Abstract
Objective
To investigate the effect of early intervention of Tongxinluo (通心络, TXL) on right ventricular function (RVF) of rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT).
Methods
A total of 30 adult male Sprague-Dawley rats were assigned to 5 groups with complete random experiment design: Sham group (Sham), MCT group, TXL group, sildenafil (SIL) group and combination group (TXL+SIL), 6 rats in each group. Rats were injected with 50 mg/kg MCT solution for inducing PAH model except for those in the sham group. From the day of modeling, rats of TXL, SIL and TXL+SIL groups were given TXL (1.2 g/kg), SIL (10 mg/kg) and combination solution (TXL:1.2 g/kg, SIL: 10 mg/kg) respectively, and rats in Sham and MCT groups were given normal saline (5 mL/kg). The samples were collected and tested after 21 consecutive days of intragastric administration. Echocardiography was used to measure the related indices of RVF, including pulmonary arterial flow spectrum, pulmonary artery diameter (PAD), right ventricular wall thickness (RVWT), right ventricular diameter (RVD), tricuspidannular plane systolic excursion (TAPSE), right atrium transverse diameter (RAT), and inferior vena cava diameter (IVCD). Elastic Verhoeff-Van Gieson staining was adopted to measure the percentage of wall thickness (WT%) of pulmonary arteriols. Hematoxylin-eosin staining was used to measure the cross-sectional area (CSA) of right ventricular cardiomyocytes.
Results
MCT-induced PAH rat model was successfully established. In MCT group the wall of pulmonary arterioles exhibited a prominent-increase thickness, PAD, RVWT, RVD, RAT, IVCD, WT%, right ventricular hypertrophy index (RVHI) as well as CSA of RV cardiomyocyte significantly increased (all P<0.01), and TAPSE markedly decreased (P<0.01). At the same time, TXL prominently improved all of the above indices (all P<0.01). In comparison with SIL, TXL significantly reduced RVD (P<0.05) and decreased CAS of RV cardiomyocytes (P<0.01), but TAPSE in SIL group was much larger than in TXL group (P<0.01). Moreover, TAPSE in TXL+SIL group was larger than that in TXL group (P<0.01), while the two groups performed equally well in terms of the other indices.
Conclusion
Early intervention of TXL could inhibit pulmonary arterioles remodeling, and improve RVF by attenuating right ventricular hypertrophy, and TXL has a stronger effect on inhibiting right ventricular remodeling than SIL.
Similar content being viewed by others
References
Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67–119.
Macchia A, Marchioli R, Tognoni G, Scarano M, Marfisi R, Tavazzi L, et al. Systematic review of trials using vasodilators in pulmonary arterial hypertension: why a new approach is needed. Am Heart J 2010;159:245–257.
Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156–163.
Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, et al. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute Working Group on cellular and molecular mechanisms of right heart failure. Circulation 2006;114:1883–1891.
van de Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, Heymans MW, Bogaard HJ, et al. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 2011;58:2511–2519.
Wu T, Harrison RA, Chen X, Ni J, Zhou L, Qiao J, et al. Tongxinluo (Tong xin luo or Tong-xin-luo) Capsule for unstable angina pectoris. Cochrane Database Syst Rev 2006;18:CD004474.
Chen WQ, Zhong L, Zhang L, Ji XP, Zhao YX, Zhang C, et al. Chinese medicine Tongxinluo signifcandy lowers serum lipid levels and stabilizes vulnerable plaques in a rabbit model. J Ethnopharmacol 2009;124:103–110.
Liang JQ, Xu HB, Wu YL, Sun SR, Jia ZH, Wei C, et al. Effect of serum from overfatigue rats on JNK/c-Jun/HO-1 pathway in human umbilical vein endothelial cells and the intervening effect of Tongxinluo Superfine Powder. Chin J Integr Med 2009;15:121–127.
Cui HH, Li N, Li XD, Qi K, Li Q, Jin C, et al. Tongxinluo modulates cytokine secretion by cardiac microvascular endothelial cells in ischemia/reperfusion injury. Am J Transl Res 2016;8:4370–4381.
Wu XM, Gao YB, Xu LP, Zou DW, Zhu ZY, Wang XL, et al. Tongxinluo inhibits renal fibrosis in diabetic nephropathy: involvement of the suppression of intercellular transfer of TGF-β1-containing exosomes from GECs to GMCs. Am J Chin Med 2017;45:1075–1092.
Bai WW, Xing YF, Wang B, Lu XT, Wang YB, Sun YY, et al. Tongxinluo improves cardiac function and ameliorates ventricular remodeling in mice model of myocardial infarction through enhancing angiogenesis. Evid Based Complement Alternat Med 2013:813247.
Wang B, Yang Q, Bai WW, Xing YF, Lu XT, Y, Sun YY. Tongxinluo protects against pressure overload-induced heart failure in mice involving VEGF/Akt/eNOS pathway activation. PLoS One 2014;9:e98047.
