Age-dependent sensitivity of the lamb ductus arteriosus to indomethacin and prostaglandins

doi:10.1016/S0022-3476(80)80338-6

The Journal of Pediatrics

Volume 96, Issue 1, January 1980, Pages 94-98

https://doi.org/10.1016/S0022-3476(80)80338-6 Get rights and content

Endogenous prostaglandins inhibit the ability of the ductus arteriosus to contract in response to oxygen. We studied the effects of endogenous prostaglandins and indomethacin (an inhibitor of endogenous prostaglandin production) on isometric contraction of isolated rings of lamb ductus arteriosus from animals of different gestational ages (98 to 103 days and 136 to 147 days; term is 150 days). Rings from animals at about 100 days' gestation have a significantly larger indomethacin-induced contraction than rings from animals near term. The lamb ductus arteriosus forms two prostaglandins that relax the vessel: postaglandin E₂ and prostacyclin. PGI₂ was three orders of magnitude less potent than PGE₂. Rings from the younger animals were significantly more sensitive to the relaxing action of PGE₂ and PGI₂ than were rings from animals near term. This increased sensitivity of immature animals to endogenous prostaglandins is consistent with the more potent effect of indomethacin on rings from immature animals. These observations are also consistent with the findings that preterm infants have an increased incidence of patent ductus arteriosus and that idomethacin can constrict the ductus arteriosus in preterm infants.

