Katsurada Kenichi
Division of Clinical Pharmacology, Department of Pharmacology, Tochigi, Japan.
Division of Cardiovascular Medicine, Department of Internal Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan.
Hypertens Res. 2025 May 2. doi: 10.1038/s41440-025-02216-w.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to suppress cardiovascular events and are widely used for treating diabetes, chronic heart failure and chronic kidney disease. Although the underlying mechanisms by which SGLT2 inhibitors suppress cardiovascular events are not entirely clear, several mechanisms have been proposed to explain the cardiorenal protective effects of SGLT2 inhibitors. One of these involves sympathoinhibition. In vitro, SGLT2 expression is upregulated by norepinephrine, and SGLT2 inhibitors have been shown to attenuate SGLT2 expression and normalize the diuretic response to volume expansion with isotonic saline in rats with heart failure. These findings suggest that inhibition of renal sympathetic nerve activity is the mechanism underlying the beneficial effects of SGLT2 inhibitors on heart failure. Increased resting afferent renal nerve activity has been observed in several disease models, including models of hypertension, heart failure, and kidney disease, and might induce augmented sympathetic outflow via the central nervous system. SGLT2 inhibitors may suppress afferent renal nerve activity via intrarenal environmental modifications such as renal tissue hypoxia, inflammation, oxidative stress, mitochondrial function, and congestion, thereby inhibiting sympathetic outflow to the peripheral organs, including the heart and kidneys. On the other hand, SGLT2 is also expressed in the brain, and electrophysiological techniques in rats have shown that SGLT2 inhibitors suppress the activities of the rostral ventrolateral medulla neurons which project to the sympathetic preganglionic nuclei of the spinal cord to control sympathetic outflow, suggesting decreased sympathetic nerve activities. This mini review focuses on the bidirectional interaction between SGLT2 and the sympathetic nervous system and introduces recent related findings from Hypertension Research and other journals.
钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂已被证明可抑制心血管事件，广泛用于治疗糖尿病、慢性心力衰竭和慢性肾脏病。尽管SGLT2抑制剂抑制心血管事件的潜在机制尚不完全清楚，但已提出多种机制来解释SGLT2抑制剂的心脏和肾脏保护作用。其中之一涉及交感神经抑制。在体外，去甲肾上腺素可上调SGLT2的表达，并且已证明SGLT2抑制剂可减弱SGLT2的表达，并使心力衰竭大鼠对等渗盐水扩容的利尿反应恢复正常。这些发现表明，抑制肾交感神经活性是SGLT2抑制剂对心力衰竭有益作用的潜在机制。在包括高血压、心力衰竭和肾脏疾病模型在内的多种疾病模型中均观察到静息肾传入神经活性增加，这可能通过中枢神经系统诱导交感神经输出增加。SGLT2抑制剂可能通过肾内环境改变（如肾组织缺氧、炎症、氧化应激、线粒体功能和充血）来抑制肾传入神经活性，从而抑制包括心脏和肾脏在内的外周器官的交感神经输出。另一方面，SGLT2也在大脑中表达，大鼠的电生理技术表明，SGLT2抑制剂可抑制投射至脊髓交感神经节前核以控制交感神经输出的延髓头端腹外侧神经元的活性，提示交感神经活性降低。本综述聚焦于SGLT2与交感神经系统之间的双向相互作用，并介绍来自《高血压研究》和其他期刊的近期相关研究结果。
