Vascular tone arises from the balance of vasoconstrictors (endothelin-1, angiotensin II, NE) and vasodilators (NO/sGC/cGMP cascade, prostacyclin, ANP/BNP). Therapeutic vasodilators split: NO donors (organic nitrates → NO → sGC activation → cGMP → PKG → vasodilation) are tolerance-prone at chronic exposure. Soluble guanylate cyclase (sGC) stimulators (riociguat) act NO-independently — synergistic with endogenous NO. PDE5 inhibitors (sildenafil family, not all in registry) preserve cGMP. Endothelin-receptor antagonists (bosentan dual ET-A/B, macitentan, ambrisentan ET-A-selective) blunt the most potent endogenous vasoconstrictor — PAH indication. Direct smooth-muscle relaxants (hydralazine, minoxidil) — mechanism less specified. ARNI (sacubitril) blocks neprilysin → preserves ANP/BNP → natriuresis + vasodilation.
Organ Systems
cardiovascular
Pathway Steps
l-arginine → nitric-oxide — via eNOS in endothelium (cross-link: nitric_oxide_synthesis). Endothelial nitric oxide synthase (eNOS) makes nitric oxide (NO) from L-arginine in response to shear stress and agonists like acetylcholine. NO is the principal endothelium-derived relaxing factor — a freely diffusing gas that signals from endothelium to the underlying smooth muscle.
nitric-oxide → cgmp-elevation — via sGC activation by NO → cGMP from GTP. NO diffuses into vascular smooth muscle and activates soluble guanylate cyclase, raising cGMP. This is the core vasodilatory signal — the same pathway amplified by PDE5 inhibitors (which prevent cGMP breakdown) and by nitrates (which donate NO).
cgmp-elevation → vasodilation — via PKG → myosin light chain phosphatase activation → smooth-muscle relaxation. cGMP activates protein kinase G, which lowers intracellular calcium and desensitizes the contractile apparatus, relaxing the smooth muscle — vasodilation. This NO-cGMP-PKG axis sets vascular tone and is the target of nitrates, PDE5 inhibitors, and the sGC stimulator riociguat.
endothelin-1 → vasoconstriction — via ET-A receptor on smooth muscle → Gq → IP3 → cytosolic Ca²⁺ rise (cross-link: inositol_phosphate_signaling). Opposing vasodilation, endothelial cells also make endothelin-1, one of the most potent endogenous vasoconstrictors, acting on smooth-muscle ETA receptors. The balance of NO (dilator) and endothelin (constrictor) sets vascular tone — and endothelin antagonists (bosentan) treat pulmonary arterial hypertension.
Known Modulators
nitroglycerin (activator) — NO release (mitochondrial ALDH2). organic nitrate; ALDH2 bioactivation; sublingual rescue for angina; tolerance with continuous exposure → daily nitrate-free interval required
isosorbide mononitrate (activator) — NO release. long-acting organic nitrate; chronic angina prophylaxis; same tolerance issue as nitroglycerin
riociguat (activator) — sGC (NO-independent stimulator). PAH + CTEPH; works even when endogenous NO is low; pregnancy contraindicated (teratogenic)