Amphetamines induce tissue factor and impair tissue factor pathway inhibitor: role of dopamine receptor type 4

Amphetamine intake is associated with acute vascular syndromes. Since these events are caused by arterial thrombosis and this in turn is triggered by tissue factor (TF), this study examines whether amphetamines regulate TF in human endothelial cells. Amphetamine (10(-7)-10(-4) mol/L) enhanced thrombin- and tumour necrosis factor (TNF)-alpha-induced as well as basal TF expression (P = 0.029, 0.0003, and 0.003 at maximal concentration), and TNF-alpha-induced plasminogen activator inhibitor (PAI)-1 expression (P = 0.003), whereas tissue factor pathway inhibitor expression was impaired (P = 0.008). Similarly, 3,4-methylenedioxymethamphetamine (10(-7)-10(-4) mol/L) enhanced TF expression (P = 0.046). These effects were paralleled by an increased TF activity (P = 0.002); moreover, clotting time of human plasma was accelerated by supernatant from amphetamine-treated cells (P = 0.03). Amphetamine enhanced TF mRNA expression via phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK) and p38 (P = 0.03 and 0.033), but not c-Jun NH2-terminal kinase (JNK; P = 0.81). The effect of amphetamine on TF expression was abrogated by the dopamine D4 receptor antagonists L-745,870 and L-750,667, but not D2 or D3 receptor antagonists; furthermore, L-745,870 blunted the amphetamine-induced activation of ERK and p38, but not JNK. Amphetamines induce endothelial TF expression via stimulation of dopamine D4 receptor and activation of the MAPKs p38 and ERK. These effects occur at clinically relevant amphetamine concentrations and may account for the increased incidence of acute vascular syndromes after amphetamine consumption.