Nitric oxide–cyclic guanosine monophosphate pathway (NO–cGMP pathway)

The Nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway is a fundamental signal transduction mechanism that regulates vascular tone, platelet aggregation, and smooth muscle cell proliferation (StatPearls, 2023). Nitric oxide (NO) is synthesized by nitric oxide synthases (NOS) and activates soluble guanylate cyclase (sGC), which catalyzes the production of the second messenger cGMP (Nature Reviews Drug Discovery, 2021). Elevated cGMP levels activate protein kinase G (PKG), leading to reduced intracellular calcium and subsequent vasodilation (Circulation, 2019). Impairment of this pathway, often due to reduced NO bioavailability or sGC oxidation, is linked to hypertension, heart failure, and erectile dysfunction (Journal of the American College of Cardiology, 2020). Therapeutic strategies target various nodes of the pathway, including NO donors, sGC stimulators like riociguat, and phosphodiesterase-5 (PDE5) inhibitors like sildenafil, which prevent cGMP degradation (The Lancet, 2013). This pathway is a cornerstone of cardiovascular pharmacology, providing essential mechanisms for managing pulmonary and systemic hemodynamic disorders. Ongoing research continues to explore sGC activators that can function even under oxidative stress, potentially expanding the therapeutic utility of pathway modulation (British Journal of Pharmacology, 2019).

Other names

Nitric oxide–soluble guanylate cyclase–cGMP pathwayNO/sGC/cGMP signaling cascadeNitric oxide signaling

The pathway is modulated through three primary mechanisms: the delivery of exogenous nitric oxide (NO donors), the direct stimulation or sensitization of soluble guanylate cyclase (sGC stimulators/activators), and the inhibition of cyclic guanosine monophosphate (cGMP) degradation by phosphodiesterase enzymes, particularly PDE5 (Pharmacological Reviews, 2018).