Effect of PGE2 on DA tone by EP4 modulating Kv channels with different oxygen tension between preterm and term Fenling Fan a,b , Aiqun Ma a,b, ⁎, Youfei Guan c, ⁎, Jianhua Huo a , Zhi Hu a , Hongyan Tian a , Lihong Chen c , Sen Zhu c , Lihong Fan a a The Cardiovascular Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China b Research Laboratory of Ion Channelopathy, Key Laboratory of Environment and Gene-related Diseases, National Ministry of Education, Xi'an, 710061, China c Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, 100191, China abstract article info Article history: Received 4 June 2009 Accepted 24 July 2009 Available online 2 September 2009 Keywords: PDA PGE2 receptor 4 Whole-Cell Patch-Clamp Kv channel Medicine Objective: To investigate common downstream mechanism of PGE2 and O2-sensitive voltage-dependent potassium (Kv) channels in preterm and term DA tone regulations, for suggesting respective prescriptions for preterm and term PDA. Study design: The expressions of Kv1.2, 1.5 and 2.1 were compared between preterm and term in rabbit and human DAs at mRNA and protein levels; DA contracting responses caused by O2, Kv channels blocker 4-AP, EP4 antagonist GW627368X, and PGE2 reduce using vessels rings and Whole-Cell Patch-Clamp were explored. Results: Kv 1.2 and 2.1 expressions were developed with pregnant age in preterm DA and decreased after birth with oxygen stimulation in term DA. GW627368X led significant DA constriction and DASMC IK current decrease in preterm, which was slimier to 4-AP effects, but just slightly influenced on DA tension and DASMC IK current at term. In addition, PGE2 led great DA dilation and IK current increase of DASMC in preterm but not in term. These DA tension and IK current changes were in line with Kv channel expressions. Conclusion: Higher levels of PGE2 binds with GPCR EP4, which activates G-protein to couple with O2-sensitive Kv channels and to open them, leading to DA vasorelaxation in the fetus. It indicates that EP4 inhibitors, instead of PGE2 or its analogue PGE1, may be a selectable strategy for preterm PDA. © 2009 Elsevier Ireland Ltd. All rights reserved. 1. Introduction The ductus arteriosus (DA) performs two vital functions: to maintain patent during fetal life and to close rapidly after birth to separate the pulmonary and systemic circulations [1]. If it remains open after birth, a condition known as patent DA (PDA) would happen [2,3]. PDA develops at a notable frequency of more than 40% in preterm infants with birth weight of 1500 g or less [4,5]. The preterm infants account for approximately 12.5% of the total neonates in the United States, costing half of total hospital charges for newborn care in the United States [5,6]. Prostaglandins, particularly prostaglandin E2 (PGE2), play a major role in maintaining the patency of the fetal DA [1,7,8]. The previous studies believe that this vasodilator role of PGE2, mainly via its E-prostanoid receptor 4 (EP4), one of a G-protein- coupled receptors (GPCRs), is to remodel DA in fetal. The duct functionally close shortly after birth caused from circulation PGE2 drop and systemic PO 2 raise by constricted leading DA smooth muscle cells (DASMCs) [9].O 2 sensitivity of K + channels have been described in various specialized O 2 -sensing tissues like chemoreceptors in the carotid body, pulmonary smooth muscle cells (SMCs), neuroepithelial bodies, placenta, and adrenal chromaffin cells [10]. As we know, potassium (K) channels are of importance to maintain the resting membrane potential of vascular smooth muscle cells, thus regulating vascular tone [11,12]. It is found that some voltage-dependent K + channels (Kv) in arteries are O 2 -sensitive [12] too. Kv channels in the peripheral PA also have been shown to be O 2 -sensitive, which the heterologously expressed Kv1.2, 1.5, 2.1, and 3.1 open in response to an increase in O 2 tension [13]. In addition, the recent studies [14,15] showed PDA results from impaired O 2 constriction because the DASMCs are “deficient” in O 2 -sensitive Kv channels and PGE1 or prostaglandin H synthase inhibitors (e.g., indomethacin) frequently fail to close the ductus arteries, particularly the DA in premature infants [16]. In vivo transfer of the gene for Kv1.5 or Kv2.1 partially restores contraction to oxygen in the DA of the preterm rabbit [14]. However, the mechanisms either for this decreased responsiveness to PGE2 or Kv channels mediation are far from being understood. So, further study of them is valuable for more effective and selective medicine of PDA. Therefore, we determined the relationship of PGE2 pathways and O 2 -and 4-aminopyridine (4-AP)-sensitive, voltage- International Journal of Cardiology 147 (2011) 58–65 ⁎ Corresponding authors. Ma is to be contacted at Center of Cardiovascular Medicine of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, China. Tel./fax: +86 29 85324128. Guan, Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, 100191, China. Tel./fax: +86 10 82801447. E-mail address: happyling@mail.xjtu.edu.cn (A. Ma). 0167-5273/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.07.045 Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard