Effects of serotonin on platelet activation in whole blood.
Serotonin (5-hydrotryptamine, 5-HT) is a weak platelet agonist, which has not been evaluated fully with respect to platelet responses in whole blood. We thus re-evaluated platelet responses to 5-HT using three whole blood techniques: flow cytometry, impedance aggregometry and filtragometry. At concentrations up to 10(-5) mol/l, 5-HT per se failed to induce platelet aggregation in whole blood, or to increase platelet fibrinogen binding or P-selectin expression. However, 5-HT potentiated platelet responses to low concentrations of adenosine diphosphate (ADP) or thrombin dose-dependently. 5-HT (10(-7), 10(-6) and 10(-5) mol/l) increased ADP-induced platelet fibrinogen binding by 40, 59 and 79%, while P-selectin expression increased by 45, 64 and 95%, respectively (P < 0.05; n = 10). The enhancing effects of 5-HT were even more pronounced in thrombin-stimulated samples, as 5-HT at 10(-8), 10(-7), 10(-6) and 10(-5) mol/l increased fibrinogen binding by 56, 128, 212 and 260% (P < 0.05), and P-selectin expression by 31, 56, 89 and 109%, respectively (P < 0.01; n = 10). The response to 5-HT was inhibited dose-dependently by a highly selective 5-HT2A receptor antagonist (SR 46349), with almost complete inhibition at 10(-6) mol/l. Impedance aggregometry showed a significant enhancement in 5 x 10(-6) mol/l ADP-induced platelet aggregation caused by 5-HT at 8 x 10(-8) mol/l (from 7.58 +/- 2.50 omega to 9.02 +/- 2.43 omega, P < 0.02, n = 12). Similarly, filtragometry readings, i.e. the time taken for platelet aggregates to occlude a microfilter, were shortened by 27% (P < 0.05, n = 9), reflecting increased platelet aggregability. Our data suggest that 5-HT per se does not activate platelets, but dose-dependently enhances platelet activation induced by ADP and, in particular, thrombin in whole blood. Thus, the idea that 5-HT is a 'helper agonist' is supported; this effect is mediated by 5-HT2A receptors.
Li
N
N
Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
Wallén
N H
NH
Ladjevardi
M
M
Hjemdahl
P
P
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D000704:Analysis of Variance; D005260:Female; D005434:Flow Cytometry; D005464:Fluorobenzenes / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010636:Phenols / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D012016:Reference Values; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology
D000244:Adenosine Diphosphate; D005464:Fluorobenzenes; D010636:Phenols; D010975:Platelet Aggregation Inhibitors; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D013917:Thrombin; C076033:SR 46349B