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phosphodiesterase inhibitors (PDE inhibitors)

see also:


  • phosphodiesterase is an enzyme that metabolises either cAMP (PDE 4,7,8), cGMP (PDE 5,6,9) or both (PDE 1,2,3,10,11) depending on the isoform.
  • in mammals, the PDE superfamily of enzymes is classified into 11 families, namely PDE1-PDE11.
  • for example, inhibition of PDE3 isoform leads to increased levels of cAMP within those tissues:
    • in the heart, this then results in increased calcium influx and uptake by the sarcoplasmic reticulum, leading to improved myocardial contractility and vasodilatation.
    • in vascular smooth muscles, results in relaxation hence vasodilatation of blood vessels.
  • high concentrations of methylxanthines such as theophylline, inhibit phosphodiesterase in a non-selective manner.

PDE isoforms

PDE type 1

  • calcium-calmodulin dependent PDE
  • inhibition may increase cerebral blood vessel vasodilatation via increased cGMP
  • may have a role in sperm function as vinpocetine appears to impair sperm motility1)
  • selective PDE1 inhibitors include:
    • vinpocetine
      • it also selectively inhibits voltage-sensitive Na+ channels
      • widely used in the body building community as an vasodilator
      • also used to improve memory but studies inconclusive

PDE type 2

  • appears to regulate the basal cGMP concentration in thalamic neurons 2)
  • selective PDE2 inhibitors include:
    • EHNA
    • anagrelide

PDE type 3

  • PDE3 is the form of phosphodiesterase which is found in cardiac and systemic vascular tissue and in general inhibition of it results in similar effects as beta2 arenergic agonists (although these act on a beta 2 adrenoceptor coupled to a Gs protein which then activates adenylyl cyclase to convert ATP into cAMP).
  • thus PDE3 inhibitors result in:
    • cardiac inotropy, chronotropy and dromotropy
    • vasodilatation ⇒ lower systemic arterial pressures ⇒ reflex tachycardia
  • selective PDE3 inhibitors include:
    • milrinone
    • amrinone
    • enoximone

PDE type 4

  • PED4 metabolises cAMP involved in the cAMP/protein kinase A (PKA) pathway
  • cAMP in this pathway has been shown to result in decreased proliferation, increased differentiation, and subsequent apoptosis of malignant glioma cells.3)
  • cAMP appears to stimulate a reporter gene containing a cAMP-responsive element in its promoter region.
  • PDE4 inhibitors may have a role as anti-inflammatory agents, antidepressants, anti-psychotic medications as well as in improving memory.
  • selective PDE4 inhibitors include:
    • rolipram (initially used as an antidepressant)
    • mesembrine, an alkaloid from the herb Sceletium tortuosum
    • ibudilast, a neuroprotective and bronchodilator drug
    • pentoxifylline, a drug that has the potential to enhance circulation
    • piclamilast, a more potent inhibitor than rolipram
    • luteolin, supplement extracted from peanuts that also possesses IGF-1 properties

PDE type 5

  • PDE5 metabolises cGMP to GMP and is found in the corpus cavernosum of the penis and in vascular smooth muscle.
  • This enzyme is responsible for breaking down cGMP that forms in response to increased nitric oxide (NO). Increased intracellular cGMP inhibits calcium entry into the cell, thereby decreasing intracellular calcium concentrations and causing smooth muscle relaxation.
  • NO also activates K+ channels, which leads to hyperpolarization and relaxation. Finally, NO acting through cGMP can stimulate a cGMP-dependent protein kinase that activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to relaxation.
PDE5 inhibitors
  • PDE5 inhibitors, by increasing intracellular cGMP, enhance smooth muscle relaxation and vasodilation, and cause penile erection.
  • PDE5 inhibitors are also being used in the Rx of pulmonary arterial hypertension.4)
    • Two important pathologic features of pulmonary arterial hypertension are decreased endothelial nitric oxide production and increased phosphodiesterase type 5 expression and activity in pulmonary-artery smooth-muscle cells and the right ventricular myocardium.
  • The most common side effects for PDE5 inhibitors include headache and cutaneous flushing, both of which are related to vascular dilation caused by increased vascular cGMP.
  • Potentially severe, fatal hypotension can occur if nitrates including GTN such as GTN are given to a patient taking PDE5 inhibitors as both agents increase cGMP.
  • relatively selective PDE5 inhibitors include:
    • sildenafil (Viagra)
    • tadalafil
    • vardenafil
    • udenafil
    • avanafil
    • dipyridamole also inhibits PDE5
phosphodiesterase_inhibitors.txt · Last modified: 2009/11/11 19:19 (external edit)