title: Angiotensin receptor blocker losartan suppresses platelet activity by interfering with thromboxane signaling.
abstract: Enhanced platelet activity and platelet endothelial interaction are hallmarks of different vascular and metabolic diseases with subsequent thrombus formation. In atherosclerosis, coronary artery disease, congestive heart failure, nitrate tolerance, chronic inflammation, or diabetic states, platelet activation may in part be due to a stimulation of the renin-angiotensin-aldosteron system, which also contributes to enhanced oxidant stress in these conditions.
  
  
  OBJECTIVE
  We examined the putative role of the angiotensin receptor (AT1) and of phospholipase A2 (PLA2) in mediating platelet activation under defined in vitro conditions using the AT1 receptor antagonists losartan, EXP 3174, candesartan, and the PLA2 inhibitor arachidonyltrifluoromethyl ketone (AACOCF3), respectively.
  
  
  RESULTS
  In washed human or canine platelet suspensions, losartan (10(-4)-10(-6) mol/L) dose-dependently suppressed thrombin-induced calcium transients as well as thromboxane (TxA2) release. In both species, aggregation of washed platelets in response to thrombin or ADP was substantially diminished by different doses of losartan. This inhibition of platelet aggregation was even maintained in ADP-stimulated platelet-rich plasma. While the PLA2 inhibitor AACOCF3 effectively inhibited thrombin-induced TxA2 release from washed human or canine platelets (similar to the effects observed with losartan), the AT1 agonist angiotensin II elicited platelet TxA2 release only at high supra-physiological doses (e.g., at 10(-4) mol/L). The AT1 specific antagonist candesartan did not diminish stimulated platelet aggregation, TxA2 formation, or calcium transients. By contrast, the active losartan metabolite EXP 3174 dose-dependently inhibited stimulated platelet calcium transients as well as TxA2 release at 1-100 micromol/L.
  
  
  CONCLUSIONS
  Losartan significantly counteracts ex vivo platelet activation, probably via the blockade of TxA2 receptor-dependent signaling (e.g. implying activation of phospholipase A2) rather than acting at the AT1 receptor itself. This implies that the TxA2 signaling pathway plays a significant role during platelet activation, which may be successfully antagonized in vivo under different pathological states with enhanced thrombus formation or platelet-endothelium interactions.
authors.affiliation: Institute of Applied Physiology, Albert-Ludwigs University, Freiburg, Germany. angphys@ruf.uni-freiburg.de
authors.forename: M
authors.initials: M
authors.lastname: Schwemmer
authors.forename: O
authors.initials: O
authors.lastname: Sommer
authors.forename: E
authors.initials: E
authors.lastname: Bassenge
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000502:physiology; D054467:Phospholipases A2; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000502:physiology; D017482:Receptors, Thromboxane / Q000187:drug effects; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology; D013928:Thromboxane A2 / Q000502:physiology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D001095:Arachidonic Acids; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D017482:Receptors, Thromboxane; D013777:Tetrazoles; C081565:arachidonyltrifluoromethane; D013928:Thromboxane A2; D010741:Phospholipases A; D054467:Phospholipases A2; C066026:losartan carboxylic acid; D019808:Losartan; C081643:candesartan