Lipopolysaccharide Delays Closure of the Rat Ductus Arteriosus by Induction of Inducible Nitric Oxide Synthase But Not Prostaglandin E₂

Abstract

Background:The incidence of patent ductus arteriosus is known to be higher in premature neonates with infection than in those without infection. However, the detailed mechanism has not been investigated.Methods and Results:Lipopolysaccharide (LPS; 100 μg/kg) was injected into timed-pregnant Wistar rats on day 18 and 19 of pregnancy. The fetuses were delivered by cesarean section on gestational day 21. Using a rapid whole-body freezing method, it was found that closure of the ductus arteriosus (DA) was significantly delayed in neonates from LPS-injected rats after birth. Histological analysis demonstrated that there was no difference in vascular remodeling of the DA. Quantitative reverse transcriptase-polymerase chain reaction analysis showed that the tumor necrosis factor α and inducible nitric oxide synthase (iNOS) mRNA expression level was significantly increased, but there was no difference in cyclooxygenase 2 and prostaglandin receptor, EP4, mRNA expression in the DA from LPS-injected rats. Moreover, the NOS inhibitor,Nω-Nitro-L-arginine methyl ester hydrochloride, significantly prevented the delayed closure of the DA after birth in neonates from LPS-injected rats.Conclusions:The present study demonstrated that LPS-mediated infection delayed closure of the rat DA without apparent histological changes. iNOS, but not prostaglandin E₂, may play a primary role in delayed functional closure of the DA.