Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 391, Issue 3, pp 323–334 | Cite as

DL-3-n-Butylphthalide reduces atrial fibrillation susceptibility by inhibiting atrial structural remodeling in rats with heart failure

  • Huiliang Qiu
  • Huanlin Wu
  • Jin Ma
  • Haiming Cao
  • Lihua Huang
  • Wencong Qiu
  • Ying Peng
  • Chunhua Ding
Original Article


Agents against atrial structural remodeling (ASR) are thought to block the occurrence of atrial fibrillation (AF). The aim of this study was to investigate the effects of DL-3-n-butylphthalide (NBP) on ASR and AF formation in rats with heart failure (HF) induced by myocardial infarction. The heart failure rats established 1 week after ligating left anterior descending coronary artery were randomly treated with vehicle (HF group, n = 24), or treated with DL-3-n-butylphthalide (100 mg/kg body weight) (NBP group, n = 26) for 4 weeks. Eighteen rats that underwent the same surgery but without ligating artery treated with vehicle were used as sham group (n = 18). Echocardiography, AF inducibility test, atrial fibrosis, gap junction, cytokine expression and serum antioxidant capacity analysis were detected at follow-up. Treatment of NBP for 4 weeks significantly improved cardiac function (P < 0.05), reduced AF inducibility and duration time (P < 0.05), and attenuated atrial fibrosis (P < 0.05). NBP also up-regulated protein expression of both overall Cx43 and phosphorylated Cx43 (P < 0.05) and improved the distribution of Cx43. Furthermore, NBP significantly inhibited the expression of TNF-α, NF-κB, and TGF-β1 and up-regulated Nrf2 and HO-1 protein expression with an increased serum T-AOC, CAT, and SOD activities and a reduced serum MDA. Collectively, NBP prevented ASR and AF in rats with HF by inhibiting atrial fibrosis, resynchronizing gap junction remodeling through inhibiting TNF-α/NF-κB/TGF-β1-related inflammatory reactions, and up-regulating Nrf2/HO-1-mediated antioxidant effects. Therefore, NBP may be a promising agent as upstream therapy for the prevention of AF.


DL-3-n-Butylphthalide Atrial structural remodeling Heart failure Atrial fibrillation 



Sincere thanks to Professor Matt Springer (Cardiovascular Research Institute, University of California, San Francisco; Division of Cardiology, University of California, San Francisco; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco), Dr. Xiaoyin Wang (Cardiovascular Research Institute, University of California, San Francisco) for continued advice, and De-Chun He (Animal Experimental Center, Guangdong Provincial Academy of Chinese Medicine) for careful care of animals and technical assistance.

Author contributions

The conception and design were proposed by Chun-Hua Ding and Ying Peng. Animal experiment was finished by Hui-Liang Qiu, Jin Ma, and Wen-Cong Qiu. Molecular biology experiments were mainly conducted by Hui-Liang Qiu, Wen-Cong Qiu, and Li-Hua Huang. Data collection and analysis were mainly finished by Hui-Liang Qiu and Hai-Ming Cao. Paper was drafted by Hui-Liang Qiu and reviewed by Chun-Hua Ding. Funding was secured by Chun-Hua Ding and Huan-Lin Wu.

Funding information

The study was supported by joint research project of the Guangdong Provincial Department of Science and Technology and the Guangdong Provincial Academy of Chinese Medicine (No. 2014A020221045), and science and technology research project of the Guangdong Provincial Hospital of Chinese Medicine (No. YN2016MJ04).

Compliance with ethical standards

This study was approved and monitored by the Animal Care Committee of Guangdong Provincial Hospital of Chinese Medicine and was implemented in compliance with the Regulations of Experimental Animal Administrations issued by the State Committee of Science and Technology of the People’s Republic of China.


