Abstract
Background:
Patent ductus arteriosus (PDA) is a common life-threatening complication among premature infants. Although cyclooxygenase inhibitors are frequently used to treat PDA, as they inhibit the synthesis of prostaglandin E2, the most potent vasodilator in the ductus arteriosus (DA), their efficacy is often limited. As thromboxane A2 (TXA2) induces vascular contraction via the TXA2 receptor (TP), we hypothesized that TP stimulation would promote DA closure.
Method:
To measure the inner diameter of the vessels, a rapid whole-body freezing method was used.
Results:
Injection of the selective TP agonists U46619 and I-BOP constricted the fetal DA at embryonic day 19 (e19) and e21 in a dose-dependent manner. Of note, U46619 also exerted a vasoconstrictive effect on two different types of postnatal PDA models: premature PDA and hypoxia-induced PDA. We also found that U46619 constricted the ex vivo DA ring to a greater extent than it constricted the ex vivo aorta. Furthermore, we found that U46619 at lower concentrations (up to 0.05 mg/g of body weight) had a minimal vasoconstrictive effect on other vessels and did not induce microthrombosis in the pulmonary capillary arteries.
Conclusion:
Low-dose TP stimulation constricts the DA with minimal adverse effects at least in rat neonates and our results could point to an alternative potent vasoconstrictor for PDA.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Van Overmeire B, Smets K, Lecoutere D, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med 2000;343:674–81.
Hermes-DeSantis ER, Clyman RI . Patent ductus arteriosus: pathophysiology and management. J Perinatol 2006;26 Suppl 1:S14–8; discussion S22–3.
Van Overmeire B, Allegaert K, Casaer A, et al. Prophylactic ibuprofen in premature infants: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2004;364:1945–9.
Smith GC . The pharmacology of the ductus arteriosus. Pharmacol Rev 1998;50:35–58.
Vida VL, Padalino MA, Boccuzzo G, et al. Minimally invasive operation for congenital heart disease: a sex-differentiated approach. J Thorac Cardiovasc Surg 2009;138:933–6.
Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A . Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the Trial of Indomethacin Prophylaxis in Preterms. J Pediatr 2007;150:229–34, 234.e1.
Nakahata N . Thromboxane A2: physiology/pathophysiology, cellular signal transduction and pharmacology. Pharmacol Ther 2008;118:18–35.
Reese J, Waleh N, Poole SD, Brown N, Roman C, Clyman RI . Chronic in utero cyclooxygenase inhibition alters PGE2-regulated ductus arteriosus contractile pathways and prevents postnatal closure. Pediatr Res 2009;66:155–61.
Smith GC, McGrath JC . Contractile effects of prostanoids on fetal rabbit ductus arteriosus. J Cardiovasc Pharmacol 1995;25:113–8.
Coceani F, Bishai I, White E, Bodach E, Olley PM . Action of prostaglandins, endoperoxides, and thromboxanes on the lamb ductus arteriosus. Am J Physiol 1978;234:H117–22.
Loftin CD, Trivedi DB, Langenbach R . Cyclooxygenase-1-selective inhibition prolongs gestation in mice without adverse effects on the ductus arteriosus. J Clin Invest 2002;110:549–57.
Dorn GW II, Becker MW, Davis MG . Dissociation of the contractile and hypertrophic effects of vasoconstrictor prostanoids in vascular smooth muscle. J Biol Chem 1992;267:24897–905.
Du Z, Zan T, Li H, Li Q . A study of blood flow dynamics in flap delay using the full-field laser perfusion imager. Microvasc Res 2011;82:
284–90.
Silver MJ, Hoch W, Kocsis JJ, Ingerman CM, Smith JB . Arachidonic acid causes sudden death in rabbits. Science 1974;183:1085–7.
Kajimoto H, Hashimoto K, Bonnet SN, et al. Oxygen activates the Rho/Rho-kinase pathway and induces RhoB and ROCK-1 expression in human and rabbit ductus arteriosus by increasing mitochondria-derived reactive oxygen species: a newly recognized mechanism for sustaining ductal constriction. Circulation 2007;115:1777–88.
Thébaud B, Wu XC, Kajimoto H, et al. Developmental absence of the O2 sensitivity of L-type calcium channels in preterm ductus arteriosus smooth muscle cells impairs O2 constriction contributing to patent ductus arteriosus. Pediatr Res 2008;63:176–81.
