Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN, 38163, USA.
Cardiovasc Drugs Ther. 2014 Apr;28(2):145-61. doi: 10.1007/s10557-014-6510-4.
We investigated the contribution of cytochrome P450 (CYP) 1B1 to hypertension and its pathogenesis by examining the effect of its selective inhibitor, 2,4,3',5'-tetramethoxystilbene (TMS), in spontaneously hypertensive rats (SHR).
Blood pressure (BP) was measured bi-weekly. Starting at 8 weeks, TMS (600 μg/kg, i.p.) or its vehicle was injected daily. At 14 weeks, samples were collected for measurement.
TMS reversed increased BP in SHR (207 ± 7 vs. 129 ± 2 mmHg) without altering BP in Wistar-Kyoto rats. Increased CYP1B1 activity in SHR was inhibited by TMS (RLU: aorta, 5.4 ± 0.7 vs. 3.7 ± 0.7; heart, 6.0 ± 0.8 vs. 3.4 ± 0.4; kidney, 411 ± 45 vs. 246 ± 10). Increased vascular reactivity, cardiovascular hypertrophy, endothelial and renal dysfunction, cardiac and renal fibrosis in SHR were minimized by TMS. Increased production of reactive oxygen species and NADPH oxidase activity in SHR, were diminished by TMS. In SHR, TMS reduced increased plasma levels of nitrite/nitrate (46.4 ± 5.0 vs. 28.1 ± 4.1 μM), hydrogen-peroxide (36.0 ± 3.7 vs. 14.1 ± 3.8 μM), and thiobarbituric acid reactive substances (6.9 ± 1.0 vs. 3.4 ± 1.5 μM). Increased plasma levels of pro-inflammatory cytokines and catecholamines, and cardiac activity of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, c-Src tyrosine kinase, and protein kinase B in SHR were also inhibited by TMS.
These data suggests that increased oxidative stress generated by CYP1B1 contributes to hypertension, increased cytokine production and sympathetic activity, and associated pathophysiological changes in SHR. CYP1B1 could be a novel target for developing drugs to treat hypertension and its pathogenesis.
通过研究细胞色素 P450（CYP）1B1 选择性抑制剂 2,4,3',5'-四甲氧基二苯乙烯（TMS）对自发性高血压大鼠（SHR）的影响，探讨 CYP1B1 对高血压及其发病机制的贡献。
每两周测量一次血压。从第 8 周开始，每天腹腔注射 TMS（600μg/kg）或其载体。在第 14 周收集样本进行测量。
TMS 逆转了 SHR 的高血压（207±7 与 129±2mmHg），而对 Wistar-Kyoto 大鼠的血压没有影响。TMS 抑制了 SHR 中 CYP1B1 活性的增加（RLU：主动脉 5.4±0.7 与 3.7±0.7；心脏 6.0±0.8 与 3.4±0.4；肾脏 411±45 与 246±10）。TMS 最小化了 SHR 中血管反应性、心血管肥大、内皮和肾功能障碍、心脏和肾脏纤维化的增加。TMS 降低了 SHR 中超氧化物和 NADPH 氧化酶活性的增加。在 SHR 中，TMS 降低了升高的血浆硝酸盐/亚硝酸盐水平（46.4±5.0 与 28.1±4.1μM）、过氧化氢水平（36.0±3.7 与 14.1±3.8μM）和硫代巴比妥酸反应物质水平（6.9±1.0 与 3.4±1.5μM）。TMS 还抑制了 SHR 中促炎细胞因子和儿茶酚胺的血浆水平升高以及细胞外信号调节激酶、p38 丝裂原激活蛋白激酶、c-Src 酪氨酸激酶和蛋白激酶 B 的心脏活性。
这些数据表明，CYP1B1 产生的氧化应激增加导致了 SHR 中的高血压、细胞因子产生和交感神经活性增加以及相关的病理生理变化。CYP1B1 可能成为治疗高血压及其发病机制的新药靶点。
