New pharmacological strategies to increase cGMP

The intracellular nucleotide cyclic guanosine monophosphate (cGMP) is found in many human organ tissues. Its concentration increases in response to the activation of receptor enzymes called guanylyl cyclases (GCs). Different ligands bind GCs, generating the second messenger cGMP, which in turn leads to a variety of biological actions. A deficit or dysfunction of this pathway at the cardiac, vascular, and renal levels manifests in cardiovascular diseases such as heart failure, arterial hypertension, and pulmonary arterial hypertension. An impairment of the cGMP pathway also may be involved in the pathogenesis of obesity as well as dementia. Therefore, agents enhancing the generation of cGMP for the treatment of these conditions have been intensively studied. Some have already been approved, and others are currently under investigation. This review discusses the potential of novel drugs directly or indirectly targeting cGMP as well as the progress of research to date.