Nitric oxide pharmacology
How the gas nitric oxide relaxes blood vessels through cGMP, and the nitrates, PDE5 inhibitors, sGC stimulators and inhaled NO that use this pathway.
Nitric oxide (NO) is a small gas made from L-arginine by nitric oxide synthase (NOS). Made in the endothelium, it diffuses into smooth muscle, switches on soluble guanylyl cyclase (sGC) and raises cGMP, which relaxes the muscle. The molecule and the enzyme have their own Biochemistry pages («Nitric oxide», «Nitric oxide synthase»); this page covers the drugs that act on the pathway.
Three NOS enzymes
Endothelial damage, as in atherosclerosis, lowers NO and favours spasm and clotting.
- eNOS (endothelial): steady low output that keeps vessels relaxed and platelets quiet
- nNOS (neuronal): signalling in the brain and in nerves to the gut and penis
- iNOS (inducible): large amounts made by immune cells in inflammation; it contributes to the vasodilation of septic shock
NO donors
Glyceryl trinitrate and the isosorbide nitrates are converted to NO in the vessel wall. At usual doses they dilate veins more than arteries, which reduces the filling of the heart and its oxygen needs; this is why sublingual nitroglycerin relieves angina within minutes. Headache is common. Sodium nitroprusside releases NO directly and dilates arteries and veins; it is used by infusion in hypertensive emergencies and releases cyanide as it is broken down, so prolonged use needs monitoring.
Protecting cGMP: PDE5 inhibitors
Sildenafil and tadalafil block PDE5, which is plentiful in the corpus cavernosum and the lung vessels. They treat erectile dysfunction (where sexual stimulation supplies the NO) and pulmonary arterial hypertension. Their labels warn against use with nitrates, including recreational alkyl nitrites («poppers»), and with riociguat.
Stimulating sGC and inhaled NO
Riociguat stimulates sGC directly and makes it more sensitive to NO; it treats pulmonary hypertension and is teratogenic. Inhaled nitric oxide relaxes only the lung vessels it reaches, because haemoglobin captures it at once in the blood; it is used for pulmonary hypertension in newborns. Binding to haemoglobin can form methaemoglobin, which is monitored during treatment.
Test yourself
Think of the answer, then tap the question to see it.
Why must a PDE5 inhibitor not be combined with a nitrate?
The nitrate raises cGMP production and the PDE5 inhibitor blocks its breakdown, so cGMP rises far more and blood pressure can fall dangerously.
Why does sublingual nitroglycerin relieve angina?
It releases NO, dilates mainly veins, reduces the filling and work of the heart and so its oxygen demand; it also relaxes coronary spasm.
How is nitrate tolerance prevented?
By leaving a nitrate-free (or low-nitrate) interval each day instead of continuous exposure.
Why does inhaled NO act only on the lungs?
Haemoglobin binds and inactivates NO as soon as it reaches the blood, so it acts only on the lung vessels next to ventilated alveoli.
Example drugs
- Glyceryl trinitrate
- Isosorbide mononitrate
- Isosorbide dinitrate
- Sodium nitroprusside
- Sildenafil
- Tadalafil
- Riociguat
- Nitric oxide (inhaled)
- Sodium nitrite
- Methylthioninium chloride (methylene blue)
Connections
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: Nitroglycerin Sublingual: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); Sildenafil: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); Tadalafil: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); Molecule of the Month: Nitric Oxide Synthase (RCSB Protein Data Bank (PDB-101), 2026).
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Representative model, for educational purposes only.