ABSTRACT. Previous studies have shown that the dilating effect of nitric oxide (NO) on the fetal ductus arteriosus (DA) is age dependent and more marked in the premature stages in rats, but the factors that mediate this effect are poorly understood. The purpose of this study is to determine the changes in the expression of NO synthase (NOS) mRNA in the fetal DA and to examine the effect of an 11--hydroxylase inhibitor of corticosterone synthesis, namely, metyrapone, on NOS expression. NOS 3 mRNA expression was observed in 17.5-day-old rat fetuses; thereafter, its level significantly increased and reached its peak on day 19.5 and then decreased until the end of the gestation period (day 21.5). To inhibit corticosterone synthesis, a constant infusion of metyrapone was administered to rats; this significantly decreased the fetal plasma corticosterone concentration as well as NOS 3 mRNA expression in the DA in a time-dependent manner. These results indicate that NO is generated by NOS 3 in the DA and that the age-dependant expression of NOS 3 in the premature DA is attributable to corticosterone-associated activity.KEY WORDS: constant infusion, metyrapone, premature ductus arteriosus, rat.J. Vet. Med. Sci. 72 (5): [555][556][557][558][559][560] 2010 The ductus arteriosus (DA) is a fetal vascular shunt that connects the main pulmonary artery (PA) to the descending aorta. In utero, the DA conducts > 90% of the right ventricular output to the aorta, bypassing the fetal pulmonary system. When respiration begins after birth, the DA rapidly closes and transforms into a fibrous cord. The relaxed state of the fetal DA was previously considered to be a passive process; however, it is now clear that vasodilating stimuli are required to maintain the DA in a dilated state in utero [25]. Previous studies have shown that dilator prostaglandins (PGs), especially PGE 2 , play major roles in maintaining DA patency in utero [2,3,5,15]. However, the dilating effect of PGs was not observed during the preterm stages in rats [18,26] and humans [17,29].Nitric oxide (NO) has emerged as a major determinant of vascular tone under both physiologic and pathophysiologic conditions [20]. In mammals, three isoforms of nitric oxide synthase (NOS), namely, NOS 1 (neuronal NOS, nNOS), NOS 2 (inducible NOS, iNOS), and NOS 3 (endothelial NOS, eNOS), have been identified. Recent studies suggest that NO is more important than PGE 2 in the regulation of ductal tone in the preterm stages [4,19]. Clyman et al. [4] reported increased sensitivity of ductal strips to the dilating effect of NO during the early fetal stage in lambs. Momma and Toyono [19] reported a change in the effect of N G -nitro-L-arginine methyl ester (L-NAME), an NOS inhibitor, which induces stronger DA contraction in preterm rats (day 19) than in term rats (day 21). In addition, we have previously reported that the constrictive effect of L-NAME on the DA depends on the age of the fetus. L-NAME-induced DA constriction was first observed in a 17-day-old fetus, and it was found to incre...