Soluble guanylyl cyclase: physiological role as an NO receptor and the potential molecular target for therapeutic application

Abstract

Nitric oxide (NO) activates soluble guanylyl cyclase, which results in an increased synthesis of cyclic guanosine 3',5'-cyclic monophosphate (cGMP), smooth muscle relaxation and vasodilation. The heme group in soluble guanylyl cyclase binds NO and allosterically activates the catalytic site. In addition, a second allosteric site that synergistically activates the enzyme has been reported. BAY 41-2272 was reported as an NO-independent activator of soluble guanylyl cyclase. Treatment with this compound results in anti-platelet activity, a decrease in blood pressure and an increase in survival, indicating a potential for treating cardiovascular diseases. YC-1, another NO-independent activator, activates soluble guanylyl cyclase and the activity is enhanced in the presence of NO. YC-1 relaxed tissue strips in organ bath. Consistent with its biochemical activity, YC-1 induced penile erection in a conscious rat model. Recently, we found a novel series of soluble guanylyl cyclase activators that also NO-independently activate soluble guanylyl cyclase and cause penile erection, suggesting a synergy with the endogenous NO production in vivo. Here I review the NO/cGMP signal transduction pathway and define soluble guanylyl cyclase modulators as a novel approach for the treatment of cardiovascular diseases and erectile dysfunction.