Role of Nitric Oxide in Regulating the Ductus Arteriosus Caliber in Fetal Rats.

Abstract

ABSTRACT. The role of nitric oxide (NO) on the ductus arteriosus (DA) patency was examined in fetal rats at various stages of gestation. N G -nitro-L-arginine methyl ester (L-NAME, 50 mg/kg, ip), an NO synthase (NOS) inhibitor, or indomethacin (3 mg/kg, po), a cyclooxygenase inhibitor, was administered at 3 hr before cesarean section to pregnant rats ranging from day 17 to day 21 of gestation. Dams were decapitated and the fetuses were obtained by cesarean section. The fetuses were rapidly frozen in an acetone-dry ice mixture. Using rapid-freezing and shaving methods, the calibers of the DA and pulmonary artery were measured. The constrictive effect of L-NAME on the fetal DA caliber was stronger than that of indomethacin in 19-day-old and immature fetuses. In near-term fetuses, the constrictive effects of L-NAME were reduced, while indomethacin caused marked DA constriction. We conclude that endogenous NO may play a major role in regulating the patency of the DA in earlier fetal stages, while dilator prostaglandins may play a greater role in regulating the ductal patency in the near-term fetus. The ductus arteriosus (DA) connects the main pulmonary artery (PA) and the descending aorta during the fetal period, allowing blood flow from the right ventricle to bypass to the lungs. Previous studies have demonstrated that dilator prostaglandins, especially PGE 2 , play a major role in maintaining DA patency in utero [4,5,7,15]. Endothelium-derived relaxing factor-nitric oxide (EDRF-NO) has emerged as a major determinant of vascular tone under both physiologic and pathophysiologic conditions [19]. Several investigators reported that NO may contribute to the patency of the DA in vivo [3,11] and in vitro [8], suggesting that NO plays an accessory role along with PGE 2 . However, the relative contribution of NO in the regulation of the DA caliber has not been studied in detail in vivo, especially, in terms of age-related changes and the relation with the dilator prostaglandins.Therefore, the present study was designed to obtain information about the role of NO in the regulation of the DA caliber of the rat fetus at various stages of development. We determined the effects of N G -nitro-L-arginine methyl ester (L-NAME), an NO synthase (NOS) inhibitor, on the DA caliber, and compared these effects with those caused by indomethacin, a cyclooxygenase inhibitor, in comparison with untreated controls. MATERIALS AND METHODS Animals:Female Wistar rats (Charles River Japan Inc., Tokyo), 10-12 weeks old at the time of mating, were used. They were given a commercial diet (CE-2, Clea Japan, Tokyo) and tap water ad libitum, and kept in a room at temperature of 22 ± 3°C with relative humidity of 55 ± 10%. Three females were placed with a male overnight and examined the next morning for the presence of sperm in the vaginal smear. The day when sperm was found was designated as day 0 of gestation, and the females were caged individually thereafter. Effects of L-NAME and indomethacin at various stages of gestation:The effects of L-NAME and ...

Increased Constriction of the Ductus Arteriosus with Combined Administration of Indomethacin and <i>L</i>-NAME in Fetal Rats

“…However, indomethacin plus L-NAME did not potentiate the constriction of the DA induced by treatment with indomethacin alone in the term fetus [10]. The constrictive effects of indomethacin and L-NAME have been reported as being age dependent [6,11,12]. Thus, we speculate that the age-dependent effect might account for the lack of increased constriction of the DA after the combined administration of these agents in the term fetus.…”

“…Indomethacin (Wako Pure Chemical, Osaka, Japan) and L-NAME (Biomol, Plymouth Meeting, USA) solutions were made as previously described [6]. Indomethacin (3 mg/kg) was administered orally via a gastric tube to each pregnant rat 3 h before cesarean section.…”

“…Nitric oxide (NO) has emerged as a major determinant of vascular tone under both physiologic and pathophysiologic conditions [5]. In a previous report, we indicated that NO plays a major role in the DA patency of premature fetuses when the PGE 2 -regulating system has not been established [6].…”

Reversal of fetal ductal constriction after maternal restriction of polyphenol-rich foods: an open clinical trial

“…3,4,40,41 It was also shown that this effect was reversible after decreasing the dosage of these drugs or completely suspending its administration. 3,42 From that time on, and based on this knowledge, utilization of NSAID in late pregnancy has been avoided whenever possible.…”

Developmental changes in the effects of prostaglandin E2 in the chicken ductus arteriosus

“…PGE 2 plays a major role in prenatal patency and postnatal closure of the mammalian DA, namely during fetal life by exerting a potent relaxant eVect (Clyman 2006;Smith 1998), possibly in conjunction with nitric oxide (NO, Coceani et al 1994;Momma and Toyono 1999;Seidner et al 2001;Takizawa et al 2000), and after birth by abruptly withdrawing its action. We have previously shown that the transition to ex ovo life is accompanied by dramatic changes in chicken DA reactivity (Agren et al 2007(Agren et al , 2008.…”