Effects of P2Y 1 and P2Y 12 receptor antagonists on ADP-induced shape change of equine platelets: comparison with human platelets

Abstract

Platelet activation by adenosine 5' -diphosphate (ADP) is via both P2Y(1 )and P2Y(12) receptors and leads to shape change and aggregation. The effects on ADP-induced platelet shape change of two P2Y(1) antagonists, adenosine 3'-phosphate, 5'-phosphosulfate (A3P5PS) and 2-deoxy-N(6)-methyladenosine 3', 5'-diphosphate (MRS-2179) and a P2Y(12) antagonist 2-propylthio-D-beta,gamma-dichloromethylene-adenosine 5'-triphosphate (AR-C67085MX) were determined by turbidimetric aggregometry and scanning electron microscopy (SEM) on equine and human platelets. The platelet aggregation was inhibited during aggregometry by 4-[4-[4(aminoiminomethyl)phenyl]-1-piperazinyl]-1-piperidin acid hydrochloride trihydrate (GR 144053F), an inhibitor of fibrinogen binding. From aggregation profiles, concentration-response curves and SEM we conclude that the shape change of equine platelets was susceptible to inhibition by the P2Y(1) antagonists A3P5PS and MRS-2179, but less so than human platelets. The P2Y(12) antagonist AR-C67085 did not influence significantly the shape change of either equine or human platelets.

P2Y12 Receptors Play a Significant Role in the Development of Platelet Microaggregation in Patients with Diabetes

“…In our experiments, inhibition of P2Y1 receptors by treatment with MRS2279 was successful in preventing microaggregates of platelets in control subjects, which demonstrated that the P2Y1 receptor must be absolutely necessary for ADP-induced microaggregates of platelets. This is an agreement with a previous finding that adenosine does not restore aggregation in the presence of a P2Y1-selective antagonist (37). This has been confirmed in P2Y1-deficient mice (17), and the refractory state is, in fact, found to be entirely due to desensitization of the P2Y1 receptor with resultant loss of shape change (38).…”

Effects of Clopidogrel and Aspirin on Platelet Aggregation, Thromboxane Production, and Serotonin Secretion in Horses

“…ADP also interacts with P2Y 1 receptors on the platelet surface, and this might provide a reason for the lack of a strong effect for collagen‐induced aggregation. The platelet shape change in response to ADP is mediated by the P2Y 1 receptor, while the aggregation response is mediated by the P2Y 12 receptor, the target of clopidogrel 28 . While the P2Y 1 receptor is responsible for the initial rate of platelet aggregation in humans, prior reports suggest that the P2Y 12 receptor also contributes to this function in the horse 29 .…”

Coagulopathy of the critically ill equine patient

“…Experimentally, a variety of assays have been used to assess platelet activation and function. These tests have included flow cytometry, aggregometry, adhesion assays, and perfusion techniques 100–102 . Template bleeding time has been evaluated in normal horses, but appears to have poor reproducibility 103 .…”