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.
Organ Systems
cardiovascular
nervous
immune-hematologic
Pathway Steps
l-arginine → nitric-oxide — via NOS (eNOS / nNOS / iNOS); also produces L-citrulline; BH4 cofactor. NO synthases (endothelial eNOS, neuronal nNOS, inducible iNOS) oxidize arginine to NO + citrulline, needing BH4, NADPH, and calmodulin. BH4 depletion “uncouples” eNOS to make superoxide instead of NO (endothelial dysfunction); citrulline/arginine supplements aim to raise NO substrate.
nitric-oxide → cyclic-gmp — via soluble guanylate cyclase (sGC) — activated by NO binding heme. NO diffuses into smooth muscle and binds the heme of soluble guanylate cyclase, raising cGMP → vasodilation. PDE5 inhibitors (sildenafil) block cGMP breakdown, nitrates donate NO directly, and riociguat directly stimulates sGC in pulmonary hypertension.