Inducible Nitric Oxide Synthase and the Regulation of Central Vessel Caliber in the Fetal Rat

Abstract

Background The purpose of this study was to evaluate the possibility that inducible nitric oxide synthase (iNOS) regulates the fetal circulation. Methods and Results Positive evidence for iNOS gene expression was noted in heart central vessels and placenta of untreated rat fetuses. Rats in the last week of pregnancy were treated for 5 days with l - N G -(1-Iminoethyl)lysine (L-NIL), a selective inhibitor of iNOS, at 1, 10, and 100 μg/mL in the drinking water. To raise NO levels, lipopolysaccharide (LPS) 30 μg/kg was given by intraperitoneal injection, and sodium nitroprusside (SNP) was placed in mini-osmotic pumps to deliver 10 μg/kg per minute. Control animals were undisturbed. On day 21 of gestation, dams were anesthetized and fetuses were delivered by cesarean section and rapidly frozen in isopentane chilled in liquid nitrogen. Frozen sections (10 μm) were used to reconstruct a computer-generated three-dimensional image of the great vessels and ductus arteriosus. Significant constriction of the great vessels and ductus arteriosus was observed with L-NIL, whereas both LPS and SNP dilated these vessels. The vasorelaxant effect of LPS was blocked by L-NIL. NO release from placental explants was 633±41 nmol/L under basal conditions, increasing to 4.0±0.4 μmol/L with LPS administration, although placental iNOS message and protein levels were unchanged. Conclusions We suggest that nitric oxide, generated by iNOS, plays a significant role in control of major vessel and ductus arteriosus caliber in the rat fetus. In regard to the nitrergic regulation of the circulation, the fetus is clearly different from the adult.