  1. Abdoulaye IA, Guo YJA (2016) Review of recent advances in neuroprotective potential of 3-N-butylphthalide and its derivatives. Biomed Res Int 2016:5012341CrossRefPubMedPubMedCentralGoogle Scholar
  2. Anter E, Jessup M, Callans DJ (2009) Atrial fibrillation and heart failure: treatment considerations for a dual epidemic. Circulation 119(18):2516–2525. CrossRefPubMedGoogle Scholar
  3. Aschar-Sobbi R, Izaddoustdar F, Korogyi AS, Wang Q, Farman GP, Yang FH, Yang W, Dorian D, Simpson JA, Tuomi JM, Jones DL, Nanthakumar K, Cox B, Wehrens XHT, Dorian P, Backx PH (2015) Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNFα. Nat Commun 6:6018. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bikou O, Thomas D, Trappe K, Lugenbiel P, Kelemen K, Koch M et al (2011) Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model. Cardiovasc Res 92(2):218–225. CrossRefPubMedGoogle Scholar
  5. Cai WX, Zhang J, Hu DH (2009) Defensive pathway of Nrf2/ARE involved in oxidative and chemical stress. Chin J Biochem Mol Biol 25(04):297–303Google Scholar
  6. Cardin S, Libby E, Pelletier P, le Bouter S, Shiroshita-Takeshita A, le Meur N, Leger J, Demolombe S, Ponton A, Glass L, Nattel S (2007) Contrasting gene expression profiles in two canine models of atrial fibrillation. Circ Res 100(3):425–433. CrossRefPubMedGoogle Scholar
  7. Cerebrovascular Disease Working Groups, Chinese Academy of Neurology (2010) Guidelines for the management of iscemic stroke (China 2010). Chin J Neurol (Chin) 43:146–153Google Scholar
  8. Choi EK, Chang PC, Lee YS, Lin SF, Zhu W, Maruyama M, Fishbein MC, Chen Z, Rubart-von der Lohe M, Field LJ, Chen PS (2012) Triggered firing and atrial fibrillation in transgenic mice with selective atrial fibrosis induced by overexpression of TGF-β1. Circ J 76(6):1354–1362. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chong E, Chang SL, Hsiao YW, Singhal R, Liu SH, Leha T, Lin WY, Hsu CP, Chen YC, Chen YJ, Wu TJ, Higa S, Chen SA (2015) Resveratrol, a red wine antioxidant, reduces atrial fibrillation susceptibility in the failing heart by PI3K/AKT/eNOS signaling pathway activation. Heart Rhythm 12(5):1046–1056. CrossRefPubMedGoogle Scholar
  10. Cui LY, Zhu YC, Gao S, Wang JM, Peng B, Ni J, Zhou LX, He J, Ma XQ (2013) Ninety-day administration of dl-3-n-butylphthalide for acute ischemic stroke: a randomized, double-blind trial. Chin Med J 126(18):3405–3410PubMedGoogle Scholar
  11. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, ..., ESC Committee for Practice Guidelines (2010) Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 12(10):1360–420Google Scholar
  12. Everett TH 4th, Olgin JE (2007) Atrial fibrosis and the mechanisms of atrial fibrillation. Heart Rhythm 4(3 Suppl):S24–S27CrossRefPubMedGoogle Scholar
  13. Feng YP, Hu D, Zhang LY (1995) Effect of DL-butylphthalide (NBP) on mouse brain energy metabolism in complete brain ischemia induced by decapitation. Yao Xue Xue Bao 30(10):741–744PubMedGoogle Scholar
  14. Fernández-Moriano C, González-Burgos E, Gómez-Serranillos MP (2015) Mitochondria-targeted protective compounds in Parkinson’s and Alzheimer'’s diseases. Oxidative Med Cell Longev 2015:408927CrossRefGoogle Scholar
  15. Gao G, Dudley SC Jr (2009) Redox regulation, NF-kappab, and atrial fibrillation. Antioxid Redox Signal 11(9):2265–2277. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Guo Y, Wu X, Zheng X, Lu J, Wang S, Huang X (2017) Usefulness of preoperative transforming growth factor-beta to predict new onset atrial fibrillation after surgical ventricular septal myectomy in patients with obstructive hypertrophic cardiomyopathy. Am J Cardiol 120(1):118–123. CrossRefPubMedGoogle Scholar
