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Hypoxia-Induced Cytosolic Calcium Decrease Is Mediated Primarily by the Forward Mode of Na+/Ca2+ Exchanger in Smooth Muscle Cells of Fetal Ductus Arteriosus

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Abstract

Closure of the ductus arteriosus (DA) after birth, essential for postnatal adaptation, is initiated by the transition from hypoxia to normoxia. The current study investigated how hypoxia affects the level of cytosolic calcium ([Ca2+]i) in fetal lamb DA smooth muscle cells (DASMCs) and the role of calcium pumps in this process. The [Ca2+]i variation in response to acute hypoxia was determined spectrofluorometrically with fura-3-AM in cultured fetal DASMCs. Interventions using chemicals or solutions including thapsigargin, vanadate, KB-R7943, alkaline PH9.0 solution, or Na+-free medium were administered when samples were exposed to acute hypoxia. The results show that [Ca2+]i decreased dramatically under acute hypoxia. This decrease was not attenuated completely by an inhibitor of sarcoplasmic/endoplasmic reticulum Ca2+ adenosine triphosphatase (ATPase) (SERCA), a blocker of plasma membrane Ca2+ ATPase (PMCA), or an inhibitor and activator of the reserve mode of the Na+/Ca2+ exchanger (NCX). In contrast, KT-R9743, an inhibitor of the forward mode of NCX at a high concentration (30 μm), greatly diminished the hypoxia-induced [Ca2+]i decrease in fetal DASMCs. These results suggest that a hypoxia-induced Ca2+ decrease in fetal DASMCs results from cytosolic Ca2+ efflux mediated primarily by the forward mode of NCX.

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References

  1. Abman S, Kinsella J, Mercier J (1999) Nitric oxide and endothelin in the developing pulmonary circulation: physiologic and clinical implications. In: Gaultier CBJ, Post M (eds) Lung development 1999. Oxford University Press, New York, p 196

    Google Scholar 

  2. Annunziato L, Pignataro G, Di Renzo GF (2004) Pharmacology of brain Na+/Ca2+ exchanger: from molecular biology to therapeutic perspectives. Pharmacol Rev 56:633–654

    Article  PubMed  CAS  Google Scholar 

  3. Assali NS, Kirchbaum TH, Dilts PV (1968) Effects of hyperbaric oxygen on utero placental and fetal circulation. Circ Res 22:573–588

    PubMed  CAS  Google Scholar 

  4. Bers DM, Despa S (2006) Cardiac myocytes Ca2+ and Na+ regulation in normal and failing hearts. J Pharmacol Sci 100:315–322

    Article  PubMed  CAS  Google Scholar 

  5. Cantley LC Jr, Josephson L, Warner R et al (1977) Vanadate is a potent (Na, K)-ATPase inhibitor found in ATP derived from muscle. J Biol Chem 252:7421–7423

    PubMed  CAS  Google Scholar 

  6. Carafoli E (1992) The Ca2+ pump of the plasma membrane. J Biol Chem 267:2115–2118

    PubMed  CAS  Google Scholar 

  7. Clyman RI (2000) Ibuprofen and patent ductus arteriosus. N Engl J Med 343:728–730

    Article  PubMed  CAS  Google Scholar 

  8. Cornfield DN, Stevens T, McMurtry IF et al (1994) Acute hypoxia causes membrane depolarization and calcium influx in fetal pulmonary artery smooth muscle cells. Am J Physiol 266:L469–L475

    PubMed  CAS  Google Scholar 

  9. Fay FS (1971) Guinea pig ductus arteriosus: I. Cellular and metabolic basis for oxygen sensitivity. Am J Physiol 221:470–479

    PubMed  CAS  Google Scholar 

  10. Gros R, Afroze T, You XM et al (2003) Plasma membrane calcium ATPase overexpression in arterial smooth muscle increases vasomotor responsiveness and blood pressure. Circ Res 93:614–621

    Article  PubMed  CAS  Google Scholar 

  11. Guibert C, Flemming R, Beech DJ (2002) Prevention of a hypoxic Ca(2+)(i) response by SERCA inhibitors in cerebral arterioles. Br J Pharmacol 135:927–934

    Article  PubMed  CAS  Google Scholar 

  12. Heyman MA, Rudolph AM (1975) Control of the ductus arteriosus. Physiol Rev 55:62–78

    Google Scholar 

  13. Host A, Halken S, Kamper J et al (1988) Prostaglandin E1 treatment in ductus dependent congenital cardiac malformation: a review of the treatment of 34 neonates. Dan Med Bull 35:81–84

    PubMed  CAS  Google Scholar 

  14. Imamura S, Nishikawa T, Hiratsuka E et al (2000) Behavior of smooth muscle cells during arterial ductal closure at birth. J Histochem Cytochem 48:35–44

