Zhou Wugang, Hong Mona, Zhang Ke, Chen Dongrui, Han Weiqing, Shen Weili, Zhu Dingliang, Gao Pingjin
Department of Hypertension, RuiJin Hospital, Shanghai Key Lab of Hypertension, Shanghai Institute of Hypertension, Shanghai Jiaotong University, School of Medicine, Shanghai, China.
PLoS One. 2014 Feb 12;9(2):e88722. doi: 10.1371/journal.pone.0088722. eCollection 2014.
This study investigates the effects on aortic stiffness and vasodilation by arotinolol and the underlying mechanisms in spontaneously hypertensive rats (SHR).
The vasodilations of rat aortas, renal and mesenteric arteries were evaluated by isometric force recording. Nitric oxide (NO) was measured in human aortic endothelial cells (HAECs) by fluorescent probes. Sixteen-week old SHRs were treated with metoprolol (200 mg·kg-1·d⁻¹), arotinolol (30 mg·kg-1·d⁻¹) for 8 weeks. Central arterial pressure (CAP) and pulse wave velocity (PWV) were evaluated via catheter pressure transducers. Collagen was assessed by immunohistochemistry and biochemistry assay, while endothelial nitric oxide synthase (eNOS) and eNOS phosphorylation (p-eNOS) of HAECs or aortas were analyzed by western blotting.
Arotinolol relaxed vascular rings and the relaxations were attenuated by Nω-nitro-L-arginine methyl ester (L-NAME, NO synthase inhibitor) and the absence of endothelium. Furthermore, arotinolol-induced relaxations were attenuated by 4-aminopyridine (4-AP, Kv channels blocker). Arotinolol produced more nitric oxide compared to metoprolol and increased the expression of p-eNOS in HAECs. These results indicated that arotinolol-induced vasodilation involves endothelium-derived NO and Kv channels. The treatement with arotinolol in 8 weeks, but not metoprolol, markedly decreased CAP and PWV. Biochemistry assay and immunohistochemistry showed that aortic collagen depositions in the arotinolol groups were reduced compared with SHRs with metoprolol. Moreover, eNOS phosphorylation was significantly increased in aortinolol-treated SHR compared with SHRs with metoprolol.
Arotinolol improves arterial stiffness in SHR, which involved in increasing NO and decreasing collagen contents in large arteries.
本研究探讨阿罗洛尔对自发性高血压大鼠（SHR）主动脉僵硬度和血管舒张功能的影响及其潜在机制。
采用等长张力记录法评估大鼠主动脉、肾动脉和肠系膜动脉的血管舒张功能。用荧光探针检测人主动脉内皮细胞（HAECs）中的一氧化氮（NO）。16周龄的SHR分别用美托洛尔（200mg·kg-1·d⁻¹）、阿罗洛尔（30mg·kg-1·d⁻¹）治疗8周。通过导管压力传感器评估中心动脉压（CAP）和脉搏波速度（PWV）。采用免疫组织化学和生化分析评估胶原蛋白，通过蛋白质印迹法分析HAECs或主动脉中的内皮型一氧化氮合酶（eNOS）和eNOS磷酸化（p-eNOS）。
阿罗洛尔使血管环舒张，Nω-硝基-L-精氨酸甲酯（L-NAME，一氧化氮合酶抑制剂）和内皮缺失可减弱这种舒张作用。此外，4-氨基吡啶（4-AP，钾通道阻滞剂）可减弱阿罗洛尔诱导的舒张作用。与美托洛尔相比，阿罗洛尔产生更多的一氧化氮，并增加了HAECs中p-eNOS的表达。这些结果表明，阿罗洛尔诱导的血管舒张涉及内皮源性一氧化氮和钾通道。阿罗洛尔治疗8周可显著降低CAP和PWV，但美托洛尔无此作用。生化分析和免疫组织化学显示，与美托洛尔治疗的SHR相比，阿罗洛尔组主动脉胶原蛋白沉积减少。此外，与美托洛尔治疗的SHR相比，阿罗洛尔治疗的SHR中eNOS磷酸化显著增加。
阿罗洛尔可改善SHR的动脉僵硬度，其机制可能与增加一氧化氮生成和减少大动脉中胶原蛋白含量有关。
