Occurrence of endothelium-derived relaxing factor – nitric oxide in the lamb ductus arteriosus

Coceani, Flavio; Kelsey, Lois; Seidlitz, Eric

doi:10.1139/y94-013

Cited by 49 publications

(58 citation statements)

References 20 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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Prostaglandin E 2 (PGE 2 ) is the major vasodilator prostanoid of the mammalian ductus arteriosus (DA). In the present study we analyzed the response of isolated DA rings from 15-, 19-and 21-day-old chicken embryos to PGE 2 and other vascular smooth muscle relaxing agents acting through the cyclic AMP signaling pathway. PGE 2 exhibited a relaxant response in the 15-day DA, but not in the 19-and 21-day DA. Moreover, high concentrations of PGE 2 (¸3 M in 15-day and ¸1 M in 19-day and 21-day DA) induced contraction of the chicken DA. The presence of the TP receptor antagonist SQ29,548, unmasked a relaxant eVect of PGE 2 in the 19-and 21-day DA and increased the relaxation induced by PGE 2 in the 15-day DA. The presence of the EP receptor antagonist AH6809 abolished PGE 2 -mediated relaxation. The relaxant responses induced by PGE 2 and the -adrenoceptor agonist isoproterenol, but not those elicited by the adenylate cyclase activator forskolin or the phosphodiesterase 3 inhibitor milrinone, decreased with maturation. High oxygen concentrations (95%) decreased the relaxation to PGE 2 . The relaxing potency and eYcacy of isoproterenol and milrinone were higher in the pulmonary than in the aortic side of the DA, whereas no regional diVerences were found in the response to PGE 2 . We conclude that, in contrast to the mammalian situation, PGE 2 is a weak relaxant agent of the chicken DA and, with advancing incubation, it even stimulates TP vasoconstrictive receptors.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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“…Cyclooxygenase inhibition causes a striking increase in DA tone in contrast to the subtle increase in DA resistance induced by the selective NOS antagonist N G -nitro-L-arginine (10). However, there is basal NO production in the DA that activates sGC and thereby contributes to maintaining the DA in a relaxed state (9,10). cGMP is important in maintaining DA patency.…”

Section: Discussionmentioning

confidence: 99%

“…Nitrovasodilators cause a marked dilatation of the DA in vitro (16) and in vivo (17), which is associated with increased DA cGMP content (16). Methylene blue, a nonspecific GC inhibitor, causes a more marked constriction of the DA in vitro (9) and in vivo (10) than does NOS inhibition. This suggests that mediators other than NO may stimulate sGC, increasing cGMP in the DA.…”

Section: Discussionmentioning

confidence: 99%

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Sildenafil Reverses O2 Constriction of the Rabbit Ductus Arteriosus by Inhibiting Type 5 Phosphodiesterase and Activating BKCa Channels

Thébaud

Michelakis

et al. 2002

Pediatr Res

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Oxygen constriction causes functional closure of the ductus arteriosus (DA) at birth. Although DA closure is crucial for postnatal adaptation, patency of the DA is critical for survival of newborns with duct-dependent cardiac malformations. In these cases, DA patency is achieved by i.v. infusion of prostaglandin E1, which, though effective, is often associated with complications. We hypothesized that sildenafil, a specific phosphodiesterase type 5 inhibitor, is an effective DA vasodilator. In isolated DA rings from term (d 30) fetal rabbits, sildenafil (10 Ϫ6 -10 Ϫ4 M) and diethylamine NONOate (10 Ϫ7 -10 Ϫ5 M) induced dosedependent relaxation of oxygen-constricted DA (Ϫ52 Ϯ 4% and Ϫ51 Ϯ 6%, respectively) that was inhibited by the soluble guanylyl-cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (5 ϫ 10 Ϫ5 M). Sildenafil increased cyclic GMP levels. Iberiotoxin (200 nM), an inhibitor of calcium-sensitive potassium channels, decreased the vasodilatory effect of sildenafil and diethylamine NONOate (Ϫ30 Ϯ 2% and Ϫ27 Ϯ 4%, respectively). Oxygen inhibition of whole-cell K ϩ current and membrane depolarization were partially restored by sildenafil, and this was inhibited by iberiotoxin. Immunohistochemistry and immunoblotting confirmed the presence of phosphodiesterase type 5 and calcium-sensitive potassium channels in the DA smooth muscle cells. This is the first study to demonstrate that sildenafil dilates the DA by increasing soluble guanylyl-cyclase-derived cGMP levels and thereby activating calcium-sensitive potassium channels, causing membrane hyperpolarization. Sildenafil, already approved for human usage, might be an alternative or a useful adjunct to prostaglandin E1 as a bridge to cardiac surgery. The DA is a vital fetal structure that connects the pulmonary artery to the descending aorta. During fetal life, the DA shunts over half of the blood flow away from the lung into the umbilico-placental circulation, where gas exchange takes place (1). At birth, closure of the DA, essential for postnatal adaptation, is initiated by an increase in O 2 . In full-term newborns, the DA closes 24 -48 h after delivery (1). However, in newborns with duct-dependent cyanotic cardiac malformations (e.g. transposition of the great vessels) or duct-dependent aortic obstructions (including hypoplastic left heart syndrome and coarctation of the aorta), patency of the DA is critical for survival until surgery. The paramount importance of PG in the regulation of ductal tone is well established [reviewed in (2)]. This has resulted in successful pharmacological manipulation of the DA (3). To date, PGE1 is the only available therapy to maintain DA patency (4). Although effective, numerous side effects are associated with PGE1 infusions (respiratory depression, fever, lethargy, irritability, myoclonic jerks, flushing, edema, pyloric stenosis, hyperostosis, necrotizing enterocolitis,

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“…Indomethacin treatment leads to the elimination of Doppler-demonstrable luminal blood flow; however, the preterm DA still has a high rate of reopening (11). We hypothesized that, although NO plays a smaller role than prostaglandins in opposing DA constriction in vitro (5,6), combined inhibition of both prostaglandin and NO production may be required to produce the necessary degree of constriction that would completely obliterate the DA lumen and produce DA wall hypoxia. In the following study, we used premature baboons to test the hypothesis that the preterm newborn is capable of remodeling its DA, just like the full-term newborn, if it can constrict its DA to a point that obliterates its lumen and produces DA wall hypoxia.…”

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confidence: 99%

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

Seidner¹,

Chen

Oprysko

et al. 2001

Pediatr Res

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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).

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Occurrence of endothelium-derived relaxing factor – nitric oxide in the lamb ductus arteriosus

Cited by 49 publications

References 20 publications

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

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

Sildenafil Reverses O2 Constriction of the Rabbit Ductus Arteriosus by Inhibiting Type 5 Phosphodiesterase and Activating BKCa Channels

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

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