Soluble guanylate cyclase: a potential therapeutic target for heart failure.

Abstract

The number of annual hospitalizations for heart failure (HF) and the mortality rates among patients hospitalized for HF remains unacceptably high. The search continues for safe and effective agents that improve outcomes when added to standard therapy. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway serves an important physiologic role in both vascular and non-vascular tissues, including regulation of myocardial and renal function, and is disrupted in the setting of HF, leading to decreased protection against myocardial injury, ventricular remodeling, and the cardio-renal syndrome. The impaired NO-sGC-cGMP pathway signaling in HF is secondary to reduced NO bioavailability and an alteration in the redox state of sGC, making it unresponsive to NO. Accordingly, increasing directly the activity of sGC is an attractive pharmacologic strategy. With the development of two novel classes of drugs, sGC stimulators and sGC activators, the hypothesis that restoration of NO-sGC-cGMP signaling is beneficial in HF patients can now be tested. Characterization of these agents in pre-clinical and clinical studies has begun with investigations suggesting both hemodynamic effects and organ-protective properties independent of hemodynamic changes. The latter could prove valuable in long-term low-dose therapy in HF patients. This review will explain the role of the NO-sGC-cGMP pathway in HF pathophysiology and outcomes, data obtained with sGC stimulators and sGC activators in pre-clinical and clinical studies, and a plan for the further clinical development to study these agents as HF therapy.

• Authors: Mihai Gheorghiade, Catherine N Marti, Hani N Sabbah, Lothar Roessig, Stephen J Greene, Michael Böhm, John C Burnett, Umberto Campia, John G F Cleland, Sean P Collins, Gregg C Fonarow, Phillip D Levy, Marco Metra, Bertram Pitt, Piotr Ponikowski, Naoki Sato, Adriaan A Voors, Johannes-Peter Stasch, Javed Butler, Academic Research Team in Heart Failure (ART-HF)
• Journal: Heart failure reviews (Heart Fail Rev) Vol. 18 Issue 2 Pg. 123-34 (Mar 2013) ISSN: 1573-7322 [Electronic] United States
• PMID: 22622468 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Receptors, Cytoplasmic and Nuclear
• Nitric Oxide
• Guanylate Cyclase
• Soluble Guanylyl Cyclase
• Cyclic GMP

Topics

• Cyclic GMP (metabolism, therapeutic use)
• Guanylate Cyclase (biosynthesis, drug effects, metabolism)
• Heart Failure (drug therapy, physiopathology)
• Hemodynamics (drug effects)
• Humans
• Nitric Oxide (metabolism, therapeutic use)
• Receptors, Cytoplasmic and Nuclear (agonists, biosynthesis, metabolism)
• Signal Transduction (drug effects)
• Soluble Guanylyl Cyclase
• Treatment Outcome