    PubMed  CAS  Google Scholar 

  15. Inesi G, Hua S, Xu C et al (2005) Studies of Ca2+ ATPase (SERCA) inhibition. J Bioenerg Biomembr 37:365–368

    Article  PubMed  CAS  Google Scholar 

  16. Ishida Y, Paul RJ (2005) Ca2+ clearance in smooth muscle: lessons from gene altered mice. J Smooth Muscle Res 41:235–245

    Article  PubMed  Google Scholar 

  17. Iwamoto T, Watano T, Shigekawa M (1996) A novel isothiourea derivative selectively inhibits the reverse mode of Na+/Ca2+ exchange in cells expressing NCX1. J Biol Chem 271:22391–22397

    Article  PubMed  CAS  Google Scholar 

  18. Karaki H, Ozaki H, Hori M (1997) Calcium movements, distribution, and functions in smooth muscle. Pharmacol Rev 49:157–230

    PubMed  CAS  Google Scholar 

  19. Keck M, Resnik E, Linden B et al (2005) Oxygen increases ductus arteriosus smooth muscle cytosolic calcium via release of calcium from inositol triphosphate-sensitive stores. Am J Physiol Lung Cell Mol Physiol 288:L917–L923

    Article  PubMed  CAS  Google Scholar 

  20. Kim MY, Seol GH, Liang GH et al (2005) Na+-K+ pump activation inhibits endothelium-dependent relaxation by activating the forward mode of Na+/Ca2+ exchanger in mouse aorta. Am J Physiol Heart Circ Physiol 289:H2020–H2029

    Article  PubMed  CAS  Google Scholar 

  21. Li SZ, Wu F, Wang B, Wei GZ et al (2007) Role of reverse mode Na+/Ca2+ exchanger in the cardioprotection of metabolic inhibition preconditioning in rat ventricular myocytes. Eur J Pharmacol 561:14–22

    Article  PubMed  CAS  Google Scholar 

  22. Penniston JT, Enyedi A (1998) Modulation of the plasma membrane Ca2+ pump. J Membr Biol 165:101–109

    Article  PubMed  CAS  Google Scholar 

  23. Pignataro G, Tortiglione A, Scorziello A et al (2004) Evidence for a protective role played by the Na+/Ca2+ exchanger in cerebral ischemia induced by middle cerebral artery occlusion in male rats. Neuropharmacology 46:439–448

    Article  PubMed  CAS  Google Scholar 

  24. Sanders KM (2001) Invited review: mechanisms of calcium handling in smooth muscles. J Appl Physiol 91:1438–1449

    PubMed  CAS  Google Scholar 

  25. Singh GK, Fong LV, Salmon AP et al (1994) Study of low-dosage prostaglandin usages and complications. Eur Heart J 15:377–381

    PubMed  CAS  Google Scholar 

  26. Szentesi P, Pignier C, Egger M et al (2004) Sarcoplasmic reticulum Ca2+ refilling controls recovery from Ca2+-induced Ca2+ release refractoriness in heart muscle. Circ Res 95:807–813

    Article  PubMed  CAS  Google Scholar 

  27. Thebaud B, Michelakis ED, Wu XC et al (2004) Oxygen-sensitive Kv channel gene transfer confers oxygen responsiveness to preterm rabbit and remodeled human ductus arteriosus: implications for infants with patent ductus arteriosus. Circulation 110:1372–1379

    Article  PubMed  CAS  Google Scholar 

  28. Tiffert T, Lew VL (2001) Kinetics of inhibition of the plasma membrane calcium pump by vanadate in intact human red cells. Cell Calcium 30:337–342

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a grant from the National Natural Science Foundation of China (no. 30471712) and Science Foundation for The Excellent Youth Scholars of Ministry of Health of Shanghai (no. 2008Y065).

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Authors and Affiliations

  1. Department of Cardiac and Thoracic Surgery, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, 1678 Dongfang Road, Shanghai, 200127, China

    Haifa Hong, Huiwen Chen, Yanjuan Sun, Meng Yin & Jinfen Liu

  2. Department of Cardiology, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Wei Gao

  3. Intensive Care Unit, Department of Cardiac and Thoracic Surgery, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Xiaoman Cai

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  1. Haifa Hong
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  2. Huiwen Chen
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  3. Wei Gao
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  4. Xiaoman Cai
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  5. Yanjuan Sun
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  6. Meng Yin
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  7. Jinfen Liu
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Correspondence to Jinfen Liu.

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Hong, H., Chen, H., Gao, W. et al. Hypoxia-Induced Cytosolic Calcium Decrease Is Mediated Primarily by the Forward Mode of Na+/Ca2+ Exchanger in Smooth Muscle Cells of Fetal Ductus Arteriosus. Pediatr Cardiol 30, 958–964 (2009). https://doi.org/10.1007/s00246-009-9478-2

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  • DOI: https://doi.org/10.1007/s00246-009-9478-2

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