Differential effects of phosphodiesterase inhibitors on platelet activating factor (PAF)- and adenosine diphosphate (ADP)-induced equine platelet aggregation

Compounds that activate adenylate cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP), inhibit equine platelet aggregation. Cyclic AMP is broken down by phosphodiesterase (PDE) and, in the present study, the effects of theophylline, a nonselective PDE inhibitor, and selective inh...

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Published in:Journal of veterinary pharmacology and therapeutics 2003-08, Vol.26 (4), p.277-282
Main Authors: Rickards, K.J, Andrews, M.J, Waterworth, T.H, Alexander, G.B.C, Cunningham, F.M
Format: Article
Language:English
Subjects:
3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors
3',5'-Cyclic-AMP Phosphodiesterases - pharmacology
adenosine diphosphate
Adenosine Diphosphate - pharmacology
adenosine monophosphate
adenylate cyclase
Animals
calcium
cyclic AMP
Cyclic AMP - metabolism
Cyclic AMP - pharmacology
Cyclic Nucleotide Phosphodiesterases, Type 3
Horses
Isoenzymes
Phosphodiesterase Inhibitors - pharmacology
platelet aggregation
Platelet Aggregation - drug effects
platelet-activating factor
theophylline
Theophylline - pharmacology
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Summary:Compounds that activate adenylate cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP), inhibit equine platelet aggregation. Cyclic AMP is broken down by phosphodiesterase (PDE) and, in the present study, the effects of theophylline, a nonselective PDE inhibitor, and selective inhibitors of PDE isoenzymes PDE3, PDE4 and PDE5, on equine platelet aggregation in response to platelet activating factor (PAF) and adenosine diphosphate (ADP) have been examined. Theophylline and the PDE3 inhibitors, trequinsin and quazinone, inhibited both PAF and ADP-induced aggregation in a concentration dependent manner. The inhibition of PAF-induced aggregation was, however, significantly greater than that of the response to ADP. The inhibitory effects of theophylline and the PDE3 inhibitors on ADP- but not PAF-, induced aggregation were reversed by addition of the calcium ionophore, A23187. Rolipram and zaprinast, inhibitors of PDE4 and PDE5, respectively, had no effect on either PAF- or ADP-induced aggregation. These results demonstrate that inhibition of aggregation caused by PAF or ADP can be achieved by selective inhibition of PDE3 but suggest that there may be agonist-specific differences in the intracellular signalling pathways that regulate equine platelet aggregation.
ISSN:0140-7783
1365-2885
DOI:10.1046/j.1365-2885.2003.00486.x