title: Tetrandrine prevents monocrotaline-induced pulmonary arterial hypertension in rats through regulation of the protein expression of inducible nitric oxide synthase and cyclic guanosine monophosphate-dependent protein kinase type 1.
abstract: OBJECTIVE
  Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a persistent elevation of pulmonary artery pressure and ventricular hypertrophy. Tetrandrine is a bisbenzylisoquinoline alkaloid that can decrease blood pressure, inhibit the proliferation of vascular smooth muscle cells, and block cardiac hypertrophy, but whether it has a therapeutic effect on PAH remains poorly defined. This study was undertaken to investigate the efficacy of tetrandrine on PAH.
  
  
  METHODS
  Forty-eight male Sprague-Dawley rats were randomly and equally divided into four groups. The control group was injected with normal saline; the others were injected with monocrotaline (MCT) to induce PAH, then treated with saline, tetrandrine, and vardenafil, respectively, from day 21 to day 42. On day 43, we measured the mean pulmonary artery pressure under general anesthesia, dissected the rat, and calculated the right ventricular hypertrophy index [right ventricle/(left ventricle plus septum)]. Later we observed the changes in the pulmonary vascular wall; measured the expression of cyclic guanosine monophosphate-dependent protein kinase type 1 and inducible nitric oxide synthase; measured the levels of superoxide dismutase, glutathione, malondialdehyde, and catalase; and then compared the results among groups.
  
  
  RESULTS
  Compared with the MCT group, rats treated with tetrandrine had attenuated mean pulmonary artery pressure (20.48 ± 1.49 vs 30.07 ± 1.51; P < .01) and right ventricular hypertrophy index (49.19 ± 2.45 vs 68.50 ± 1.95; P < .01), inhibited proliferation of pulmonary artery smooth muscle cells, and improved endothelial function. Tetrandrine also upregulated the expression of protein kinase type 1 (90.86 ± 1.95 vs 67.34 ± 1.50; P < .01); downregulated the expression of inducible nitric oxide synthase (74.76 ± 1.48 vs 80.19 ± 0.28; P < .01); increased levels of superoxide dismutase (245.54 ± 12.98 vs 166.16 ± 21.42; P < .01), glutathione (0.699 ± 0.032 vs 0.514 ± 0.056; P < .01), and catalase (32.13 ± 2.33 vs 27.19 ± 2.72; P < .01); and decreased malondialdehyde (1.027 ± 0.039 vs 1.462 ± 0.055; P < .01).
  
  
  CONCLUSIONS
  Tetrandrine alleviated MCT-induced PAH through regulation of nitric oxide signaling pathway and antioxidant and antiproliferation effects.
authors.affiliation: Department of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong, China.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Science/Guangdong General Hospital, Guangzhou, Guangdong, China.
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong, China.
authors.forename: Dongpeng
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Tong
authors.affiliation: Department of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Lv
authors.affiliation: Department of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong, China.
authors.forename: Changfu
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong, China. Electronic address: 806258233@qq.com.
authors.forename: Wenpeng
authors.initials: W
authors.lastname: Dong
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D062186:Arterial Pressure / Q000187:drug effects*; D044182:Benzylisoquinolines / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000378:metabolism*; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D066253:Vascular Remodeling / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D000975:Antioxidants; D044182:Benzylisoquinolines; C009438:tetrandrine; D008315:Malondialdehyde; D016686:Monocrotaline; D002374:Catalase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D013482:Superoxide Dismutase; D062965:Cyclic GMP-Dependent Protein Kinase Type I; C569721:Prkg1 protein, rat; D005978:Glutathione