Eplerenone blocks nongenomic effects of aldosterone on the Na+/H+ exchanger, intracellular Ca2+ levels, and vasoconstriction in mesenteric resistance vessels
Eplerenone blocks nongenomic effects of aldosterone on the Na+/H+ exchanger, intracellular Ca2+ levels, and vasoconstriction in mesenteric resistance vessels
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DOI：
10.1210/en.2004-1130
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发表时间：
2005-03-01
期刊：
影响因子：
4.8
通讯作者：
Marusic, ET
中科院分区：
文献类型：
--
作者：
Michea, L;Delpiano, AM;Marusic, ET
越来越多的证据表明醛固酮具有快速的非基因组效应。已证明醛固酮改变分离细胞中的细胞内pH和钙。然而，很少有研究将这些作用与醛固酮介导的生理反应相关联。因此，我们研究了醛固酮对血管反应性、细胞内Ca 2+和阻力血管pH的快速影响。此外，我们探讨了新的抗盐皮质激素药物依普利酮是否可以有效地阻断非基因组醛固酮介导的作用。通过测定小阻力肠系膜血管的直径（160-200 μ m静息直径），同时测定细胞内pH或Ca 2+，直接检查醛固酮的血管收缩作用。醛固酮（10 nM）引起阻力血管的快速收缩（直径比对照条件下减少8.1% +/-1.0%，P < 0.05）。醛固酮增强苯肾上腺素介导的肠系膜小血管和大血管收缩。醛固酮引起细胞内Ca ~（2+）迅速升高，细胞碱性化。醛固酮的血管收缩作用和非基因组对钠质子交换体（NHE 1）活性或细胞内Ca 2+反应的影响被依普利酮消除。醛固酮的血管收缩反应与磷脂酰肌醇3-激酶（PI 3-K）有关：激素降低蛋白激酶B磷酸化;药理学抑制PI 3-K（10 μM LY 294002或1 μM渥曼青霉素）增加动脉收缩力。ERK 1/2磷酸化抑制剂（15 μM PD 98059）对醛固酮介导的血管收缩无影响。用1 μM双吲哚马来酰亚胺I抑制蛋白激酶C和/或用100 μM阿米洛利抑制NHE 1可阻断醛固酮对肠系膜阻力动脉的缩血管作用。我们的结论是，醛固酮介导的血管紧张度的增加是相关的非基因组机制，涉及蛋白激酶C，PI 3-K，和NHE 1活性。依普利酮是醛固酮在血管组织中的非基因组效应的有效阻断剂。
There is increasing evidence for rapid nongenomic effects of aldosterone. Aldosterone has been demonstrated to alter intracellular pH and calcium in isolated cells. However, few studies have correlated these effects with aldosterone-mediated physiological responses. Therefore, we studied rapid effects of aldosterone on vascular reactivity, intracellular Ca2+, and pH in resistance vessels. Furthermore, we explored whether the new antimineralocorticoid drug eplerenone could effectively block nongenomic aldosterone-mediated effects. The vasoconstrictor action of aldosterone was examined directly by determining the diameter of small resistance mesenteric vessels (160-200 mum resting diameter), simultaneously with intracellular pH or Ca2+. Aldosterone (10 nM) caused a rapid constriction of resistance vessels (8.1% +/- 1.0% reduction in the diameter below control conditions, P < 0.05). Aldosterone potentiated phenylephrine-mediated constriction in small and large mesenteric vessels. Aldosterone induced a rapid increase of intracellular Ca2+ and cellular alkalinization. Vasoconstrictor action of aldosterone and nongenomic effects on the sodium-proton exchanger (NHE1) activity or intracellular Ca2+ responses was abolished by eplerenone. The vasoconstrictor response of aldosterone was related to phosphatidylinositol 3-kinase (PI3-K): the hormone decreased protein kinase B phosphorylation; pharmacological inhibition of PI3-K (10 μM LY294002 or 1 μM wortmannin) increased arterial contractility. Inhibitors of ERK 1/2 phosphorylation (15 μM PD98059) had no effect on aldosterone-mediated vasoconstriction. Inhibition of protein kinase C with 1 μM bisindolylmaleimide I and/or inhibition of NHE1 with 100 μM amiloride abolished aldosterone vasoconstrictor action of resistance mesenteric arteries. We conclude that aldosterone-mediated increase in vascular tone is related to a nongenomic mechanism that involves protein kinase C, PI3-K, and NHE1 activity. Eplerenone is an effective blocker of nongenomic effects of aldosterone in vascular tissue.