INDUCIBLE NITRIC-OXIDE SYNTHASE AND THE REGULATION OF CENTRAL VESSEL CALIBER IN THE FETAL-RAT

Background The purpose of this study was to evaluate the possibility t hat inducible nitric oxide synthase (iNOS) regulates the fetal circula tion. Methods and Results Positive evidence for iNOS gene expression w as noted in heart central vessels and placenta of untreated rat fetuse s. 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 mu g/mL in the drinking water. To raise NO levels, lipopol ysaccharide (LPS) 30 mu g/kg was given by intraperitoneal injection, a nd sodium nitroprusside (SNP) was placed in mini-osmotic pumps to deli ver 10 mu g/kg per minute. Control animals were undisturbed. On day 21 of gestation, dams were anesthetized and fetuses were delivered by ce sarean section and rapidly frozen in isopentane chilled in liquid nitr ogen. Frozen sections (10 mu m) were used to reconstruct a computer-ge nerated three-dimensional image of the great vessels and ductus arteri osus. Significant constriction of the great vessels and ductus arterio sus was observed with L-NIL, whereas both LPS and SNP dilated these ve ssels. The vasorelaxant effect of LPS was blocked by L-NIL. NO release from placental explants was 633+/-41 nmol/L under basal conditions, i ncreasing to 4.0+/-0.4 mu mol/L with LPS administration, although plac ental iNOS message and protein levels were unchanged. Conclusions We s uggest that nitric oxide, generated by iNOS, plays a significant role in control of major vessel and ductus arteriosus caliber in the rat fe tus. In regard to the nitrergic regulation of the circulation, the fet us is clearly different from the adult.