FRCA Notes

Nitric Oxide

  • Nitric oxide (NO) is an endogenous molecule, formerly known as endothelium-derived relaxing factor
  • It can be a contaminant in nitrous oxide cylinders

  • Colourless gas
  • Highly reactive; reacts with oxygen to form nitrogen dioxide (NO2), which is toxic
  • Boiling point -152ºC
  • Metabolised to nitrate, which is excreted renally

  • Synthesised from L-arginine (has terminal nitrogen atoms)
  • The L-arginine is converted to L-citrulline and NO is released
  • This is catalysed by NOS (nitric oxide synthase), which has two forms:

    1. Constitutive NOS
      • Present in the endothelial, neuronal, skeletal muscle and cardiac tissues, and platelets
      • NOS is stimulated by cGMP and is dependent on Ca2+/calmodulin

    2. Inducible NOS
      • Induced by endotoxin/cytokine exposure in endothelium, vascular smooth muscle, myocytes and WBC's (macrophages and neutrophils)
      • Produces large quantities of NO that may be cytotoxic or form free-radicals

  • It is created as a by-product of nitric acid manufacture
  • Stored as a gas in cylinders with nitrogen
  • Occupational exposure should be <25ppm for 8hrs

Respiratory

  • Endogenous NO provides basal vasodilator tone in pulmonary and bronchial vessels
  • When inhaled (up to 40ppm) may reduce V/Q mismatching in ARDS and reduce pulmonary HTN in neonates
  • No bronchodilator properties
  • Has a 1500x greater affinity for Hb than carbon monoxide

Cardiovascular

  • Endogenous NO provides vasodilator tone in small arteries/arterioles
  • Shear stress increases NO production and may account for flow-dependent vasodilation (autoregulation)
  • No systemic circulatory effects as rapidly inactivated by RBC's
  • In septic shock, overproduction contributes to hypotension and capillary leakage

Neurological

  • Neurones containing NO may have roles in:
    • Modulation of the state of arousal
    • Pain perception
    • Apoptosis
  • Blood flow to the corpus cavernosum is controlled by NO-containing neurones

Other

  • Inhibits platelet aggregation
  • Synthesised in macrophages and neutrophils by inducible NOS as it is toxic to certain pathogens

  • GTN and sodium nitroprusside exert their effect by spontaneous release of or metabolism to NO in smooth muscle cells

  • L-NMMA is a guanidine-substituted analogue of L-arginine that inhibits NOS
    • Has been used to antagonise NOS and increase BP in septic shock
    • Doesn't alter survival

  • Severe ARDS/right heart failure/pulmonary hypertension
    • Use at minimal effective dose, maximal 40ppm
    • Is delivered via the gas flow of a standard ventilator
    • Delivered to lung units with good ventilation, causing selective pulmonary vasodilation and improving V/Q mismatch
    • Inhalational route means it tends not to cause systemic vasodilation and hypotension
    • Meta-analyses have failed to demonstrate an improvement in survival
    • Can cause methaemoglobinaemia; contraindicated in those with methaemoglobinaemia as this can cause bleeding diathesis, intracranial haemorrhage and severe liver failure