In its Fe(II) form, this heme moiety is the target of nitric oxide, which is synthesized by endothelial cells following appropriate stimulation.

Binding of nitric oxide to the heme results in activation of the C-terminal catalytic domain, which produces cGMP from GTP.

The HNOX domain uses the bound heme to sense gaseous ligands such as nitric oxide, oxygen, and/or possibly carbon monoxide.

In late 2009, the crystal structure of a human guanylate cyclase catalytic domain, that of the beta subunit, was reported (pdb code 2WZ1).

Because nitric oxide has a partially filled pi* orbital, back bonding prefers a bent geometry for the heme-NO complex.

NO has a strong trans effect, in which the histidine-iron bond is weakened when NO binding delocalizes electrons to the dz2 orbital toward the axial ligand.

However, the identification of two distinct [NO] dependent processes in sGC activation has led to speculation that a proximal NO is responsible for histidine displacement, giving an intermediate 6-coordinate NO-Fe-NO complex.

[5] Cinaciguat was another sGC stimulator that failed to demonstrate effectiveness in clinical trials for acute decompensated heart failure due to a high incidence of treatment induced hypotensive events requiring emergency intervention.