F11iii: Nitric Oxide

Definition

NO = signalling molecule produced by many cells

Synthesis

  • Produced in endothelial cells
  • From amino acid L-arginine
  • Catalysed by NOS (nitric oxide synthase) which is Ca2+ dependent
  • Stimulated by ACh/BK/shear stress from blood flow, all these ↑Ca2+ → ∴↑NOS activity
Synthesis

MoA

  • NO diffuses into vascular smooth m.
  • Binds to & activates guanylyl cyclase
  • CGMP is a secondary messenger:
    1. Inhibits Ca2+ entry into smooth m. cell
    2. Activates K+ → hyperpolarises cell
    3. Stimulates CGMP-dependent-protein-kinase → activates MLC phosphatases → this enzyme dephosphorylates MLC

Actions

DIRECT VD

  • CGMP absorption has anti-platelet, anti-aggregatory effects
  • Inhibits AII & symp VD (indirect VD)
  • Anti-thrombotic (inhibits platelet adhering to vascular endothelium)
  • Anti-inflammatory (inhibits leukocyte adhering to endothelium, scavenges super oxide anion)
  • Anti-proliferative (inhibits smooth m. hyperplasia)

Metabolism

  • Short t ½ 1 – 2 secs
  • Superoxide anion (O2–) has high affinity (both have unpaired E– ∴highly reactive) → binds NO ∴ ↓bioavilability
  • RBC → Hb binds NO → broken down