Soluble guanylate cyclase (sGC) is the primary cellular receptor for NO. NO binds and activates a heme group in sGC, initiating the conversion of GTP to the second messenger cGMP. cGMP subsequently mediates a number of signaling cascades leading to vasorelaxation and inhibiting smooth muscle proliferation, leukocyte recruitment, and platelet aggregation. Oxidation of the heme results in its dissociation from sGC and an impairment of NO signaling, which has been linked to hypertension, hyperlidemia, cardiovascular disease, and diabetes. Cinaciguat is an activator of sGC that binds to a regulatory site, resulting in activation in an NO-independent manner (Kd = 3.2 nM). It activates the enzyme even if it has been oxidized or rendered heme deficient. In animals, cinaciguat has been shown to reduce hypertension, limit cardiomyocyte hypertrophy, protect against ischemia/reperfusion injury, and reduce morbidity and mortality in response to endotoxic shock.
