钙通道激动剂BAY K 8644对血管紧张素II和钾刺激的醛固酮分泌的选择性增强作用。

Selective enhancement of angiotensin II- and potassium-stimulated aldosterone secretion by the calcium channel agonist BAY K 8644.

作者信息

Hausdorff W P, Aguilera G, Catt K J

出版信息

Endocrinology. 1986 Feb;118(2):869-74. doi: 10.1210/endo-118-2-869.

Abstract

Recent studies with dihydropyridine calcium channel antagonists have indicated that voltage-sensitive calcium channels (VSCC) play a major role in the control of aldosterone secretion. The modulation of VSCC by physiological regulators of zona glomerulosa function was further evaluated by analysis of the actions of the dihydropyridine calcium channel agonist BAY K 8644 (BK 8644) on basal and stimulated aldosterone production in isolated rat glomerulosa cells. In the presence of normal K+ concentrations (3.5-4.5 mM), only high concentrations of BK 8644 (greater than or equal to 100 nM) stimulated aldosterone secretion. However, addition of 10 nM BK 8644 markedly enhanced steroid production (70% over control) in cells stimulated by incubation in 7.5 mM K+ or 0.1 nM angiotensin II (AII). Greater enhancement was achieved with 1 microM BK 8644, with aldosterone secretion 150% and 300% above control levels for K+ and AII, respectively. In AII-stimulated cells, 30 nM BK 8644 enhanced aldosterone secretion at all peptide concentrations studied, including a 70% increase in the maximum steroid response, with no change in sensitivity to AII. In K+-stimulated cells, the effects of BK 8644 were dependent on the medium concentration of K+. At submaximally stimulating K+ concentrations (less than 9 mM), 30 nM BK 8644 increased the sensitivity of glomerulosa cells to K+ with no change in the maximal aldosterone response. However, at supramaximally stimulating concentrations of K+ (greater than 10 mM), BK 8644 reduced aldosterone production by 50%. In contrast to the effects of BK 8644 on cells stimulated with K+ or AII, the channel agonist had no effect on the action of ACTH. The ability of BK 8644 to enhance the maximum aldosterone response to AII suggests that AII, unlike K+, does not fully activate the Ca2+ influx pathway that leads to aldosterone secretion. Since BK 8644 is believed to facilitate Ca2+ influx primarily through previously activated channels, these results suggest that VSCC in the rat glomerulosa cell are partially operative under basal conditions, and that the same types of channels are further activated by AII and K+.

摘要

近期有关二氢吡啶类钙通道拮抗剂的研究表明，电压敏感性钙通道（VSCC）在醛固酮分泌的调控中起主要作用。通过分析二氢吡啶类钙通道激动剂BAY K 8644（BK 8644）对分离的大鼠球状带细胞基础状态及刺激状态下醛固酮生成的作用，进一步评估了球状带功能的生理调节因子对VSCC的调节作用。在正常钾离子浓度（3.5 - 4.5 mM）条件下，只有高浓度的BK 8644（大于或等于100 nM）能刺激醛固酮分泌。然而，加入10 nM BK 8644能显著增强在7.5 mM钾离子或0.1 nM血管紧张素II（AII）孵育刺激的细胞中的类固醇生成（比对照高70%）。1 μM BK 8644能实现更大程度的增强，钾离子和AII刺激下醛固酮分泌分别比对照水平高150%和300%。在AII刺激的细胞中，30 nM BK 8644在所有研究的肽浓度下均能增强醛固酮分泌，包括最大类固醇反应增加70%，且对AII的敏感性无变化。在钾离子刺激的细胞中，BK 8644的作用取决于培养基中钾离子的浓度。在次最大刺激钾离子浓度（小于9 mM）时，30 nM BK 8644增加了球状带细胞对钾离子的敏感性，而最大醛固酮反应无变化。然而，在超最大刺激钾离子浓度（大于10 mM）时，BK 8644使醛固酮生成减少50%。与BK 8644对钾离子或AII刺激的细胞的作用相反，该通道激动剂对促肾上腺皮质激素（ACTH）的作用无影响。BK 8644增强对AII的最大醛固酮反应的能力表明，与钾离子不同，AII不能完全激活导致醛固酮分泌的钙离子内流途径。由于BK 8644被认为主要通过先前激活的通道促进钙离子内流，这些结果表明大鼠球状带细胞中的VSCC在基础条件下部分发挥作用，且相同类型的通道可被AII和钾离子进一步激活。