Fitzpatrick S C, McKenna T J
Department of Biochemistry, University College, Dublin, Ireland.
J Steroid Biochem Mol Biol. 1992 Jul;42(6):575-80. doi: 10.1016/0960-0760(92)90447-q.
This study investigated the effects of the calcium channel blockers nifedipine (a dihydropyridine) and verapamil (a papaverine derivative), on aldosterone production utilizing isolation of the early and late phases of aldosterone biosynthesis. Pregnenolone production (the early phase of aldosterone biosynthesis) was assessed in trilostane-treated bovine glomerulosa cells, used to inhibit the conversion of pregnenolone onwards to aldosterone. Conversion of exogenous corticosterone to aldosterone, an index of late phase activity, was assessed using aminoglutethimide to inhibit endogenous aldosterone production. Low concentrations of nifedipine, 10(-11)-10(-9) M, stimulated basal total aldosterone biosynthesis by enhancing the late phase although the early phase was inhibited. In the presence of 12 mM potassium (K+), which is less effective in stimulating aldosterone production than lower K+ concentrations, aldosterone production was enhanced by nifedipine, 10(-8) M, by an effect on the late phase. At K+ 6 and 8 mM, nifedipine, 10(-4) M, inhibited the early phase. Nifedipine 10(-5) inhibited angiotensin II (AII)-stimulated total aldosterone biosynthesis by independent effects on the early and late phases. Verapamil, 10(-4) M, inhibited total and early phase aldosterone production at K+, 4 mM and inhibited both phases at K+, 8 mM, stimulation was not observed using verapamil. Verapamil, 10(-4) M, also inhibited AII-stimulated aldosterone production. Basal and AII-stimulated pregnenolone production were inhibited by verapamil, 10(-4) M (basal) and 10(-6) M (AII-stimulated). These studies using nifedipine have revealed subtle calcium-dependent mechanisms involved in the tonic inhibition of activity in the late phase of aldosterone biosynthesis and the reversal of the inhibitory effect of high K+ concentrations also on the late phase. In addition, the data reported indicate that both AII and K+ independently enhance activity in the early and late phases of aldosterone production by calcium-dependent mechanisms.
本研究利用醛固酮生物合成早期和晚期的分离技术，调查了钙通道阻滞剂硝苯地平（一种二氢吡啶）和维拉帕米（一种罂粟碱衍生物）对醛固酮生成的影响。在曲洛司坦处理的牛肾小球细胞中评估孕烯醇酮生成（醛固酮生物合成的早期阶段），该细胞用于抑制孕烯醇酮向醛固酮的转化。使用氨鲁米特抑制内源性醛固酮生成，评估外源性皮质酮向醛固酮的转化，这是晚期活性的一个指标。低浓度的硝苯地平，10(-11)-10(-9)M，通过增强晚期阶段刺激基础总醛固酮生物合成，尽管早期阶段受到抑制。在12mM钾（K+）存在的情况下，其刺激醛固酮生成的效果不如较低的K+浓度，10(-8)M的硝苯地平通过对晚期阶段的作用增强了醛固酮生成。在K+浓度为6和8mM时，10(-4)M的硝苯地平抑制早期阶段。10(-5)的硝苯地平通过对早期和晚期阶段的独立作用抑制血管紧张素II（AII）刺激的总醛固酮生物合成。10(-4)M的维拉帕米在K+浓度为4mM时抑制总醛固酮生成和早期阶段，在K+浓度为8mM时抑制两个阶段，未观察到维拉帕米的刺激作用。10(-4)M的维拉帕米也抑制AII刺激的醛固酮生成。10(-4)M（基础）和10(-6)M（AII刺激）的维拉帕米抑制基础和AII刺激的孕烯醇酮生成。使用硝苯地平的这些研究揭示了参与醛固酮生物合成晚期阶段活性的紧张性抑制以及高K+浓度对晚期阶段抑制作用逆转的微妙钙依赖性机制。此外，报告的数据表明，AII和K+均通过钙依赖性机制独立增强醛固酮生成早期和晚期阶段的活性。
