Perinatal Nicotine Exposure Increases Hypoxic‐Ischemic Brain Injury in Neonatal Rats

Abstract

Maternal cigarette smoking increases the risk of neonatal morbidity. This study determined whether perinatal nicotine exposure causes heightened brain vulnerability to hypoxic‐ischemic (HI) injury in neonatal rats via altered expression patterns of angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors. Nicotine was administered via subcutaneous osmotic minipumps from gestational day 4 to postnatal day 10. HI brain injury was determined in 10‐day‐old pups. Nicotine treatment significantly enhanced HI brain infarct size in male pups. In fetal brains, nicotine caused downregulation of AT2R, but not AT1R, expression. The downregulation of AT2R persisted in male pup brains. In female brains, there was an increase in AT2R, but a decrease in AT1R. Intracerebroventricular (ICV) administration of AT1R antagonist losartan or AT2R antagonist PD123319 exaggerated HI brain infarction in both male and female pups. AT2R agonist CGP42112 (ICV) abrogated nicotine‐induced increase in HI brain infarction in male pups. PD123319 (ICV) uncovered nicotine's effect on HI brain infarction in females. The results suggest that perinatal nicotine exposure causes aberrant AT2R gene expression in the developing brain, resulting in heightened brain vulnerability to HI injury in neonatal male rats in a sex‐dependent manner. (Supported in part by NIH grants HL82779 and HL83966).