Calcium channel blocker azelnidipine enhances vascular protective effects of AT1 receptor blocker olmesartan
Calcium channel blocker azelnidipine enhances vascular protective effects of AT1 receptor blocker olmesartan
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DOI：
10.1161/01.hyp.0000113627.08110.6f
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发表时间：
2004-02-01
期刊：
影响因子：
8.3
通讯作者：
Horiuchi, M
中科院分区：
文献类型：
--
作者：
Jinno, T;Iwai, M;Horiuchi, M
本研究旨在探讨钙通道阻滞剂（CCB）增强血管紧张素Ⅱ 1型（AT（1））受体阻滞剂（ARB）对血管损伤的抑制作用，并探讨CCB对血管重构影响的细胞机制。在聚乙烯套囊诱导的小鼠股动脉血管损伤中，血管平滑肌细胞（VSMC）增殖和新生内膜形成与细胞外信号调节激酶（ERK）激活以及信号转导和转录激活因子（STAT）1和STAT 3的酪氨酸磷酸化相关，通过单核细胞趋化蛋白-1和肿瘤坏死因子-α表达评估炎症反应，以及氧化应激如NADH/NADPH氧化酶p22（phox）亚单位的表达和超氧化物的产生在AT（1a）受体敲除小鼠中较少。给予非膨胀剂量的CCB，阿折地平（0.5或1 mg/kg/天）减弱野生型和AT（1）a受体缺失小鼠的这些参数。同时给予较低剂量的ARB、奥美沙坦（0.5 mg/kg/天）和阿折地平（0.1 mg/kg/天）（不影响血管重塑）可显著抑制野生型小鼠的这些参数。此外，阿折地平的有效剂量（1 mg/kg/天）增强了奥美沙坦在1或3 mg/kg/天有效剂量下对受损动脉中VSMC增殖的抑制作用。这些结果表明，阿折地平可抑制血管损伤，至少部分不依赖于AT（1）受体激活的抑制，阿折地平可增强奥美沙坦的血管保护作用，提示CCB和ARB联合治疗血管疾病的临床可能性可能更有效。
The present studies were undertaken to investigate the potential effect of a calcium channel blocker (CCB) to enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT(1)) receptor blocker (ARB) on vascular injury and the cellular mechanism of the effect of CCB on vascular remodeling. In polyethylene cuff-induced vascular injury of the mouse femoral artery, proliferation of vascular smooth muscle cells (VSMCs) and neointimal formation associated with activation of extracellular signal-regulated kinase (ERK), and tyrosine-phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT3, inflammatory response assessed by monocyte chemoattractant protein-1 and tumor necrosis factor-alpha expression, as well as oxidative stress such as expression of NADH/NADPH oxidase p22(phox) subunit and superoxide production, were less in AT(1a) receptor null mice. Administration of nonhypotensive doses of a CCB, azelnidipine (0.5 or 1 mg/kg per day) attenuated these parameters in wild-type and AT(1)a receptor null mice. Coadministration of lower doses of an ARB, olmesartan ( 0.5 mg/kg per day), and azelnidipine (0.1 mg/kg per day), which did not affect vascular remodeling, significantly inhibited these parameters in wild-type mice. Moreover, the effective dose of azelnidipine ( 1 mg/kg per day) exaggerated the inhibitory action of olmesartan at effective doses of 1 or 3 mg/kg per day on VSMC proliferation in the injured arteries. These results suggest that azelnidipine could inhibit vascular injury at least partly independent of the inhibition of AT(1) receptor activation and that azelnidipine could exaggerate the vascular protective effects of olmesartan, suggesting clinical possibility that the combination of CCB and ARB could be more effective in the treatment of vascular diseases.