  17. Huang JZ, Chen YZ, Su M et al (2010) dl-3-n-Butylphthalide prevents oxidative damage and reduces mitochondrial dysfunction in an MPP(+)-induced cellular model of Parkinson’s disease. Neurosci Lett 475(2):89–94. CrossRefPubMedGoogle Scholar
  18. Igarashi T, Finet JE, Takeuchi A, Fujino Y, Strom M, Greener ID, Rosenbaum DS, Donahue JK (2012) Connexin gene transfer preserves conduction velocity and prevents atrial fibrillation. Circulation 125(2):216–225. CrossRefPubMedGoogle Scholar
  19. Jalife J (2016) Novel upstream approaches to prevent atrial fibrillation perpetuation. Heart Fail Clin 12(2):309–322. CrossRefPubMedGoogle Scholar
  20. Jongsma HJ, Wilders R (2000) Gap junctions in cardiovascular disease. Circ Res 86(12):1193–1197. CrossRefPubMedGoogle Scholar
  21. Kumar RR, Narasimhan M, Shanmugam G, Hong J, Devarajan A, Palaniappan S, Zhang J, Halade GV, Darley-Usmar VM, Hoidal JR, Rajasekaran NS (2016) Abrogation of Nrf2 impairs antioxidant signaling and promotes atrial hypertrophy in response to high-intensity exercise stress. J Transl Med 14(1):86. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Le Grand B, Letienne R, Dupont-Passelaigue E, Lantoine-Adam F, Longo F, David-Dufilho M, Michael G, Nishida K, Catheline D, Legrand P, Hatem S, Nattel S (2014) F 16915 prevents heart failure-induced atrial fibrillation: a promising new drug as upstream therapy. Naunyn Schmiedeberg's Arch Pharmacol 387(7):667–677. CrossRefGoogle Scholar
  23. Lee KW, Everett TH 4th, Rahmutula D et al (2006) Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure. Circulation 114(16):1703–1712. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Fu H, Li G, Liu C, Li J, Wang X, Cheng L, Liu T (2015) Probucol prevents atrial remodeling by inhibiting oxidative stress and TNF-α/NF-κB/TGF-β signal transduction pathway in alloxan-induced diabetic rabbits. J Cardiovasc Electrophysiol 26(2):211–222. CrossRefPubMedGoogle Scholar
  25. Rahmutula D, Marcus GM, Wilson EE, Ding CH, Xiao Y, Paquet AC, Barbeau R, Barczak AJ, Erle DJ, Olgin JE (2013) Molecular basis of selective atrial fibrosis due to overexpression of transforming growth factor-β1. Cardiovasc Res 99(4):769–779. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Naser AR, Sankaranarayanan K, Kensuke T et al (2013) Disruption of Nrf2 promotes atrial remodeling and fibrillation on aging. Circ Res 113:A284Google Scholar
  27. Rucker-Martin C, Milliez P, Tan S, Decrouy X, Recouvreur M, Vranckx R, Delcayre C, Renaud JF, Dunia I, Segretain D, Hatem SN (2006) Chronic hemodynamic overload of the atria is an important factor for gap junction remodeling in human and rat hearts. Cardiovasc Res 72(1):69–79. CrossRefPubMedGoogle Scholar
  28. Woods CE, Olgin J (2014) Atrial fibrillation therapy now and in the future: drugs, biologicals, and ablation. Circ Res 114(9):1532–1546. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Xue LX, Zhang T, Zhao YW, Geng Z, Chen JJ, Chen H (2016) Efficacy and safety comparison of DL-3-n-butylphthalide and Cerebrolysin: effects on neurological and behavioral outcomes in acute ischemic stroke. Exp Ther Med 11(5):2015–2020. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Wang HM, Zhang T, Huang JK, Sun XJ (2013) 3-N-butylphthalide (NBP) attenuates the amyloid-β-induced inflammatory responses in cultured astrocytes via the nuclear factor-κB signaling pathway. Cell Physiol Biochem 32(1):235–242. CrossRefPubMedGoogle Scholar