Roehl AB, Steendijk P, Baumert JH, Schnoor J, Rossaint R, Hein M . Comparison of 3 methods to induce acute pulmonary hypertension in pigs. Comp Med 2009;59:280–6.
Gresele P, Corona C, Alberti P, Nenci GG . Picotamide protects mice from death in a pulmonary embolism model by a mechanism independent from thromboxane suppression. Thromb Haemost 1990;64:80–6.
Pfister SL, Kotulock DA, Campbell WB . Vascular smooth muscle thromboxane A2 receptors mediate arachidonic acid-induced sudden death in rabbits. Hypertension 1997;29(1 Pt 2):303–9.
Thomas DW, Mannon RB, Mannon PJ, et al. Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2. J Clin Invest 1998;102:1994–2001.
Rajasekhar D, Kestin AS, Bednarek FJ, Ellis PA, Barnard MR, Michelson AD . Neonatal platelets are less reactive than adult platelets to physiological agonists in whole blood. Thromb Haemost 1994;72:957–63.
Hinton M, Mellow L, Halayko AJ, Gutsol A, Dakshinamurti S . Hypoxia induces hypersensitivity and hyperreactivity to thromboxane receptor agonist in neonatal pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 2006;290:L375–84.
Hinton M, Gutsol A, Dakshinamurti S . Thromboxane hypersensitivity in hypoxic pulmonary artery myocytes: altered TP receptor localization and kinetics. Am J Physiol Lung Cell Mol Physiol 2007;292:L654–63.
Fineman JR, Chang R, Soifer SJ . EDRF inhibition augments pulmonary hypertension in intact newborn lambs. Am J Physiol 1992;262(5 Pt 2):H1365–71.
Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM . Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991;83:2038–47.
Huang JS, Ramamurthy SK, Lin X, Le Breton GC . Cell signalling through thromboxane A2 receptors. Cell Signal 2004;16:521–33.
Becker KP, Garnovskaya M, Gettys T, Halushka PV . Coupling of thromboxane A2 receptor isoforms to Galpha13: effects on ligand binding and signalling. Biochim Biophys Acta 1999;1450:288–96.
Allan CJ, Higashiura K, Martin M, et al. Characterization of the cloned HEL cell thromboxane A2 receptor: evidence that the affinity state can be altered by G alpha 13 and G alpha q. J Pharmacol Exp Ther 1996;277:1132–9.
Kovalcik V . The response of the isolated ductus arteriosus to oxygen and anoxia. J Physiol (Lond) 1963;169:185–97.
Agren P, Cogolludo AL, Kessels CG, et al. Ontogeny of chicken ductus arteriosus response to oxygen and vasoconstrictors. Am J Physiol Regul Integr Comp Physiol 2007;292:R485–96.
Pace-Asciak CR, Rangaraj G . The 6-ketoprostaglandin F1alpha pathway in the lamb ductus arteriousus. Biochim Biophys Acta 1977;486:583–5.
Yokoyama U, Minamisawa S, Katayama A, et al. Differential regulation of vascular tone and remodeling via stimulation of type 2 and type 6 adenylyl cyclases in the ductus arteriosus. Circ Res 2010;106:1882–92.
Akaike T, Jin MH, Yokoyama U, et al. T-type Ca2+ channels promote oxygenation-induced closure of the rat ductus arteriosus not only by vasoconstriction but also by neointima formation. J Biol Chem 2009;284:24025–34.
Yokoyama U, Minamisawa S, Adachi-Akahane S, et al. Multiple transcripts of Ca2+ channel alpha1-subunits and a novel spliced variant of the alpha1C-subunit in rat ductus arteriosus. Am J Physiol Heart Circ Physiol 2006;290:H1660–70.
Acknowledgements
We thank K. Iwai, Q. Jiao, and N. Liu (Waseda University), and R. Aoki (Yokohama City University) for technical advice and/or support.
Author information
Authors and Affiliations
Corresponding author
Supplementary information
Supplementary Figure S1.
(TIFF 1520 kb)
Supplementary Figure S2.
(TIFF 1520 kb)
Supplemental Methods.
(DOC 25 kb)
Rights and permissions
About this article
Cite this article
Yokota, T., Aida, T., Ichikawa, Y. et al. Low-dose thromboxane A2 receptor stimulation promotes closure of the rat ductus arteriosus with minimal adverse effects. Pediatr Res 72, 129–136 (2012). https://doi.org/10.1038/pr.2012.68
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/pr.2012.68
