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 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.
Rickards
K J
KJ
Department of Veterinary Basic Sciences, The Royal Veterinary College, North Mymms, Hertfordshire, UK.
Andrews
M J
MJ
Waterworth
T H
TH
Alexander
G B C
GB
Cunningham
F M
FM
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D006736:Horses; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D013806:Theophylline / Q000494:pharmacology*
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D000244:Adenosine Diphosphate; D013806:Theophylline; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3