  31. Wang F, Ma J, Han F, Guo X, Meng L, Sun Y, Jin C, Duan H, Li H, Peng Y (2016a) DL-3-n-butylphthalide delays the onset and progression of diabetic cataract by inhibiting oxidative stress in rat diabetic model. Sci Rep 6(1):19396. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Wang YG, Li Y, Wang CY, Ai JW, Dong XY, Huang HY, Feng ZY, Pan YM, Lin Y, Wang BX, Yao LL (2014) L-3-n-Butylphthalide protects rats’ cardiomyocytes from ischaemia/reperfusion-induced apoptosis by affecting the mitochondrial apoptosis pathway. Acta Physiol (Oxf) 210(3):524–533. CrossRefGoogle Scholar
  33. Tian X, He W, Yang R, Liu Y (2017) Dl-3-n-butylphthalide protects the heart against ischemic injury and H9c2 cardiomyoblasts against oxidative stress: involvement of mitochondrial function and biogenesis. J Biomed Sci 24(1):38. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Yeh YH, Kuo CT, Chang GJ, Chen YH, Lai YJ, Cheng ML, Chen WJ (2015) Rosuvastatin suppresses atrial tachycardia-induced cellular remodeling via Akt/Nrf2/heme oxygenase-1 pathway. J Mol Cell Cardiol 82:84–92. CrossRefPubMedGoogle Scholar
  35. Severs NJ (2001) Gap junction remodeling and cardiac arrhythmogenesis: cause or coincidence? J Cell Mol Med 5(4):355–366. CrossRefPubMedGoogle Scholar
  36. Verheule S, Sato T, Everett T 4th et al (2004) Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-beta1. Circ Res 94(11):1458–1465. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Swaney JS, Roth DM, Olson ER, Naugle JE, Meszaros JG, Insel PA (2005) Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase. Proc Natl Acad Sci U S A 102(2):437–442. CrossRefPubMedGoogle Scholar
  38. Wang CY, Wang ZY, Xie JW, Wang T, Wang X, Xu Y, Cai JH (2016b) Dl-3-n-butylphthalide-induced upregulation of antioxidant defense is involved in the enhancement of cross talk between CREB and Nrf2 in an Alzheimer’s disease mouse model. Neurobiol Aging 38:32–46. CrossRefPubMedGoogle Scholar
  39. Yang W, Li L, Huang R, Pei Z, Liao S, Zeng J (2012) Hypoxia inducible factor-1alpha mediates protection of DL-3-n-butylphthalide in brain microvascular endothelial cells against oxygen glucose deprivation-induced injury. Neural Regen Res 7(12):948–954. PubMedPubMedCentralGoogle Scholar
  40. Yeh YH, Hsu LA, Chen YH, Kuo CT, Chang GJ, Chen WJ (2016) Protective role of heme oxygenase-1 in atrial remodeling. Basic Res Cardiol 111(5):58. CrossRefPubMedGoogle Scholar
  41. Zhao Y, Lee JH, Chen D, et al (2017) DL-3-n-butylphthalide induced neuroprotection, regenerative repair, functional recovery and psychological benefits following traumatic brain injury in mice. Neurochem Int 111:82–92Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Second Clinical Medical CollegeGuangzhou University of Chinese MedicineGuangzhouChina
  2. 2.Department of CardiologyGuangdong Provincial Hospital of Chinese MedicineGuangzhouChina
  3. 3.State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia MedicaChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
  4. 4.Pharmacology Department, Institute of Materia MedicaChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
  5. 5.Cardiac Department, Aerospace Center HospitalPeking University Aerospace Clinical College of MedicineBeijingChina

Personalised recommendations