Soluble guanylate cyclase: a new therapeutic target for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

Clin Pharmacol Ther. 2015 Jan;97(1):88-102. doi: 10.1002/cpt.10. Epub 2014 Nov 28.


Nitric oxide (NO) activates soluble guanylate cyclase (sGC) by binding its prosthetic heme group, thereby catalyzing cyclic guanosine monophosphate (cGMP) synthesis. cGMP causes vasodilation and may inhibit smooth muscle cell proliferation and platelet aggregation. The NO-sGC-cGMP pathway is disordered in pulmonary arterial hypertension (PAH), a syndrome in which pulmonary vascular obstruction, inflammation, thrombosis, and constriction ultimately lead to death from right heart failure. Expression of sGC is increased in PAH but its function is reduced by decreased NO bioavailability, sGC oxidation and the related loss of sGC's heme group. Two classes of sGC modulators offer promise in PAH. sGC stimulators (e.g., riociguat) require heme-containing sGC to catalyze cGMP production, whereas sGC activators (e.g., cinaciguat) activate heme-free sGC. Riociguat is approved for PAH and yields functional and hemodynamic benefits similar to other therapies. Its main serious adverse effect is dose-dependent hypotension. Riociguat is also approved for inoperable chronic thromboembolic pulmonary hypertension.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Benzoates / adverse effects
  • Benzoates / pharmacology
  • Benzoates / therapeutic use
  • Chronic Disease
  • Cyclic GMP / metabolism
  • Drug Design*
  • Guanylate Cyclase / drug effects*
  • Guanylate Cyclase / metabolism
  • Humans
  • Hypertension, Pulmonary / complications
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / physiopathology
  • Nitric Oxide / metabolism
  • Pyrazoles / adverse effects
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyrimidines / adverse effects
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Receptors, Cytoplasmic and Nuclear / drug effects*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Soluble Guanylyl Cyclase
  • Thromboembolism / drug therapy
  • Thromboembolism / physiopathology


  • Benzoates
  • Pyrazoles
  • Pyrimidines
  • Receptors, Cytoplasmic and Nuclear
  • Nitric Oxide
  • BAY 58-2667
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase
  • Cyclic GMP
  • riociguat