Boerrigter Guido, Lapp Harald, Burnett John C
Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Heart and Lung Research Center, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Handb Exp Pharmacol. 2009(191):485-506. doi: 10.1007/978-3-540-68964-5_21.
Heart failure (HF) is a common disease that continues to be associated with high morbidity and mortality warranting novel therapeutic strategies. Cyclic guanosine monophosphate (cGMP) is the second messenger of several important signaling pathways based on distinct guanylate cyclases (GCs) in the cardiovascular system. Both the nitric oxide/soluble GC (NO/sGC) as well as the natriuretic peptide/GC-A (NP/GC-A) systems are disordered in HF, providing a rationale for their therapeutic augmentation. Soluble GC activation with conventional nitrovasodilators has been used for more than a century but is associated with cGMP-independent actions and the development of tolerance, actions which novel NO-independent sGC activators now in clinical development lack. Activation of GC-A by administration of naturally occurring or designer natriuretic peptides is an emerging field, as is the inhibition of enzymes that degrade endogenous NPs. Finally, inhibition of cGMP-degrading phosphodiesterases, particularly phosphodiesterase 5 provides an additional strategy to augment cGMP-signaling.
心力衰竭（HF）是一种常见疾病，仍然与高发病率和死亡率相关，因此需要新的治疗策略。环磷酸鸟苷（cGMP）是心血管系统中基于不同鸟苷酸环化酶（GCs）的几种重要信号通路的第二信使。一氧化氮/可溶性GC（NO/sGC）以及利钠肽/GC-A（NP/GC-A）系统在HF中均紊乱，这为增强它们的治疗作用提供了理论依据。使用传统的硝基血管扩张剂激活可溶性GC已有一个多世纪，但与不依赖cGMP的作用和耐受性的发展有关，而目前正在临床开发的新型不依赖NO的sGC激活剂则没有这些作用。通过给予天然存在的或设计的利钠肽激活GC-A是一个新兴领域，抑制降解内源性NP的酶也是如此。最后，抑制降解cGMP的磷酸二酯酶，特别是磷酸二酯酶5，提供了增强cGMP信号传导的另一种策略。
