Department of Surgery, Vanderbilt University Medical Center, Medical Center North, Suite CCC-4312, 1161 21st Avenue South, Nashville, TN 37232-2730, USA.
Vanderbilt University School of Medicine, 428 Eskind Family Biomedical Library and Learning Center, Nashville, TN 37240-0002, USA.
Cells. 2023 Jul 21;12(14):1903. doi: 10.3390/cells12141903.
Ischemia and reperfusion (IR) damage organs and contribute to many disease states. Few effective treatments exist that attenuate IR injury. The augmentation of nitric oxide (NO) signaling remains a promising therapeutic target for IR injury. NO binds to soluble guanylyl cyclase (sGC) to regulate vasodilation, maintain endothelial barrier integrity, and modulate inflammation through the production of cyclic-GMP in vascular smooth muscle. Pharmacologic sGC stimulators and activators have recently been developed. In preclinical studies, sGC stimulators, which augment the reduced form of sGC, and activators, which activate the oxidized non-NO binding form of sGC, increase vasodilation and decrease cardiac, cerebral, renal, pulmonary, and hepatic injury following IR. These effects may be a result of the improved regulation of perfusion and decreased oxidative injury during IR. sGC stimulators are now used clinically to treat some chronic conditions such as heart failure and pulmonary hypertension. Clinical trials of sGC activators have been terminated secondary to adverse side effects including hypotension. Additional clinical studies to investigate the effects of sGC stimulation and activation during acute conditions, such as IR, are warranted.
缺血再灌注（IR）损伤器官，并导致许多疾病状态。目前几乎没有有效的治疗方法可以减轻 IR 损伤。增加一氧化氮（NO）信号仍然是治疗 IR 损伤的一个有前途的治疗靶点。NO 与可溶性鸟苷酸环化酶（sGC）结合，通过在血管平滑肌中产生环鸟苷酸来调节血管舒张、维持内皮屏障完整性，并调节炎症。最近已经开发出了药理学 sGC 刺激剂和激活剂。在临床前研究中，sGC 刺激剂增强了 sGC 的还原形式，而激活剂则激活了氧化的非 NO 结合形式的 sGC，这增加了 IR 后血管舒张，并减少了心脏、大脑、肾脏、肺和肝脏损伤。这些作用可能是由于在 IR 期间改善了灌注的调节和减少了氧化损伤。sGC 刺激剂现在被用于治疗一些慢性疾病，如心力衰竭和肺动脉高压。由于低血压等不良反应，sGC 激活剂的临床试验已被终止。需要进行更多的临床研究，以调查在急性情况下（如 IR）sGC 刺激和激活的效果。
