Learning Objective

By the end of this note, the learner should be able to explain how NO activates cGMP and how this leads to smooth muscle relaxation and vasodilation.

NO production

• Synthesized from L-arginine by endothelial nitric oxide synthase (eNOS).
• Stimulated by:
  • Shear stress
  • Acetylcholine (M3)
  • Bradykinin
  • Histamine

NO diffusion

• NO diffuse from endothelial cells into vascular smooth muscle because it is lipid-soluble.

cGMP activation

• In smooth muscle, NO activates soluble guanylyl cyclase (sGC).
• sGC converts GTP → cGMP.

Physiologic effect

• cGMP activates protein kinase G (PKG).
• PKG → dephosphorylation of myosin light chains, preventing actin–myosin interaction.
• Result: smooth muscle relaxation → vasodilation.

Drugs Involving NO–cGMP Pathway

• ↑ NO synthesis (endothelium-dependent vasodilation)
  • Nitrates (nitroglycerin, isosorbide dinitrate)
  • M3 agonists (bethanechol)
  • Endogenous: bradykinin, histamine
  • Prevent the breakdown of cGMP
• PDE-5 inhibitors (sildenafil, tadalafil)
  → prolong cGMP action → enhanced vasodilation

Activity