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There is limited evidence on the association between the clinical course of patent ductus arteriosus (PDA) and prostaglandin (PG) metabolites. This study aimed to determine the influence of PDA treatment on urinary PG metabolite excretion in very-low-birth-weight (VLBW) infants.
Urine samples were collected from 25 VLBW infants at 1, 3, and 7 days of age. Infants were separated into two groups: a PDA-treated group that received a cyclooxygenase-2 (COX) inhibitor (n = 12) and a control group that did not receive a COX inhibitor during the first 7 days after birth (n = 13). Urinary PG metabolite tetranor prostaglandin E₂ metabolite (t-PGEM) and tetranor prostaglandin D₂ metabolite (t-PGDM) levels were analyzed using liquid chromatography–tandem mass spectrometry.
Urinary t-PGEM excretion levels were not significantly different between the groups at 1, 3, and 7 days of age. Urinary t-PGDM excretion levels at 1 day of age were higher in PDA-treated infants than in control infants (median [interquartile range]: 5.5 [2.6, 12.2] versus 2.1 [1.0, 3.9] ng/mg creatinine; p = 0.017); however, among PDA-treated infants, the levels were significantly lower at 3 and 7 days than at 1 day of age (5.5 [2.6, 12.2] versus 3.4 [1.7, 4.5] and 4.0 [1.7, 5.3] ng/mg creatinine, respectively; p < 0.05). The urinary t-PGDM excretion level in the control group did not significantly differ among the time points.
PDA and COX inhibitor administration affected PG metabolism in VLBW infants. Our results indicated that urinary t-PGDM excretion was significantly associated with PDA-treatment in preterm infants.
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Increasing oxygen tension causes ductal constriction and hypoxaemia relaxation [16]. This sensitivity to oxygen is greatest at term and diminishes within 24 h of birth [17]. In contrast, as the fetus approaches term, the duct becomes less sensitive to the dilating effects of prostaglandins [18–21] whereas the preterm infant demonstrates increased sensitivity even after initial constriction [22], and paradoxically, there is some evidence that oxygen metabolites may stimulate prostaglandin E2 production and ductus dilatation.
Treatment of a haemodynamically significant patent ductus arteriosus (PDA) in the very preterm infant has been an accepted approach for several decades. However, the rationale for closure of PDA has recently been challenged due to reports of success with conservative approaches and the lack of evidence for longer-term benefits from treatment. In this article, we address an approach to assess treatment of those babies most likely to benefit.
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PGE2 is a potent vasodilator of the mammalian ductus arteriosus. In preterm and term lambs and rabbits, PGE2 relaxes the ductus at concentrations as low as 10–11 to 10–10 M PGE2.29,30 There is an age dependency to PGE2 sensitivity in a number of mammalian species with the ductus becoming more sensitive closer to term.
The ductus arteriosus is typically viewed as a mammalian fetal blood vessel providing a right-to-left shunt of right ventricular outflow away from the lungs and to the systemic circuit, that must close at birth. This review provides a wider comparative examination of the ductus arteriosus in lungfish, reptiles, birds, and mammals. The ductus arteriosus evolved with the lung in the ancestors of the lungfish as a connection between the pulmonary arteries and dorsal aorta. During embryonic development, reptiles, birds, and mammals all possess either one or two paired ductus arteriosi that provide a fetal shunt of blood away from the lungs. Differences in the fetal circulatory arrangement are seen between these groups and this influences the importance of the ductus arteriosus as an embryonic shunt. The ductus arteriosus from lungfish and tetrapod vertebrates is an oxygen sensitive blood vessel, with shared conserved pathways involved in oxygen sensing. By expanding studies into more comparative models such as lungfish or developing birds a better understanding of the physiology of the ductus arteriosus can be developed.
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The emu DA and the DA from less mature day 15 chicken embryos both relaxed in response to PGE2 (Dzialowski and Greyner, 2008; Ågren et al., 2009). The mammalian DA has a much stronger relaxation response to PGE2 when compared with the chicken DA (Clyman et al., 1978, 1980a, 1980b, 1999; Bouayad et al., 2001, 2002; Kajino et al., 2001; Waleh et al., 2004). These results suggest that regardless of O2 availability, the role of prostaglandins in maintaining ductal patency is less important in the chicken embryo than in the mammalian DA.
The ductus arteriosus (DA) are O₂-sensitive, embryonic blood vessels that serve as a right-to-left shunt in developing avian embryos. Prior to internal pipping, the chicken DA produces a weak O₂-induced contraction. During hatching, the O₂-sensitivity of the avian DA vessels increases significantly. To see if we could accelerate the maturation of chicken DA O₂-sensitivity, we exposed the vessel in vitro to elevated O₂ (25 kPa) for 3-h prior to internal pipping on day 19 of incubation. The DA initially responded to increasing O₂ with a weak contraction (0.15 ± 0.04 N/m) that significantly increased in strength (0.63 ± 0.06 N/m) during 3-h 25 kPa O₂ exposure. A tonic influence of nitric oxide, not present at low O₂, appeared during the 3-h 25 kPa O₂ exposure. The long-term O₂-induced contraction was mediated by both L-type Ca²⁺ channels and internal Ca²⁺ stores. The Rho-kinase pathway inhibitors Y-27632 and fasudil produced significant relaxation, suggesting a role for Ca²⁺ sensitization in the contractile response to the 3 h of elevated O₂. While the day 19 DA initially exhibited an immature contractile response to O₂, maturation of the pathways regulating O₂-induced contraction was accelerated by exposure to 25 kPa O₂, producing contractions similar in magnitude to those found during the final stage of hatching. This suggests that maturation of O₂-sensitivity may be accelerated in vivo by increasing arterial O₂ levels.
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^**: Supported by United States Public Health Service Program Project Gran HL-06285 from the National Heart, Lung, and Blood Institute.

¹: Dr. Clyman is the recipient of a Young Investigator's Award from the National Heart, Lung, and Blood Institute, HL 21409-01.

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Age-dependent sensitivity of the lamb ductus arteriosus to indomethacin and prostaglandins**

Biochim Biophys Acta

Prostaglandins

Prostaglandins

Prostaglandins

Eur J Pharmacol

Prostaglandins

Prostaglandins

Prostaglandins

Prostaglandins Med

Prostaglandins

Prostaglandins

Prostaglandins