Gawrys Olga, Kala Petr, Sadowski Janusz, Melenovský Vojtěch, Sandner Peter, Červenka Luděk
Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Department of Cardiology, Motol University Hospital and Second Faculty of Medicine, Charles University, Prague, Czech Republic.
Eur J Pharmacol. 2025 Jan 15;987:177175. doi: 10.1016/j.ejphar.2024.177175. Epub 2024 Dec 5.
Nitric oxide (NO)-stimulated cyclic guanosine monophosphate (cGMP) is a key regulator of cardiovascular health, as NO-cGMP signalling is impaired in diseases like pulmonary hypertension, heart failure and chronic kidney disease. The development of NO-independent sGC stimulators and activators provide a novel therapeutic option to restore altered NO signalling. sGC stimulators have been already approved for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and chronic heart failure (HFrEF), while sGC activators are currently in phase-2 clinical trials for CKD. The best characterized effect of increased cGMP via the NO-sGC-cGMP pathway is vasodilation. However, to date, none of the sGC agonists are in development for hypertension (HTN). According to WHO, the global prevalence of uncontrolled HTN continues to rise, contributing significantly to cardiovascular mortality. While there are effective antihypertensive treatments, many patients require multiple drugs, and some remain resistant to all therapies. Thus, in addition to improved diagnosis and lifestyle changes, new pharmacological strategies remain in high demand. In this review we explore the potential of sGC stimulators and activators as novel antihypertensive agents, starting with the overview of NO-sGC-cGMP signalling, followed by potential mechanisms by which the increase in cGMP may regulate vascular tone and BP. These effects may encompass not only acute vasodilation, but also mid-term and chronic effects, such as the regulation of salt and water balance, as well as mitigation of vascular ageing and remodelling. The main section summarizes the preclinical and clinical evidence supporting the BP-lowering efficacy of sGC agonists.
一氧化氮（NO）刺激产生的环磷酸鸟苷（cGMP）是心血管健康的关键调节因子，因为在肺动脉高压、心力衰竭和慢性肾病等疾病中，NO-cGMP信号通路会受损。非NO依赖性可溶性鸟苷酸环化酶（sGC）刺激剂和激活剂的开发为恢复改变的NO信号提供了一种新的治疗选择。sGC刺激剂已被批准用于治疗肺动脉高压（PAH）、慢性血栓栓塞性肺动脉高压（CTEPH）和慢性心力衰竭（射血分数降低的心力衰竭，HFrEF），而sGC激活剂目前正处于治疗慢性肾病的2期临床试验阶段。通过NO-sGC-cGMP途径增加cGMP的最显著作用是血管舒张。然而，迄今为止，尚无sGC激动剂用于高血压（HTN）的研发。据世界卫生组织称，全球未控制高血压的患病率持续上升，对心血管死亡率有重大影响。虽然有有效的抗高血压治疗方法，但许多患者需要多种药物，而且一些患者对所有治疗仍有抵抗性。因此，除了改善诊断和改变生活方式外，新的药理学策略仍然有很高的需求。在这篇综述中，我们探讨了sGC刺激剂和激活剂作为新型抗高血压药物的潜力，首先概述NO-sGC-cGMP信号通路，然后阐述cGMP增加可能调节血管张力和血压的潜在机制。这些作用可能不仅包括急性血管舒张，还包括中期和慢性作用，如盐和水平衡的调节，以及减轻血管老化和重塑。主要部分总结了支持sGC激动剂降血压疗效的临床前和临床证据。
