Icahn School of Medicine at Mount Sinai, New York, NY, USA
Pulmonary Hypertension Unit, Thoraxklinik at Heidelberg University Hospital Heidelberg, Heidelberg, Germany.
Eur Respir Rev. 2024 Mar 20;33(171). doi: 10.1183/16000617.0183-2023. Print 2024 Jan 31.
The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway plays a key role in the pathogenesis of pulmonary hypertension (PH). Targeted treatments include phosphodiesterase type 5 inhibitors (PDE5i) and sGC stimulators. The sGC stimulator riociguat is approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). sGC stimulators have a dual mechanism of action, enhancing the sGC response to endogenous NO and directly stimulating sGC, independent of NO. This increase in cGMP production a dual mechanism differs from PDE5i, which protects cGMP from degradation by PDE5, rather than increasing its production. sGC stimulators may therefore have the potential to increase cGMP levels under conditions of NO depletion that could limit the effectiveness of PDE5i. Such differences in mode of action between sGC stimulators and PDE5i could lead to differences in treatment efficacy between the classes. In addition to vascular effects, sGC stimulators have the potential to reduce inflammation, angiogenesis, fibrosis and right ventricular hypertrophy and remodelling. In this review we describe the evolution of treatments targeting the NO-sGC-cGMP pathway, with a focus on PH.
一氧化氮（NO）-可溶性鸟苷酸环化酶（sGC）-环鸟苷酸（cGMP）通路在肺动脉高压（PH）的发病机制中起关键作用。靶向治疗包括磷酸二酯酶 5 抑制剂（PDE5i）和 sGC 刺激剂。sGC 刺激剂 riociguat 被批准用于治疗肺动脉高压（PAH）和慢性血栓栓塞性肺动脉高压（CTEPH）。sGC 刺激剂具有双重作用机制，增强 sGC 对内源性 NO 的反应，并独立于 NO 直接刺激 sGC。这种 cGMP 产生的增加——双重机制与 PDE5i 不同，PDE5i 保护 cGMP 不被 PDE5 降解，而不是增加其产生。因此，sGC 刺激剂可能具有在可能限制 PDE5i 有效性的 NO 耗竭条件下增加 cGMP 水平的潜力。sGC 刺激剂和 PDE5i 之间作用模式的这些差异可能导致两类药物在治疗效果上的差异。除了血管作用外，sGC 刺激剂还有可能减轻炎症、血管生成、纤维化以及右心室肥厚和重塑。在这篇综述中，我们描述了靶向 NO-sGC-cGMP 通路的治疗方法的演变，重点是 PH。
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