Soluble guanylate cyclase stimulators like riociguat offer a dual mechanism of action that may increase cGMP levels even under conditions of NO depletion, unlike PDE5 inhibitors.
This review highlights the mechanistic differences between sGC stimulators and PDE5 inhibitors in the treatment of pulmonary hypertension, suggesting sGC stimulators may be effective even in NO-depleted states.
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 via 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.
Benza et al. (Wed,) conducted a review in Pulmonary hypertension. sGC stimulators and PDE5 inhibitors was evaluated. Soluble guanylate cyclase stimulators like riociguat offer a dual mechanism of action that may increase cGMP levels even under conditions of NO depletion, unlike PDE5 inhibitors.