title: Phosphodiesterase activity in neutrophils from horses with chronic obstructive pulmonary disease.
abstract: Neutrophils are recruited to the lungs of horses with chronic obstructive pulmonary disease (COPD) and exhibit increased activity after antigen challenge. Phosphodiesterase type4 (PDE4) inhibitors have been shown to attenuate human neutrophil activation. The aim of this study was to establish the PDE isoenzyme profile of equine neutrophils using isoenzyme selective inhibitors to determine if these compounds should be evaluated in horses with COPD. Total cAMP and cGMP dependent PDE activity was no different in neutrophils from normal (156.2+/-7.1 and 6.8+/-0.6 pmol/min/mg for cAMP and cGMP, respectively) and COPD susceptible horses (146.0+/-10.2 and 5.5+/-0.6 pmol/min/mg for cAMP and cGMP, respectively). The PDE4 inhibitors, CDP840 and rolipram, caused significant, concentration related and almost complete inhibition of PDE activity (IC(50) values=8.8+/-0.1 x 10(-9) and 7.3+/-0.2 x 10(-9)M for CDP840; 1.2+/-0.1 x 10(-6) and 1.1+/-0.1 x 10(-6)M for rolipram in normal and COPD susceptible horses, respectively). The inhibitory effects of the mixed PDE3/ PDE4 inhibitor, zardaverine were of similar magnitude and potency to rolipram. However, the limited inhibitory effects of the PDE3 inhibitor, siguazodan, suggest that zardaverine is acting primarily via PDE4 inhibition. These results indicate that PDE4 is the predominant isoenzyme present in the equine neutrophil and inhibition of PDE activity using selective PDE4 inhibitors may, therefore, modulate equine neutrophil activation in horses with COPD.
authors.affiliation: Department of Veterinary Basic Sciences, The Royal Veterinary College, Hawkshead Campus, North Mymms, Hertfordshire AL9 7TA, UK. krickard@rvc.ac.uk
authors.forename: K J
authors.initials: KJ
authors.lastname: Rickards
authors.forename: C P
authors.initials: CP
authors.lastname: Page
authors.forename: P
authors.initials: P
authors.lastname: Lees
authors.forename: F M
authors.initials: FM
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D004306:Dose-Response Relationship, Immunologic; D006146:Guanidines / Q000494:pharmacology; D006734:Horse Diseases / Q000201:enzymology / Q000276:immunology*; D006736:Horses; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000276:immunology / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000276:immunology / Q000662:veterinary*; D011724:Pyridazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020889:Rolipram / Q000494:pharmacology
chemical_list: D006146:Guanidines; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011725:Pyridines; C102660:CDP 840; C056215:siguazodan; D010727:Phosphoric Diester Hydrolases; D020889:Rolipram; C066436:zardaverine