Tetramethylpyrazine: A promising drug for the treatment of pulmonary hypertension

Yuqin Chen; Wenju Lu; Kai Yang; Xin Duan; Mengxi Li; Xiuqing Chen; Jie Zhang; Meidan Kuang; Shiyun Liu; Xiongting Wu; Guofa Zou; Chunli Liu; Cheng Hong; Wenjun He; Jing Liao; Chi Hou; Zhe Zhang; Qiuyu Zheng; Jiyuan Chen; Nuofu Zhang; Haiyang Tang; Rebecca R. Vanderpool; Ankit A. Desai; Franz Rischard; Stephen M. Black; Joe G.N. Garcia; Ayako Makino; Jason X.J. Yuan; Nanshan Zhong; Jian Wang

doi:10.1111/bph.15000

Tetramethylpyrazine: A promising drug for the treatment of pulmonary hypertension

Yuqin Chen, Wenju Lu, Kai Yang, Xin Duan, Mengxi Li, Xiuqing Chen, Jie Zhang, Meidan Kuang, Shiyun Liu, Xiongting Wu, Guofa Zou, Chunli Liu, Cheng Hong, Wenjun He, Jing Liao, Chi Hou, Zhe Zhang, Qiuyu Zheng, Jiyuan Chen, Nuofu ZhangHaiyang Tang, Rebecca R. Vanderpool, Ankit A. Desai, Franz Rischard, Stephen M. Black, Joe G.N. Garcia, Ayako Makino, Jason X.J. Yuan, Nanshan Zhong, Jian Wang

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

Background and Purpose: Tetramethylpyrazine (TMP) was originally isolated from the traditional Chinese herb ligusticum and the fermented Japanese food natto and has since been synthesized. TMP has a long history of beneficial effects in the treatment of many cardiovascular diseases. Here we have evaluated the therapeutic effects of TMP on pulmonary hypertension (PH) in animal models and in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). Experimental Approach: Three well-defined models of PH -chronic hypoxia (10% O₂)-induced PH (HPH), monocrotaline-induced PH (MCT-PH) and Sugen 5416/hypoxia-induced PH (SuHx-PH) - were used in Sprague-Dawley rats, and assessed by echocardiography, along with haemodynamic and histological techniques. Primary cultures of rat distal pulmonary arterial smooth muscle cells (PASMCs) were used to study intracellular calcium levels. Western blots and RT-qPCR assays were also used. In the clinical cohort, patients with PAH or CTEPH were recruited. The effects of TMP were evaluated in all systems. Key Results: TMP (100 mg·kg⁻¹·day⁻¹) prevented rats from developing experimental PH and ameliorated three models of established PH: HPH, MCT-PH and SuHx-PH. The therapeutic effects of TMP were accompanied by inhibition of intracellular calcium homeostasis in PASMCs. In a small cohort of patients with PAH or CTEPH, oral administration of TMP (100 mg, t.i.d. for 16 weeks) increased the 6-min walk distance and improved the 1-min heart rate recovery. Conclusion and Implications: Our results suggest that TMP is a novel and inexpensive medication for treatment of PH. Clinical trial is registered with www.chictr.org.cn (ChiCTR-IPR-14005379).

Original language	English (US)
Pages (from-to)	2743-2764
Number of pages	22
Journal	British Journal of Pharmacology
Volume	177
Issue number	12
DOIs	https://doi.org/10.1111/bph.15000
State	Published - Jun 1 2020

ASJC Scopus subject areas

Pharmacology

Access to Document

10.1111/bph.15000

Cite this

Chen, Y., Lu, W., Yang, K., Duan, X., Li, M., Chen, X., Zhang, J., Kuang, M., Liu, S., Wu, X., Zou, G., Liu, C., Hong, C., He, W., Liao, J., Hou, C., Zhang, Z., Zheng, Q., Chen, J., ... Wang, J. (2020). Tetramethylpyrazine: A promising drug for the treatment of pulmonary hypertension. British Journal of Pharmacology, 177(12), 2743-2764. https://doi.org/10.1111/bph.15000

