cAMP is not an important messenger for ADP-induced platelet aggregation.
In rat platelets, basal cAMP level did not vary significantly during ADP-induced aggregation. In the same conditions, no variation in the cAMP content was observed in platelets from rats treated with clopidogrel, whereas ADP-induced aggregation was totally inhibited. ADP decreased cAMP level in control prostacyclin- or forskolin-stimulated platelets whereas, in treated platelets, adenylyl cyclase down-regulation was strongly inhibited. SQ 22536 (500 microM), an inhibitor of adenylyl cyclase, strongly reduced the cAMP content of both control and treated platelets but did not reverse the anti-aggregating activity of clopidogrel, showing that inhibition of ADP-induced adenylyl cyclase down-regulation in treated platelets was not responsible for the anti-aggregating effect of clopidogrel. Similar results were obtained in rabbit platelets. These results therefore demonstrate that cAMP is not an important second messenger for ADP-induced platelet aggregation and suggest that another activating pathway, linked to the low affinity ADP receptor present on the platelet surface might be involved in the aggregation process.
Savi
P
P
SANOFI Recherche, Haemobiology Research Department, Toulouse, France.
Pflieger
A M
AM
Herbert
J M
JM
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D000242:Cyclic AMP / Q000494:pharmacology*; D015536:Down-Regulation; D005260:Female; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000502:physiology*
D000067956:Adenylyl Cyclase Inhibitors; D010975:Platelet Aggregation Inhibitors; C017759:9-(tetrahydro-2-furyl)-adenine; D000244:Adenosine Diphosphate; D000242:Cyclic AMP; D000225:Adenine