School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China.
School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China; Institute of Cardiovascular Research, The Key Laboratory of Medical Electrophysiology, Ministry of Education of China, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Medical Key Laboratory for Drug Discovery and Druggability Evaluation of Sichuan Province, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Luzhou, 646000, China.
Biomed Pharmacother. 2020 Jun;126:110073. doi: 10.1016/j.biopha.2020.110073. Epub 2020 Mar 13.
Myocardial fibrosis (MF) is an unavoidable complication in patients with hypertensive heart disease. Valsartan, a widely used antihypertensive drug, was reported to inhibit MF. Deficiency in the 5-hydroxytryptamine (5-HT, serotonin) transporter gene has been proven to cause MF. Long-term sympathetic nerve excitability activates renin angiotensin aldosterone system leading to MF. Tandospirone, a partial agonist of the 5-HT1A receptor, has been commonly used to relieve psychiatric symptoms. However, there is limited evidence on the combination of valsartan and tandospirone for the treatment of MF. Therefore, we investigated the synergistic effect of tandospirone on the anti-MF activity of valsartan in spontaneously hypertensive rats (SHRs).
Systolic blood pressure (SBP) of SHRs (12-week-old) was measured weekly using the tail-cuff method for eight weeks; the left ventricular was collected and weighted for calculation of the left ventricular mass index (LVMI). The myocardial histopathology of left ventricle was evaluated in rats by hematoxylin and eosin (H&E) and Mason's trichrome staining assays. The mRNA and protein expressions of transforming growth factor β (TGF-β1), Sma- and Mad-related protein 3 (Smad3), and fibronectin (Fn) were investigated by real time PCR, immunohistochemistry, and Western blotting analysis, respectively.
Tandospirone (40 mg/kg) could significantly improve the effect of valsartan (30 mg/kg) in decreasing the SBP of SHRs and lower the ratio of the LVMI in SHRs, compared to that of rats treated with valsartan or tandospirone alone. Tandospirone could also enhance the valsartan-induced reduction in collagen deposition in the myocardial tissues of SHRs. Furthermore, tandospirone could enhance the effect of valsartan on downregulating the expression levels of TGF-β1, Smad3, and Fn at both mRNA and protein levels.
We report for the first time that tandospirone could improve the anti-MF efficacy of valsartan via the TGF-β1/Smad3 signaling pathway in SHRs. Our findings may provide valuable insight into the scientific rationale for combining tandospirone and valsartan in the treatment of MF clinically.
心肌纤维化（MF）是高血压性心脏病患者不可避免的并发症。缬沙坦是一种广泛应用的降压药物，据报道其具有抑制 MF 的作用。5-羟色胺（5-HT，血清素）转运体基因缺失已被证明可导致 MF。长期的交感神经兴奋性激活肾素-血管紧张素-醛固酮系统导致 MF。坦度螺酮是 5-HT1A 受体的部分激动剂，常用于缓解精神症状。然而，关于缬沙坦联合坦度螺酮治疗 MF 的证据有限。因此，我们研究了坦度螺酮对自发性高血压大鼠（SHR）缬沙坦抗 MF 活性的协同作用。
使用尾套法每周测量 SHR（12 周龄）的收缩压（SBP），共 8 周；收集左心室并称重，计算左心室质量指数（LVMI）。通过苏木精和伊红（H&E）及 Mason 三色染色法评估大鼠左心室心肌组织病理学变化。通过实时 PCR、免疫组化和 Western blot 分析分别检测转化生长因子β（TGF-β1）、Smad 相关蛋白 3（Smad3）和纤维连接蛋白（Fn）的 mRNA 和蛋白表达。
坦度螺酮（40mg/kg）可显著增强缬沙坦（30mg/kg）降低 SHR 收缩压和降低 SHR 左心室质量指数比值的作用，与单独给予缬沙坦或坦度螺酮的大鼠相比。坦度螺酮还可增强缬沙坦减少 SHR 心肌组织胶原沉积的作用。此外，坦度螺酮可增强缬沙坦下调 TGF-β1、Smad3 和 Fn 表达水平的作用，无论是在 mRNA 还是蛋白水平上。
我们首次报道，坦度螺酮可通过 TGF-β1/Smad3 信号通路增强缬沙坦在 SHR 中的抗 MF 作用。我们的研究结果可能为临床联合应用坦度螺酮和缬沙坦治疗 MF 提供有价值的科学依据。
