title: Amphetamines induce tissue factor and impair tissue factor pathway inhibitor: role of dopamine receptor type 4.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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 NH(2)-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Cathérine
authors.initials: C
authors.lastname: Gebhard
authors.forename: Alexander
authors.initials: A
authors.lastname: Breitenstein
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Gebhard
authors.forename: Giovanni G
authors.initials: GG
authors.lastname: Camici
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Felix C
authors.initials: FC
authors.lastname: Tanner
mesh_terms: D000662:Amphetamines / Q000009:adverse effects*; D001011:Aorta / Q000187:drug effects; D001777:Blood Coagulation / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000187:drug effects*; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000009:adverse effects; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050638:Receptors, Dopamine D4 / Q000502:physiology*; D013925:Thromboplastin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014652:Vascular Diseases / Q000139:chemically induced*
chemical_list: D000662:Amphetamines; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D050638:Receptors, Dopamine D4; D013925:Thromboplastin; D020929:Mitogen-Activated Protein Kinase Kinases; D018817:N-Methyl-3,4-methylenedioxyamphetamine