Wang Y, Ma TT, Gao NN, Zhou XL, Jiang H, Guo R, et al. Effect of Tongxinluo on pulmonary hypertension and pulmonary vascular remodeling in rats exposed to a low pressure hypoxic environment. J Ethnopharmacol 2016;194:668–673.
Long L, Crosby A, Yang X, Southwood M, Upton PD, Kimet DK. Altered bone morphogenetic protein and transforming growth factor-beta signaling in rat models of pulmonary hypertension: potential for activin receptor-like kinase-5 inhibition in prevention and progression of disease. Circulation 2009;119:566–576.
Voelkel NF, Cool C. Pathology of pulmonary hypertension. Cardiol Clin 2004;22:343–351.
Li XL, Guan RJ, Li JJ. Attenuation of monocrotaline-induced pulmonary arterial hypertension in rats by rosuvastatin. J Cardiovasc Pharmacol 2012;60:219–226.
Michelakis ED, Wilkins M, Rabinovitch M. Emerging concepts and translational priorities in pulmonary arterial hypertension. Circulation 2008;118:1486–1495.
Carlsson M, Ugander M, Heiberg E, Arheden H. The quantitative relationship between longitudinal and radial function in left, right, and total heart pumping in humans. Am J Physiol Heart Circ Physiol 2007;293:H636–H644.
Henein MY, Gibson OG. Normal long axis function. Heart 1999;81:111–113.
Omens JH, Moculloeh AD, Criseione JC. Complex distributions of residual stress and strain in the mouse left ventricle rimental and theoretical models. Biomech Model Mechanobiol 2003;1:267–277.
Borges AC, Knebel F, Eddicks S, Panda A, Schattke S, Witt C, et al. Right ventricular function assessed by two-dimensional and tissue Doppler echocardiography in patients with arterial hypertension and effect of vasodilator therapy. Am J Cardiol 2006;98:530–534.
Burke DL, Frid MG, Kunrath CL, Karoor V, Anwar A, Wagner BD, et al. Sustained hypoxia promotes the development of a pulmonary artery-specific chronic inflammatory microenvironment. Am J Physiol Lung Cell Mol Physiol 2009;297:238–250.
Kolb TM, Peabody J, Baddoura P, Fallica J, Mock JR, Singer BD, et al. Right ventricular angiogenesis is an early adaptive response to chronic hypoxia-induced pulmonary hypertension. Microcirculation 2015;22:724–736.
Gomez-Arroyo JG, Farkas L, Alhussaini AA, Farkas D, Kraskauskas D, Voelkel NF, et al. The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol 2012;302:363–369.
Nogueira-Ferreira R, Vitorino R, Ferreira R, Henriques-Coelho T. Exploring the monocrotaline animal model for the study of pulmonary arterial hypertension: a network approach. Pulm Pharmacol Ther 2015;35:8–16.
Gao L, Li SD, Liu Y, Yang MH. Research progress of traditional Chinese medicine in prevention and treatment of pulmonary arterial hypertension. Chin J Integr Med Cardio-/Cerebrovasc Dis (Chin) 2017;15:2396–2400.
D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary hypertension: Results from a national prospective registry. Ann Intern Med 1991;115:343–349.
Elias-Al-Mamun M, Satoh K, Tanaka S, Shimizu T, Nergui S, Miyata S, et el. Combination therapy with fasudil and sildenafil ameliorates monocrotaline-induced pulmonary hypertension and survival in rats. Circ J 2014;78:967–976.
Yoshiyuki R, Tanaka R, Fukushima R, Machida N. Preventive effect of sildenafil on right ventricular function in rats with monocrotaline-induced pulmonary arterial hypertension. Exp Anim 2016;65:215–222.
Acknowledgement
All authors thank Dr. Gao Y and Professor Ren JP for their kind assistance and valuable suggestions.
Author information
Authors and Affiliations
Contributions
Yang MH contributed to the scientific content and study design. Gao L has contributed to the experiment operation, statistical analysis and manuscript preparation. Li SD, Zhang Y, and Liu Y have contributed to study design, technical support and material support.
Corresponding author
Ethics declarations
All the authors report no conflict of interest. None of the contents of this manuscript has been published previously. All the authors have read and approved the final version of the manuscript prior to submission.
Additional information
Supported by National Key Basic Research Special Foundation of China (No. 2012CB518600)
Rights and permissions
About this article
Cite this article
Gao, L., Li, Sd., Zhang, Y. et al. Early Intervention of Tongxinluo (通心络) on Right Ventricular Function Assessed by Echocardiography in Rats with Pulmonary Arterial Hypertension Induced by Monocrotaline. Chin. J. Integr. Med. 26, 913–920 (2020). https://doi.org/10.1007/s11655-020-3229-x
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11655-020-3229-x