Blockade of T-type voltage-dependent Ca2+ channels by benidipine, a dihydropyridine calcium channel blocker, inhibits aldosterone production in human adrenocortical cell line NCI-H295R
Blockade of T-type voltage-dependent Ca2+ channels by benidipine, a dihydropyridine calcium channel blocker, inhibits aldosterone production in human adrenocortical cell line NCI-H295R
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DOI：
10.1016/j.ejphar.2008.02.001
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发表时间：
2008-04-28
影响因子：
5
通讯作者：
Matsubara, Masahiro
中科院分区：
文献类型：
--
作者：
Akizuki, Osamu;Inayoshi, Atsushi;Matsubara, Masahiro
贝尼地平是一种长效二氢吡啶类钙通道阻滞剂，用于治疗高血压和心绞痛。贝尼地平具有多效药理特性，例如肾脏保护和心脏保护作用。在病理生理条件下，抗利尿激素醛固酮会导致肾脏和心血管疾病的发生。在肾上腺肾小球细胞中，醛固酮是响应细胞外钾而产生的，这主要由 T 型电压依赖性 Ca2+ 通道介导。最近，已证明贝尼地平除了抑制 L 型 Ca2+ 通道外，还抑制 T 型 Ca2+ 通道。因此，使用人肾上腺皮质细胞系 NCI-H295R 研究了钙通道阻滞剂（包括贝尼地平）对醛固酮生成和 T 型 Ca2+ 通道的影响。贝尼地平在低浓度（3 和 10 nM）下可有效抑制 KCI 诱导的醛固酮产生，其抑制活性比其他钙通道阻滞剂更有效。膜片钳分析表明，贝尼地平在 10、100 和 1000 nM 时浓度依赖性地抑制 T 型 Ca2+ 电流。至于所检测的钙通道阻滞剂，T 型 Ca2+ 电流的抑制活性与醛固酮的产生密切相关。 L 型特异性钙通道阻滞剂卡西肽和硝苯地平在两项测定中均未显示效果。这些结果表明 T 型 Ca2+ 通道的抑制是抑制 NCI-H295R 细胞中醛固酮产生的原因。贝尼地平有效抑制 KCI 诱导的 11-β-羟化酶 mRNA 和醛固酮合酶 mRNA 的上调以及 KCI 诱导的 Ca2+ 内流，表明它是最可能的抑制机制。贝尼地平部分抑制血管紧张素 II 诱导的醛固酮产生，并且与血管紧张素 II I 型受体阻滞剂缬沙坦联合使用时显示出相加效应。贝尼地平还部分抑制血管紧张素 II 诱导的上述 mRNA 上调以及贝尼地平对醛固酮生成的 Ca2+ 内流抑制活性。除了阻断 L 型 Ca2+ 通道的主要抗高血压作用之外，T 型 Ca2+ 通道可能有助于该药物治疗肾脏和心血管疾病的额外益处。 (c) 2008 Elsevier B.V. 保留所有权利。
Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for treatment of hypertension and angina. Benidipine exerts pleiotropic pharmacological features, such as renoprotective and cardioprotective effects. In pathophysiological conditions, the antidiuretic hormone aldosterone causes development of renal and cardiovascular diseases. In adrenal glomerulosa cells, aldosterone is produced in response to extracellular potassium, which is mainly mediated by T-type voltage-dependent Ca2+ channels. More recently, it has been demonstrated that benidipine inhibits T-type Ca2+ channels in addition to L-type Ca2+ channels. Therefore, effect of calcium channel blockers, including benidipine, on aldosterone production and T-type Ca2+ channels using human adrenocortical cell line NCI-H295R was investigated. Benidipine efficiently inhibited KCI-induced aldosterone production at low concentration (3 and 10 nM), with inhibitory activity more potent than other calcium channel blockers. Patch clamp analysis indicated that benidipine concentration-dependently inhibited T-type Ca2+ currents at 10, 100 and 1000 nM. As for examined calcium channel blockers, inhibitory activity for T-type Ca2+ currents was well correlated with aldosterone production. L-type specific calcium channel blockers calciseptine and nifedipine showed no effect in both assays. These results indicate that inhibition of T-type Ca2+ channels is responsible for inhibition of aldosterone production in NCI-H295R cells. Benidipine efficiently inhibited KCI-induced upregulation of 11-beta-hydroxylase mRNA and aldosterone synthase mRNA as well as KCI-induced Ca2+ influx, indicating it as the most likely inhibition mechanism. Benidipine partially inhibited angiotensin II-induced aldosterone production, plus showed additive effects when used in combination with the angiotensin II type I receptor blocker valsartan. Benidipine also partially inhibited angiotensin II-induced upregulation of the above mRNAs and Ca2+ influx inhibitory activities of benidipine for aldosterone production. T-type Ca2+ channels may contribute to additional benefits of this drug for treating renal and cardiovascular diseases, beyond its primary anti-hypertensive effects from blocking L-type Ca2+ channels. (c) 2008 Elsevier B.V. All rights reserved.