Modulation of cGMP in heart failure: a new therapeutic paradigm.
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.
Boerrigter
Guido
G
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.
Lapp
Harald
H
Burnett
John C
JC
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000187:drug effects / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D045265:Natriuretic Peptides / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase
D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D045265:Natriuretic Peptides; D010726:Phosphodiesterase Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP