Letter to the Editor Sodium tanshinone IIA sulfonate and sodium danshensu open the placental barrier through down-regulation of placental P-glycoprotein in mice: Implications in the transplacental digoxin treatment for fetal heart failure Chuan Wang a,c , Huaying Li a , Kaiyu Zhou a, ⁎, Chunyan Luo c , Yifei Li a,c , Liang Xie b , Yimin Hua a,c,d, ⁎⁎ a Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China b The Pulmonary Vascular Remodeling Research Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China c West China Medical School of Sichuan University, Chengdu, Sichuan, China d Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China article info Article history: Received 8 June 2014 Accepted 27 July 2014 Available online 3 August 2014 Keywords: Danshen P-glycoprotein Digoxin Fetal heart failure Congestive fetal heart failure (CFHF), defined as inability of the heart to deliver adequate blood flow to organs such as the brain, liver, and kidneys, is a common final outcome of many intrauterine disease states that may lead to fetal demise [1]. Over the past several decades, the increasing rates of infertility and advances in fetal medicine have changed the attitude to CFHF from simply terminating the pregnancy by interruption to possible active therapy of the fetus [2]. Nowadays, the treatment of CFHF usually consists of the transplacental administra- tion of digoxin as the drug of first choice [2]. Although transplacental passage of digoxin has been confirmed using the technique of ex vivo perfused human term placenta, in vivo data indicate relatively lower umbilical cord to maternal plasma drug concentration ratio with con- siderable inter-individual variability [3]. Our previous study showed that fetal-to-maternal digoxin concentration ratio ranges between 0.46 and 0.89 and those with hydrops showed a significant lower trans- placental rate (0.46–0.77) than that without hydrops (0.69–0.89) [4,5]. Several reports [2,6] and our study [4,5] showed that maternal therapy with digoxin alone was always not effective in treating CFHF once hydrops was present, which might result from the lower transplacental rate of digoxin in such conditions. Therefore, how to maximize fetal exposure to digoxin (and therefore drug effectiveness) and to minimize its toxicity in the mother still remains a challenging task when treating CFHF with transplacental digoxin. The P-glycoprotein (P-gp), specially located in the maternal-facing apical membrane of the syncytiotrophoblast of placenta, has been wide- ly proved to have the capacity to actively efflux a wide range of drugs back to the maternal circulation, thus playing a crucial role in drug transport across the placenta barrier [7]. Digoxin was proved to be a substrate of P-gp. Studies in abcb1 knock-out mice have shown that P-gp deficiency could result in many fold higher concentrations of digoxin in fetal compartment [8]. In light of these findings, it is speculated that the low digoxin concentrations in the fetal umbilical vessels may, at least partly, be caused by placental P-gp. In this scenario, pharmacological manipulations, such as inhibition of placental P-gp would offer the advantage of enhance digoxin availability to the fetus, while minimizing drug exposure of the mother. Various P-gp inhibitors have been developed for reversing drug resistance in cancer chemotherapy or enhancing pharmacotherapy effi- cacy in the nervous system. However, almost all those inhibitors are the U.S. food and drug administration (FDA) category D or X drugs, and thus could not be used during pregnancy [9]. Encouragingly, more recently, several natural products have also been identified for their effectiveness in reversing multi-drug resistance by inhibiting P-gp expression. Among them, Tanshinone IIA (Tan-IIA), a main pharmacologically active component of Danshen, was proved to potentiate the efficacy of 5-FU in colo205 colon cancer cells in vivo through down-regulation of P-gp [10]. Danshen, the dried root of Salvia miltiorrhiza Bunge, has been widely used for the treatment of maternal or fetal pregnant complications in China, such as fetal growth restriction (FGR), intrahepatic cholestasis of pregnancy (ICP), pregnancy-induced hypertension (PIH)/severe pre- eclampsia [11–13]. In light of these findings, it is quite critical to deter- mine whether or how Danshen could affect placental P-gp expression and its functionality. If Danshen could inhibit placental P-gp expression International Journal of Cardiology 176 (2014) 1331–1333 ⁎ Corresponding author. Tel.: +86 28 85501352; fax: +86 28 85501059. ⁎⁎ Correspondence to: Y. Hua, Department of Pediatric Cardiovascular Disease, West China Second University Hospital, Sichuan University, No. 20, Section 3, RenminNanLu Road, Chengdu, Sichuan 610041, China. Tel.: +86 28 85501069; fax: +86 28 85501059. E-mail addresses: kaiyuzhou313@163.com (K. Zhou), nathan_hua@126.com, nathan_hua@163.com (Y. Hua). http://dx.doi.org/10.1016/j.ijcard.2014.07.147 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved. Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard