The effects of anti-hypertensive drugs and the mechanism of hypertension in vascular smooth muscle cell-specific ATP2B1 knockout mice.
The effects of anti-hypertensive drugs and the mechanism of hypertension in vascular smooth muscle cell-specific ATP2B1 knockout mice.
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DOI：
10.1038/hr.2017.92
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Tamura K
中科院分区：
文献类型：
--
作者：
Okuyama Y;Hirawa N;Fujita M;Fujiwara A;Ehara Y;Yatsu K;Sumida K;Kagimoto M;Katsumata M;Kobayashi Y;Saka S;Umemura S;Tamura K
ATP2B1是一种与高血压相关的基因。我们之前报道过，血管平滑肌细胞中缺乏ATP2B1的小鼠（血管平滑肌细胞ATP2B1基因敲除小鼠）表现出高血压以及细胞内钙浓度升高。本研究旨在探讨ATP2B1基因缺失是否会导致对钙通道阻滞剂（CCBs）的反应比对其他类型的抗高血压药物更强。在监测血压变化的同时，给血管平滑肌细胞ATP2B1基因敲除小鼠和对照小鼠都施用抗高血压药物。我们还检测了这些小鼠中一氧化氮合酶（NOS）的活性，以研究是否存在另一种高血压机制。血管平滑肌细胞ATP2B1基因敲除小鼠单次注射尼卡地平后表现出明显更强的降压效果，但血管紧张素II受体阻滞剂（ARB）、α - 受体阻滞剂和氨氯地平对血压的影响都与对照小鼠相似。然而，与对照小鼠相比，长期使用氨氯地平（而非ARB）可显著降低基因敲除小鼠的血压。L型钙通道的mRNA和蛋白质表达水平在基因敲除的血管平滑肌细胞中均显著上调。两组之间血管平滑肌细胞的神经型NOS蛋白表达以及尿液中NO的产生均无变化。血管平滑肌细胞ATP2B1基因敲除小鼠在降压效果上对钙通道阻滞剂的反应比对其他抗高血压药物更强。这些结果意味着，由于ATP2B1缺失导致血管平滑肌细胞内钙浓度升高以及随后L型钙通道的激活主要影响血压，并表明在这种类型的高血压中对钙通道阻滞剂的敏感性增加。
ATP2B1 is a gene associated with hypertension. We reported previously that mice lacking ATP2B1 in vascular smooth muscle cells (VSMC ATP2B1 KO mice) exhibited high blood pressure and increased intracellular calcium concentration. The present study was designed to investigate whether lack of the ATP2B1 gene causes a higher response to calcium channel blockers (CCBs) than to other types of anti-hypertensive drugs. Both VSMC ATP2B1 KO and control mice were administered anti-hypertensive drugs while monitoring blood pressure shifts. We also examined the association of nitric oxide synthase (NOS) activity in those mice to investigate whether another mechanism of hypertension existed. VSMC ATP2B1 KO mice exhibited significantly greater anti-hypertensive effects with a single injection of nicardipine, but the effects of an angiotensin II receptor blocker (ARB), an α-blocker and amlodipine on blood pressure were all similar to control mice. However, long-term treatment with amlodipine, but not an ARB, significantly decreased the blood pressure of KO mice compared with control mice. Both mRNA and protein expression levels of the L-type calcium channel were significantly upregulated in KO VSMCs. There were no alterations in neural NOS protein expression of VSMCs or in urinary NO production between the two groups. VSMC ATP2B1 KO mice had a higher response to CCBs for blood pressure-lowering effects than other anti-hypertensive drugs. These results mean that increased intracellular calcium concentration in VSMCs due to lack of ATP2B1 and subsequent activation of L-type calcium channels mainly affects blood pressure and suggests increased susceptibility to CCBs in this type of hypertension.
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影响因子：
5.3
作者：
Doran, Derek E.;Weiss, Daiana;Taylor, W. Robert
通讯作者：
Taylor, W. Robert
影响因子：
8.3
作者：
Pratt, PF;Bonnet, S;Rusch, NJ
通讯作者：
Rusch, NJ
影响因子：
64.8
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通讯作者：
Johnson, Toby
影响因子：
3.7
作者：
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通讯作者：
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DOI：
10.1111/j.1365-2125.1996.tb00164.x
发表时间：
1996-02-01
影响因子：
3.4
作者：
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通讯作者：
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