine.