Abstract 1659: Amphetamines Induce Endothelial Tissue Factor - Role of Dopamine Receptor Type 4
Background: Amphetamine intake is associated with acute vascular syndromes such as myocardial infarction and ischemic stroke. 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.
Methods and Results: Amphetamine (10−7-10−4 mol/L) enhanced thrombin induced endothelial TF expression by 1.6-fold (P < 0.05), TNF-α induced TF by 1.8-fold (P < 0.05), and basal TF by 2.2-fold (P < 0.05). Similarly, methylenedioxy-methamphetamine (MDMA, “Ecstasy”, 10−7-10−4 mol/L) enhanced TNF-α induced TF expression (P < 0.05). These effects were paralleled by an increased TF surface activity (P < 0.05). In contrast, amphetamine impaired tissue factor pathway inhibitor (TFPI) expression (P < 0.05). Amphetamine enhanced TNF-α induced TF mRNA expression, and, in line with this observation, amphetamine increased phosphorylation of the MAP kinases ERK and p38 (P < 0.05), while JNK remained unaffected (p = NS). Dopamine (10−7-10−4 mol/L) enhanced TNF-α induced TF expression (P < 0.05). The effect of amphetamine on TF expression was abrogated by the dopamine D4 receptor antagonists L-745,870 and L-750667, but not the D2 receptor antagonist raclopride or the D3 receptor antagonist NGB 2904. Real-time PCR confirmed endothelial expression of the D4 receptor, and L-745,870 blunted the amphetamine induced activation of ERK and p38, while JNK remained unaffected.
Conclusions: Amphetamines induce endothelial TF expression and activity via stimulation of the dopamine D4 receptor and activation of the MAP kinases 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.