Novel agents targeting inflammation and NO bioavailability. Hemolysis in SCD and the resultant cell-free Hb leads to NO scavenging. Increased bioavailability of NO and its downstream target cyclic guanosine monophosphate (cGMP) lead to salutary effects in the endothelium, smooth muscles, leukocytes, platelets, and increased γ-globin. Therapeutic agents enhancing NO bioavailability by various mechanisms are depicted here. Of note, PDE9 has restricted tissue expression in the hematopoietic cells and brain with the potential for reduced off-target effects as opposed to PDE5, which is more widely expressed. Glutamine increases NADH within RBCs, thus reducing effects of oxidative stress. Dietary glutamine also serves as a precursor for the de novo production of arginine through the citrulline-arginine pathway, contributing to increased NO production. PDE, phosphodiesterase; sGC, soluble guanylate cyclase. Adapted from Morrone et al⁴⁸  with permission.