Chen, Y, Lu, W, Yang, K, Duan, X, Li, M, Chen, X, Zhang, J, Kuang, M, Liu, S, Wu, X, Zou, G, Liu, C, Hong, C, He, W, Liao, J, Hou, C, Zhang, Z, Zheng, Q, Chen, J, Zhang, N, Tang, H, Vanderpool, RR, Desai, AA, Rischard, F, Black, SM, Garcia, JGN , Makino, A, Yuan, JXJ, Zhong, N & Wang, J 2020, 'Tetramethylpyrazine: A promising drug for the treatment of pulmonary hypertension', British Journal of Pharmacology, vol. 177, no. 12, pp. 2743-2764. https://doi.org/10.1111/bph.15000

@article{87f0979878c5452a97c426603f753999,

title = "Tetramethylpyrazine: A promising drug for the treatment of pulmonary hypertension",

abstract = "Background and Purpose: Tetramethylpyrazine (TMP) was originally isolated from the traditional Chinese herb ligusticum and the fermented Japanese food natto and has since been synthesized. TMP has a long history of beneficial effects in the treatment of many cardiovascular diseases. Here we have evaluated the therapeutic effects of TMP on pulmonary hypertension (PH) in animal models and in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). Experimental Approach: Three well-defined models of PH -chronic hypoxia (10% O2)-induced PH (HPH), monocrotaline-induced PH (MCT-PH) and Sugen 5416/hypoxia-induced PH (SuHx-PH) - were used in Sprague-Dawley rats, and assessed by echocardiography, along with haemodynamic and histological techniques. Primary cultures of rat distal pulmonary arterial smooth muscle cells (PASMCs) were used to study intracellular calcium levels. Western blots and RT-qPCR assays were also used. In the clinical cohort, patients with PAH or CTEPH were recruited. The effects of TMP were evaluated in all systems. Key Results: TMP (100 mg·kg−1·day−1) prevented rats from developing experimental PH and ameliorated three models of established PH: HPH, MCT-PH and SuHx-PH. The therapeutic effects of TMP were accompanied by inhibition of intracellular calcium homeostasis in PASMCs. In a small cohort of patients with PAH or CTEPH, oral administration of TMP (100 mg, t.i.d. for 16 weeks) increased the 6-min walk distance and improved the 1-min heart rate recovery. Conclusion and Implications: Our results suggest that TMP is a novel and inexpensive medication for treatment of PH. Clinical trial is registered with www.chictr.org.cn (ChiCTR-IPR-14005379).",

author = "Yuqin Chen and Wenju Lu and Kai Yang and Xin Duan and Mengxi Li and Xiuqing Chen and Jie Zhang and Meidan Kuang and Shiyun Liu and Xiongting Wu and Guofa Zou and Chunli Liu and Cheng Hong and Wenjun He and Jing Liao and Chi Hou and Zhe Zhang and Qiuyu Zheng and Jiyuan Chen and Nuofu Zhang and Haiyang Tang and Vanderpool, {Rebecca R.} and Desai, {Ankit A.} and Franz Rischard and Black, {Stephen M.} and Garcia, {Joe G.N.} and Ayako Makino and Yuan, {Jason X.J.} and Nanshan Zhong and Jian Wang",

note = "Publisher Copyright: {\textcopyright} 2020 The British Pharmacological Society",

year = "2020",

month = jun,

day = "1",

doi = "10.1111/bph.15000",

language = "English (US)",

volume = "177",

pages = "2743--2764",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "John Wiley and Sons Inc.",

number = "12",

}

TY - JOUR

T1 - Tetramethylpyrazine

T2 - A promising drug for the treatment of pulmonary hypertension

AU - Chen, Yuqin

AU - Lu, Wenju

AU - Yang, Kai

AU - Duan, Xin

AU - Li, Mengxi

AU - Chen, Xiuqing

AU - Zhang, Jie

AU - Kuang, Meidan

AU - Liu, Shiyun

AU - Wu, Xiongting

AU - Zou, Guofa

AU - Liu, Chunli

AU - Hong, Cheng

AU - He, Wenjun

AU - Liao, Jing

AU - Hou, Chi

AU - Zhang, Zhe

AU - Zheng, Qiuyu

AU - Chen, Jiyuan

AU - Zhang, Nuofu

AU - Tang, Haiyang

AU - Vanderpool, Rebecca R.

