Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors

Am J Physiol. 1994 May;266(5 Pt 1):L536-43. doi: 10.1152/ajplung.1994.266.5.L536.

Abstract

The effects of the nonselective phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the selective PDE inhibitors motapizone (type III), rolipram (type IV), zardaverine (type III/IV), and zaprinast (type V and I) on prostaglandin F2 alpha (PFG2 alpha)-induced tone in human pulmonary arteries was investigated. Relaxation was achieved by IBMX [concentration eliciting 50% of maximum response (EC50): 11.3 microM, n = 10], motapizone (EC50:3.0 microM, n = 7), zardaverine (EC50: 3.2 microM, n = 9), and zaprinast (EC50: 31.8 microM, n = 6), whereas rolipram was almost ineffective. The combination of motapizone and zaprinast (10 microM) was the most effective relaxant with supra-additive relaxation and a motapizone EC50 of 575 nM. Biochemical studies revealed the presence of the PDE isozymes I, III, IV and V in the cytosolic and particulate phases of arterial homogenates; PDE II was not detectable. Partial inhibition of adenosine 3',5'-cyclic monophosphate (cAMP)-hydrolyzing PDE activity was achieved with rolipram (26 +/- 2.2%) or motapizone (60 +/- 5.4%), whereas there was almost complete inhibition of total PDE activity with zardaverine (81 +/- 2.0%) or the combination of motapizone and rolipram (82 +/- 2.3%). Inhibition of guanosine 3',5'-cyclic monophosphate (cGMP)-hydrolyzing PDE activity was achieved with zaprinast (62 +/- 2.6%) and motapizone (13 +/- 2.3%), indicating the cGMP-hydrolyzing activity of PDE III. We conclude that four out of the five recognized PDE isozyme families are present in human pulmonary artery. PGF2 alpha-induced tone in this tissue is effectively relaxed through PDE inhibitors with selectivity for type III, III/IV, and type V PDE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Adult
  • Aged
  • Antihypertensive Agents / pharmacology
  • Carbachol / pharmacology
  • Colforsin / pharmacology
  • Cytosol / enzymology
  • Dinoprost / pharmacology
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Isoenzymes / analysis
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Kinetics
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / surgery
  • Male
  • Middle Aged
  • Muscle Contraction / drug effects*
  • Muscle Relaxation / drug effects
  • Muscle Tonus / drug effects
  • Muscle Tonus / physiology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / physiology
  • Nitroprusside / pharmacology
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / analysis
  • Phosphoric Diester Hydrolases / metabolism*
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / enzymology*
  • Pulmonary Artery / physiology
  • Purinones / pharmacology
  • Pyridazines / pharmacology
  • Pyrrolidinones / pharmacology
  • Rolipram

Substances

  • Antihypertensive Agents
  • Isoenzymes
  • Phosphodiesterase Inhibitors
  • Purinones
  • Pyridazines
  • Pyrrolidinones
  • Nitroprusside
  • Colforsin
  • Carbachol
  • Dinoprost
  • motapizone
  • Phosphoric Diester Hydrolases
  • zaprinast
  • Rolipram
  • 1-Methyl-3-isobutylxanthine
  • zardaverine