Combined Prostaglandin and Nitric Oxide Inhibition Produces Anatomic Remodeling and Closure of the Ductus Arteriosus in the Premature Newborn Baboon

Abstract

After birth, the full-term ductus arteriosus actively constricts and undergoes extensive histologic changes that prevent subsequent reopening. These changes are thought to occur only if a region of intense hypoxia develops within the ductus wall after the initial active constriction. In preterm infants, indomethacininduced constriction of the ductus is often transient and is followed by reopening. Prostaglandins and nitric oxide both play a role in inhibiting ductus closure in vitro. We hypothesized that combined inhibition of both prostaglandin and nitric oxide production (with indomethacin and N-nitro-L-arginine (L-NA), respectively) may be required to produce the degree of functional closure that is needed to cause intense hypoxia. We used preterm (0.67 gestation) newborn baboons that were mechanically ventilated for 6 d: 6 received indomethacin alone, 7 received indomethacin plus L-NA, and 16 received no treatment (control). Just before necropsy, only 25% of control ductus and 33% of indomethacin-treated ductus were closed on Doppler examination; in contrast, 100% of the indomethacin-plus-L-NA-treated ductus were closed. Control and indomethacin-treated baboons developed negligible-to-mild ductus hypoxia (EF5 technique). Similarly, there was minimal evidence of ductus remodeling. In contrast, indomethacin-plus-L-NA-treated baboons developed intense hypoxia in regions where the ductus was most constricted. The hypoxic muscle strongly expressed vascular endothelial growth factor, and proliferating luminal endothelial cells filled and occluded the lumen. In addition, cells in the most hypoxic regions were undergoing DNA fragmentation. In conclusion, preterm newborns are capable of remodeling their ductus, just like the full-term newborn, if they can reduce their luminal blood flow to a point that produces intense ductus wall hypoxia. Combined prostaglandin and nitric oxide inhibition may be necessary to produce permanent closure of the ductus and prevent reopening in preterm infants. In the full-term infant, closure of the DA occurs in two phases: 1) initial "functional" closure of the DA lumen by smooth muscle constriction, and 2) "anatomic" occlusion of the lumen resulting from endothelial proliferation, neointimal thickening, and loss of smooth muscle cells from the inner muscle media (1, 2). Hypoxia of the DA wall seems to be the required stimulus for irreversible, anatomic closure (3). Anatomic remodeling occurs only in the presence of moderate to intense hypoxia (3).

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.…”

Factors Associated With Permanent Closure of the Ductus Arteriosus: A Role for Prolonged Indomethacin Therapy

“…1,2,12 We hypothesize that, in contrast with earlier studies, a significant proportion of the infants in the recent studies may have developed complete Doppler closure with just 3 doses of indomethacin (as occurred in 214 of the 313 infants treated with the standard 3-dose course in our study). Because the degree of ductus constriction seems to determine the rate of anatomic remodeling and permanent closure, [1][2][3][4] daily echocardiographic evaluations of ductal patency may be the best way to decide when indomethacin therapy is no longer needed. 22,23 Our study suggests that infants that still have evidence of luminal patency, after a standard 3-dose course of indomethacin, may be likely to benefit from a longer course of indomethacin.…”

“…The hypoxic signal initiates the process of anatomic remodeling and permanent closure. 3,5,6 Infants born at Ͻ28 weeks' gestation, who have no evidence of luminal flow on a Doppler examination, performed 12 to 24 hours after the third dose of indomethacin, have an 80% to 90% chance of staying closed permanently. 1 Previously, we observed that even when the ductus is clinically closed, if any luminal flow is detected on the posttreatment Doppler examination, the chances are Ͻ15% that it will remain closed; 85% of these infants will develop symptoms of clinical reopening at some time in the future.…”

“…[1][2][3][4] Muscular constriction produces a region of ischemic hypoxia in the middle of the ductus muscle media. The hypoxic signal initiates the process of anatomic remodeling and permanent closure.…”

Regulation of vascular tone and remodeling of the ductus arteriosus

“…This implies that cAMP signaling is more important than cGMP signaling in near-term DA. On the other hand, in premature DA, the combined use of an NO synthase-inhibitor and COX inhibitor produces a much greater degree of the DA contraction than COX inhibitor alone (Seidner et al, 2001).…”