Service of Endocrinology and Diabetology, University Hospital of Geneva, 4 Rue Gabrielle-Perret-Gentil, CH-1211 Geneva 14, Switzerland.
Endocrinology. 2010 Jun;151(6):2777-87. doi: 10.1210/en.2009-1375. Epub 2010 Apr 14.
Mineralocorticoids and glucocorticoids have been involved in the genesis of ventricular arrhythmias associated with pathological heart hypertrophy. We previously observed, using isolated neonate rat ventricular cardiomyocytes, that both aldosterone (Aldo) and corticosterone induced in vitro a marked acceleration of the spontaneous contractions of these cells, a phenomenon dependent on the expression of the low threshold T-type calcium channels. Because both mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mediated the chronotropic response to corticosteroids, we characterized the role of each receptor using spironolactone and mifepristone (RU-486) as specific antagonists. We first observed that GR antagonism, but not MR antagonism, completely disrupted the significant correlation existing between the level of T channel mRNA and the beating frequency; this difference could not be explained by a specific regulation of channel expression or activity by one of the receptors. Moreover, the chronotropic action of Aldo was additive to that of forskolin, a direct activator of the cAMP pathway. This additive response was selectively abolished upon GR inhibition. Finally, myocyte hypertrophy induced in vitro by Aldo was completely prevented by GR antagonism, whereas spironolactone had only a marginal effect. These results suggest that, in isolated rat ventricular cardiomyocytes, the activation of both MR and GR is necessary for a complete electrical remodeling and a maximal chronotropic response to corticosteroids. However, GR alone appears involved in the sensitization of the cells to the chronotropic regulation through the cAMP pathway and in the hypertrophic response to steroids. These observations have therapeutic implications given the fact that MR becomes a major target of pharmacological drugs in the clinical practice for preventing cardiac function decompensation and evolution toward heart failure and lethal arrhythmias.
醛固酮和皮质醇已被牵涉到与病理性心脏肥大相关的室性心律失常的发生中。我们之前在分离的新生大鼠心室肌细胞中观察到，醛固酮（Aldo）和皮质酮在体外均显著加速这些细胞的自发性收缩，这一现象依赖于低阈值 T 型钙通道的表达。由于盐皮质激素受体（MR）和糖皮质激素受体（GR）介导了对皮质类固醇的变时反应，我们使用螺内酯和米非司酮（RU-486）作为特异性拮抗剂来描述每个受体的作用。我们首先观察到，GR 拮抗作用，但不是 MR 拮抗作用，完全破坏了 T 型通道 mRNA 水平与搏动频率之间存在的显著相关性；这种差异不能通过一个受体对通道表达或活性的特异性调节来解释。此外，Aldo 的变时作用可被 forskolin（cAMP 途径的直接激活剂）增强。这种相加反应在 GR 抑制时被选择性地消除。最后，Aldo 体外诱导的心肌细胞肥大完全被 GR 拮抗作用所阻止，而螺内酯仅有轻微作用。这些结果表明，在分离的大鼠心室肌细胞中，MR 和 GR 的激活对于完全的电重构和对皮质类固醇的最大变时反应都是必需的。然而，GR 本身似乎参与了细胞对 cAMP 途径变时调节的敏感性以及对类固醇的促肥大反应。这些观察结果具有治疗意义，因为在临床实践中，MR 已成为药物治疗预防心脏功能失代偿和向心力衰竭和致命性心律失常发展的主要靶标。
