The Role of Nitric Oxide in Dilating the Fetal Ductus Arteriosus in Rats

Abstract

Prostaglandin E is a major dilator of the fetal ductus arteriosus (DA), but the role of nitric oxide in fetal ductal dilation has not been established. We studied the effects of a potent nitric oxide synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), on the fetal DA in rats. L-NAME was injected into the dorsum of pregnant rats, and fetal DA was studied 4 h later with a rapid whole body freezing method. The inner diameters of the DA and the main pulmonary artery were measured on a freezing microtome. The inner diameter ratio of DA to main pulmonary artery (DA/PA) was 1.02+/-0.03 (mean +/- SEM; number of fetuses [n], 21) in normal near-term fetuses. The effect of prostaglandin synthesis inhibition was studied after orogastric administration of indomethacin to pregnant rats. In near-term rats on the 21st day of gestation (term, 21.5 d), a large dose of L-NAME (100 mg/kg) caused only mild ductal constriction, with DA/PA reduced to 0.83+/-0.05 (n = 20). Indomethacin (1 mg/kg) caused moderate ductal constriction, and DA/PA was decreased to 0.65+/-0.05 (n = 21). Combined administration of L-NAME (10 mg/kg) and indomethacin (1 mg/kg) caused severe ductal constriction, with DA/PA of 0.26+/-0.03 (n = 16). In preterm rats on the 19th day of gestation, a moderate dose of L-NAME (10 mg/kg) caused severe ductal constriction, with a DA/PA of 0.32+/-0.05 (n = 24). Indomethacin (1 mg/kg) alone caused only mild ductal constriction, with DA/PA 0.86+/-0.02 (n = 16). In conclusion, prostaglandin has a major role and nitric oxide has a minor role in dilating the DA in the near-term fetal rat. In contrast, nitric oxide has a major role and prostaglandin has a minor role in dilating the DA in preterm fetal rats.

Oxygen-Sensitive Kv Channel Gene Transfer Confers Oxygen Responsiveness to Preterm Rabbit and Remodeled Human Ductus Arteriosus

“…PGs have a major role in dilating the DA in near-term rats, whereas NO has a minor role; the reverse is true in premature DAs, in which the NO pathway predominates. 38 Accordingly, we show that PGH synthase and NO synthase inhibition enhanced O 2 constriction more in preterm than in term DAs. Nonetheless, O 2 constriction in the preterm DAs remained weaker, despite inhibition of PGH synthase and NO synthase (Figure 1).…”

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

“…47 This report supports the study by Momma and Toyomo. 46 These findings including the present study suggest that NO inhibitors could be a therapeutic agent to prevent infection-related PDA, especially in immature fetuses. In addition to NO, it has been known that reactive oxygen species 48 and calpain 49 are therapeutic targets for inflammation-related vascular diseases.…”

“…It should be noted that the dilatory effect of NO on the DA is more significant in immature fetuses. 45- 47 Momma and Toyono reported that NO, but not PGE2, played a major role in dilating the DA in preterm fetal rats (embryonic day 19), 46 and that the importance of NO was relatively decreased during development. 46 Clyman reviewed that the DA in preterm newborn produced an increased amount of NO after birth although the DA responded to PGE2 persistently.…”

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.…”