title: Characterization of the in vivo antiplatelet activity of the antihypertensive agent losartan.
abstract: OBJECTIVE
  The purpose of this study is to investigate the potential in vivo antiplatelet and thromboprotective properties of the antihypertensive drug losartan in mice.
  
  
  METHODS
  Aggregometry studies were performed on platelets obtained from mice administered losartan for 5 days, via tail vein to examine the ex vivo effects (dose dependence) of this agent and to select an appropriate dose for the in vivo studies. Next, the tail bleeding time test and the time for occlusion in a carotid artery injury thrombosis model (ferric chloride) were also performed to assess the in vivo effects of losartan treatment.
  
  
  RESULTS
  These data indicate that the antihypertensive agent losartan exerts dose-dependent inhibition of the thromboxane receptor-mediated (U46619/agonist)-induced platelet aggregation (ex vivo), whereas it produced no detectable effects on aggregation triggered by adenosine diphosphate or the thrombin receptor activating peptide 4. Findings from the in vivo analysis revealed that tail bleeding time of losartan-treated mice was not different from vehicle-treated mice. On the other hand, in the carotid artery injury thrombosis model, it was found that the losartan-treated mice had significantly longer time for occlusion in comparison with those treated with vehicle control.
  
  
  CONCLUSIONS
  These findings provide evidence that administration of the antihypertensive drug losartan into live mice produces thromboxane A(2) receptor-specific antiplatelet effects. Furthermore, interestingly, this antiplatelet activity appears to translate into thromboprotective properties, without resulting in a bleeding phenotype. Consequently, aside from its potential use as an antithrombotic agent, losartan's chemistry may provide a "blueprint" for designing or repurposing novel derivatives which may have the potential to serve as an antiplatelet and thromboprotective agents but are deprived of the usually concomitant bleeding adverse effects.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA.
authors: John P
authors: JP
authors: Murad
authors: Enma V P
authors: EV
authors: Espinosa
authors: Harold J
authors: HJ
authors: Ting
authors: Fadi T
authors: FT
authors: Khasawneh
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D016718:Arachidonic Acid; D001777:Blood Coagulation / Q000187:drug effects; D020212:Carotid Artery Injuries / Q000473:pathology; D019808:Losartan / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D018179:Receptors, Thrombin / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control
chemical_list: D000959:Antihypertensive Agents; D010975:Platelet Aggregation Inhibitors; D018179:Receptors, Thrombin; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019808:Losartan