Toyama Institute for Cardiovascular Pharmacology Research, Osaka, Japan.
Br J Pharmacol. 2013 Feb;168(3):519-33. doi: 10.1111/j.1476-5381.2012.02194.x.
Aldosterone, in doses inappropriate to the salt status, plays an important role in the development of cardiovascular injury, including endothelial dysfunction, independent of its hypertensive effects. Acute non-genomic effects of aldosterone acting on mineralocorticoid receptors are inconsistent in healthy humans: vasoconstriction or forearm blood flow decrease via endothelial dysfunction, vasodilatation mediated by increased NO actions, or no effects. However, in studies with experimental animals, aldosterone mostly enhances vasodilatation mediated by endothelium-derived NO. Chronic exposure to aldosterone, which induces genomic responses, results in impairments of endothelial function through decreased NO synthesis and action in healthy individuals, experimental animals and isolated endothelial cells. Chronic aldosterone reduces NO release from isolated human endothelial cells only when extracellular sodium is raised. Oxidative stress is involved in the impairment of endothelial function by promoting NO degradation. Aldosterone liberates endothelin-1 (ET-1) from endothelial cells, which elicits ET(A) receptor-mediated vasoconstriction by inhibiting endothelial NO synthesis and action and through its own direct vasoconstrictor action. Ca(2+) flux through T-type Ca(2+) channels activates aldosterone synthesis and thus enhances unwanted effects of aldosterone on the endothelium. Mineralocorticoid receptor inhibitors, ET(A) receptor antagonists and T-type Ca(2) + channel blockers appear to diminish the pathophysiological participation of aldosterone in cardiovascular disease and exert beneficial actions on bioavailability of endothelium-derived NO, particularly in resistant hypertension and aldosteronism.
醛固酮在与盐状态不相关的剂量下发挥作用，对心血管损伤的发展起着重要作用，包括内皮功能障碍，独立于其高血压作用。醛固酮通过盐皮质激素受体的急性非基因组作用在健康人中是不一致的：通过内皮功能障碍导致血管收缩或前臂血流量减少，通过增加 NO 作用导致血管舒张，或无作用。然而，在实验动物的研究中，醛固酮大多增强了内皮源性一氧化氮介导的血管舒张。慢性暴露于醛固酮诱导基因组反应，导致健康个体、实验动物和分离的内皮细胞中内皮功能障碍，通过减少一氧化氮合成和作用。只有当细胞外钠升高时，慢性醛固酮才会减少分离的人内皮细胞中一氧化氮的释放。氧化应激通过促进一氧化氮降解参与内皮功能障碍。醛固酮从内皮细胞释放内皮素-1（ET-1），通过抑制内皮一氧化氮合成和作用以及通过其自身的直接血管收缩作用，引起内皮素（A）受体介导的血管收缩。通过 T 型钙（Ca2+）通道的 Ca2+通量激活醛固酮合成，从而增强醛固酮对内皮的不良影响。盐皮质激素受体抑制剂、内皮素（A）受体拮抗剂和 T 型 Ca2+通道阻滞剂似乎可减少醛固酮在心血管疾病中的病理生理参与，并对内皮源性一氧化氮的生物利用度发挥有益作用，特别是在耐药性高血压和醛固酮增多症中。
