Steps for modeling NO˙-cGMP signaling pathway.

Abstract

<p>The reaction schema: NO˙ is synthesized in a generator cell and freely diffuses, either within the same cell or to a target cell, to activate sGC; sGC is oxidized by H₂O₂ and inactivated. Either sGC or NO˙-sGC can convert GTP to cGMP, which is degraded by PDE to GMP. Note that oxidative stress drives the system toward the oxidative limb, and that the goal of pharmacological modulation of this pathway is to reverse the adverse effects of oxidative stress and to minimize PDE inhibition in order to optimize cGMP levels. NAC can be used as an antioxidant (impairing hydrogen peroxide-dependent oxidation of SGC and, perhaps, oxidation of NO˙), sildenafil as a PDE5 inhibitor, and SNAP as an NO˙ donor to modulate this pathway experimentally. Abbreviations: cGMP, cyclic guanosine 3', 5'-monophosphate; GMP, guanosine-5'-monophosphate; GTP, guanosine-5'-triphosphate; H₂O₂, hydrogen peroxide; NAC, N-acetylcysteine; NO˙, nitric oxide; NO_x, oxidized (inactive) nitrogen oxides; PDE, phosphodiesterase; SNAP, S-Nitroso-n-nacetylpenicillamine; sGC, soluble guanylyl cyclase.</p