title: Doxepin inhibits GPVI-dependent platelet Ca2+signaling and collagen-dependent thrombus formation.
abstract: Platelet adhesion, activation, and aggregation are essential for primary hemostasis, but are also critically involved in the development of acute arterial thrombotic occlusion. Stimulation of the collagen receptor glycoprotein VI (GPVI) leads to phospholipase Cγ2-dependent inositol triphosphate (IP3) production with subsequent platelet activation, due to increased intracellular Ca2+concentration ([Ca2+]i). Although tricyclic antidepressants have been shown to potentially impair platelet activation, nothing is hitherto known about potential effects of the tricyclic antidepressant doxepin on platelet Ca2+signaling and thrombus formation. As shown in the present study, doxepin significantly diminished the stimulatory effect of GPVI agonist collagen-related peptide (CRP) on intracellular Ca2+release as well as subsequent extracellular Ca2+influx. Doxepin was partially effective by impairment of CRP-dependent IP3production. Moreover, doxepin abrogated CRP-induced platelet degranulation and integrin αIIbβ3activation and aggregation. Finally, doxepin markedly blunted in vitro platelet adhesion to collagen and thrombus formation under high arterial shear rates (1,700-s). In conclusion, doxepin is a powerful inhibitor of GPVI-dependent platelet Ca2+signaling, platelet activation, and thrombus formation.
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tuebingen, Tuebingen, Germany; and.
authors.forename: Sascha
authors.initials: S
authors.lastname: Geue
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tuebingen, Tuebingen, Germany; and.
authors.forename: Britta
authors.initials: B
authors.lastname: Walker-Allgaier
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tuebingen, Tuebingen, Germany; and.
authors.forename: Daniela
authors.initials: D
authors.lastname: Eißler
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tuebingen, Tuebingen, Germany; and.
authors.forename: Roland
authors.initials: R
authors.lastname: Tegtmeyer
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tuebingen, Tuebingen, Germany; and.
authors.forename: Malte
authors.initials: M
authors.lastname: Schaub
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tuebingen, Tuebingen, Germany; and.|Department of Physiology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Florian
authors.identifier: http://orcid.org/0000-0003-2962-1540
authors.initials: F
authors.lastname: Lang
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tuebingen, Tuebingen, Germany; and.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tuebingen, Tuebingen, Germany; and oliver.borst@med.uni-tuebingen.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Borst
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tuebingen, Tuebingen, Germany; and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Münzer
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D004316:Doxepin / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013314:Stress, Mechanical; D013927:Thrombosis / Q000517:prevention & control
chemical_list: D000929:Antidepressive Agents, Tricyclic; D002352:Carrier Proteins; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; C435908:collagen-related peptide; C098341:platelet membrane glycoprotein VI; D004316:Doxepin; D015544:Inositol 1,4,5-Trisphosphate; D051966:Phospholipase C gamma; D002118:Calcium
keywords: calcium signaling; doxepin; phospholipase C; platelet activation