title: 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.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, Illinois 60064-6119, USA. masaki.nakane@abbott.com
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakane
mesh_terms: D000818:Animals; D001665:Binding Sites; D003001:Cloning, Molecular; D006162:Guanylate Cyclase; D006801:Humans; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase
chemical_list: D021122:Protein Subunits; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D019331:NG-Nitroarginine Methyl Ester