Category: biosynthesis
L-arginine + O2 → nitric oxide (NO) + L-citrulline via nitric oxide synthase. Three isoforms with distinct biology: eNOS (endothelial, Ca2+/calmodulin-regulated, basal vasodilation), nNOS (neuronal, NMDA-receptor-coupled), iNOS (inducible, cytokine-driven, macrophage anti-microbial). NO diffuses into adjacent smooth muscle, activates soluble guanylate cyclase → cGMP → PKG → vasodilation. PDE5 (sildenafil/tadalafil target) degrades cGMP — sildenafil amplifies endogenous NO signaling, doesn't generate it. Nitrates (nitroglycerin, isosorbide) bypass NOS by donating NO directly; tolerance develops via sulfhydryl depletion.