Nitric oxide (NO), an important endogenous signaling molecule released from vascular
endothelial cells and nerves, activates the enzyme soluble guanylate cyclase to catalyze
the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate.
cGMP, in turn, activates protein kinase G to phosphorylate a range of effector proteins in
smooth muscle cells that reduce intracellular Ca2+ levels to inhibit both contractility and proliferation.
The enzyme phosphodiesterase type 5 (PDE5) curtails the actions of cGMP by hydrolyzing
it into inactive 5’-GMP. Small molecule PDE5 inhibitors (PDE5is), such as sildenafil,
prolong the availability of cGMP and therefore, enhance NO-mediated signaling.
PDE5is are the first-line treatment for erectile dysfunction but are also now approved for the
treatment of pulmonary arterial hypertension (PAH) in adults. Persistent pulmonary hypertension
in neonates (PPHN) is currently treated with inhaled NO, but this is an expensive option
and around 1/3 of newborns are unresponsive, resulting in the need for alternative approaches.
Here the development, chemistry and pharmacology of PDE5is, the use of sildenafil for erectile
dysfunction and PAH, are summarized and then current evidence for the utility of further
repurposing of sildenafil, as a treatment for PPHN, is critically reviewed.