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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• 作者：Osamu Akizuki ; Atsushi Inayoshi ; Tetsuya Kitayama ; Kozo Yao ; Shiro Shirakura ; Katsutoshi Sasaki ; Hideaki Kusaka ; Masahiro Matsubara
• 关键词：Benidipine ; Aldosterone ; T-type Ca²⁺ channel
• 刊名：European Journal of Pharmacology
• 出版年：2008
• 期刊代码：24_00142999
• 类别：neu
• 出版时间：28 April 2008
• 卷：584
• 期：2-3
• 页码：424-434
• 文件大小：1427 K

摘要

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 KCl-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 KCl-induced upregulation of 11-β-hydroxylase mRNA and aldosterone synthase mRNA as well as KCl-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.