Lesson 7

Phosphodiesterases Overview

• ATP (adenosine triphosphate): Energy source, produces 38 moles ATP per mole glucose in oxygen.
• ATP roles:
  • Energy transfer (molecular currency).
  • Signal transduction precursor.

Adenylate Cyclase and cAMP Production

• Activation of Gs protein initiates adenylate cyclase to convert ATP to cAMP.
• cAMP activates protein kinases for specific cellular functions.

Role of Phosphodiesterase 3 (PDE3)

• PDE3 metabolizes cAMP to 5'-AMP, inactivating protein kinases.
• PDE3 inhibitors (inodilators) elevate cAMP levels:
  • Increases myocardial performance in the heart.
  • Causes vasodilation and decreases systemic vascular resistance (SVR) in vascular smooth muscle.

Clinical Implications of PDE3 Inhibition

• Benefits of inhibiting PDE3:
  • Increases intracellular calcium and contraction force in cardiac muscle.
  • Improves relaxation rate (lusitropy).
  • Induces vasodilation and reduces SVR in vascular muscle.

Therapeutic Uses of PDE3 Inhibitors

• Useful in conditions like:
  • Beta-blocker-induced myocardial depression.
  • Acute heart failure.
  • Unresponsiveness to IV catecholamines.
• Allows increased inotropy and reduced afterload.

Phosphodiesterase Varieties

• Eleven types of phosphodiesterases exist (types 1 to 11).
• Theophylline: Prototype nonselective phosphodiesterase inhibitor.