AU - Desai, Ankit A.

AU - Rischard, Franz

AU - Black, Stephen M.

AU - Garcia, Joe G.N.

AU - Makino, Ayako

AU - Yuan, Jason X.J.

AU - Zhong, Nanshan

AU - Wang, Jian

PY - 2020/6/1

Y1 - 2020/6/1

N2 - Background and Purpose: Tetramethylpyrazine (TMP) was originally isolated from the traditional Chinese herb ligusticum and the fermented Japanese food natto and has since been synthesized. TMP has a long history of beneficial effects in the treatment of many cardiovascular diseases. Here we have evaluated the therapeutic effects of TMP on pulmonary hypertension (PH) in animal models and in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). Experimental Approach: Three well-defined models of PH -chronic hypoxia (10% O2)-induced PH (HPH), monocrotaline-induced PH (MCT-PH) and Sugen 5416/hypoxia-induced PH (SuHx-PH) - were used in Sprague-Dawley rats, and assessed by echocardiography, along with haemodynamic and histological techniques. Primary cultures of rat distal pulmonary arterial smooth muscle cells (PASMCs) were used to study intracellular calcium levels. Western blots and RT-qPCR assays were also used. In the clinical cohort, patients with PAH or CTEPH were recruited. The effects of TMP were evaluated in all systems. Key Results: TMP (100 mg·kg−1·day−1) prevented rats from developing experimental PH and ameliorated three models of established PH: HPH, MCT-PH and SuHx-PH. The therapeutic effects of TMP were accompanied by inhibition of intracellular calcium homeostasis in PASMCs. In a small cohort of patients with PAH or CTEPH, oral administration of TMP (100 mg, t.i.d. for 16 weeks) increased the 6-min walk distance and improved the 1-min heart rate recovery. Conclusion and Implications: Our results suggest that TMP is a novel and inexpensive medication for treatment of PH. Clinical trial is registered with www.chictr.org.cn (ChiCTR-IPR-14005379).

AB - Background and Purpose: Tetramethylpyrazine (TMP) was originally isolated from the traditional Chinese herb ligusticum and the fermented Japanese food natto and has since been synthesized. TMP has a long history of beneficial effects in the treatment of many cardiovascular diseases. Here we have evaluated the therapeutic effects of TMP on pulmonary hypertension (PH) in animal models and in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). Experimental Approach: Three well-defined models of PH -chronic hypoxia (10% O2)-induced PH (HPH), monocrotaline-induced PH (MCT-PH) and Sugen 5416/hypoxia-induced PH (SuHx-PH) - were used in Sprague-Dawley rats, and assessed by echocardiography, along with haemodynamic and histological techniques. Primary cultures of rat distal pulmonary arterial smooth muscle cells (PASMCs) were used to study intracellular calcium levels. Western blots and RT-qPCR assays were also used. In the clinical cohort, patients with PAH or CTEPH were recruited. The effects of TMP were evaluated in all systems. Key Results: TMP (100 mg·kg−1·day−1) prevented rats from developing experimental PH and ameliorated three models of established PH: HPH, MCT-PH and SuHx-PH. The therapeutic effects of TMP were accompanied by inhibition of intracellular calcium homeostasis in PASMCs. In a small cohort of patients with PAH or CTEPH, oral administration of TMP (100 mg, t.i.d. for 16 weeks) increased the 6-min walk distance and improved the 1-min heart rate recovery. Conclusion and Implications: Our results suggest that TMP is a novel and inexpensive medication for treatment of PH. Clinical trial is registered with www.chictr.org.cn (ChiCTR-IPR-14005379).

UR - http://www.scopus.com/inward/record.url?scp=85084138504&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85084138504&partnerID=8YFLogxK

U2 - 10.1111/bph.15000

DO - 10.1111/bph.15000

M3 - Article

C2 - 31976548

AN - SCOPUS:85084138504

SN - 0007-1188

VL - 177

SP - 2743

EP - 2764

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 12

ER -

Tetramethylpyrazine: A promising drug for the treatment of pulmonary hypertension

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this