Systems Pharmacology and Rational Polypharmacy: Nitric Oxide−Cyclic GMP Signaling Pathway as an Illustrative Example and Derivation of the General Case
Fig 2
Monitoring cGMP levels after single perturbation of oxidatively impaired NO˙-cGMP pathway.
(A) The effect of H2O2 on cGMP dynamics. H2O2 caused ~6-fold reduction in cGMP levels. (B and C) Reducing either k3 or k10 during oxidative stress was not an effective perturbation for restoring cGMP to the normal level. The value of k3 or k10 was reduced to 10% of their original values (S1 Table), with perturbation of k3 or k10 denoted as ρk3 and ρk10, respectively. While these perturbations can be effective strategies in enhancing cGMP levels in the absence of H2O2, they are not effective in restoring cGMP levels to normal in the presence of H2O2. (D) All single perturbations of the NO˙-cGMP pathway in the presence of H2O2. The cGMP levels were monitored in the absence of H2O2. Subsequently, in the presence of H2O2, the system was perturbed by reducing one of thirteen rate constants (k1‒k13) to 10% of their original values, denoted as ρks, and then the cGMP levels calculated. Note that ρk1, ρk3, ρk10, and ρk12 markedly increased the cGMP levels beyond other perturbations.