Potentiation of ADP-induced aggregation in human platelet-rich plasma by 5-hydroxytryptamine and adrenaline.
1. We have used dose-response curves to quantitate the potentiation of adenosine 5'-diphosphate (ADP)-induced aggregation and thromboxane (TXA2) generation by 5-hydroxytryptamine (5-HT) and adrenaline in human citrated platelet-rich plasma. We have also quantitated the inhibition of these responses by aspirin, ketanserin and yohimbine, singly and in pairs. 2. Ketanserin (5 microM) inhibited TXA2 production and the second wave of platelet aggregation induced by a range of concentrations of ADP alone. This indicates that endogenous 5-HT, released from the platelet dense granules, contributes significantly to responses induced by ADP. 3. When 5-HT (10 microM) was added before ADP, a lower concentration of ADP was required to cause 50% aggregation and TXA2 generation. The ratio of ADP concentrations (CR) to cause 50% aggregation in the presence and absence of 5-HT was 2.1 when only added 5-HT was considered, and 5.0 when endogenous 5-HT was also taken into account. 4. Potentiation of ADP-induced aggregation by 5-HT also occurred in the presence of aspirin, resulting in a CR of 2.3. As expected, ketanserin inhibited potentiation by 5-HT in the presence and absence of aspirin. Although aspirin caused substantial inhibition of aggregation induced by ADP and 5-HT (CR 3.4), further inhibition occurred when ketanserin was also present (CR 6.5). 5. A subthreshold concentration of adrenaline (0.25 microM) caused substantial potentiation of ADP-induced aggregation in the absence (CR 4.0) and presence (CR 2.0) of aspirin. As expected, yohimbine (9 microM) inhibited this potentiation.Maximum TXA2 generation induced by ADP increased from 32.5 to 59.4 pg per 106 platelets when adrenaline was present. Aggregation induced by ADP and adrenaline was markedly inhibited by aspirin (CR 5.1) but was further inhibited when yohimbine (9 microM) was also present (CR 10.0).6. Results from this in vitro study show ketanserin and yohimbine have the potential to be used in combination with aspirin as antithrombotic agents in vivo.
Vanags
D M
DM
Department of Clinical and Experimental Pharmacology, University of Adelaide, South Australia.
Rodgers
S E
SE
Duncan
E M
EM
Lloyd
J V
JV
Bochner
F
F
D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000328:Adult; D001241:Aspirin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004837:Epinephrine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology*; D015016:Yohimbine / Q000494:pharmacology
D015016:Yohimbine; D012701:Serotonin; D000244:Adenosine Diphosphate; D007650:Ketanserin; D001241:Aspirin; D004837:Epinephrine