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Angiotensin Receptor Blocker Losartan Suppresses Platelet Activity by Interfering with Thromboxane Signaling

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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.

Aims. 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 μmol/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.

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References

  1. Rokitansky CV. Über einige der Wichtigsten Krankheiten der Arterien. Wien: KK Hof-und Staatsdruckerei, 1852.

    Google Scholar 

  2. Bizzozero J. Über einen neuen Formbestandteil des Blutes und dessen Rolle bei der Thrombose und der Blutgerinnung. Virchows Arch Pathol Anat 1982; 90: 261.

    Google Scholar 

  3. Duguid JB. Thrombosis as a factor in the pathogenesis of coronary atherosclerosis. Am J Pathol Bacteriol 1946; 58: 207-467.

    Google Scholar 

  4. Munro JM, Cotran RS. The pathogenesis of atherosclerosis: Atherogenesis and inflammation. Lab Invest 1988; 58(3): 249-261.

    PubMed  Google Scholar 

  5. Strobl-Jager E, Widhalm K, Sinzinger H. Influence of type IIa, IIb and IV-hyperlipoproteinemia on platelet prostaglandin sensitivity, plasma thromboxane B2 and platelet half-life. Prostagland Leuk Med 1986; 25(1): 39-47.

    Google Scholar 

  6. Fitscha P, Kaliman J, Sinzinger H. Platelet sensitivity to antiaggregatory prostaglandins (PGE1,D2,I2) in patients with peripheral vascular disease. Am J Hematology 1985; 19(1): 13-19.

    Google Scholar 

  7. Packham MA. Role of platelets in thrombosis and hemostasis. Can J Physiol Pharmacol 1994; 72: 278-284.

    PubMed  Google Scholar 

  8. Trip MD, Cats VM, van CFJ, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. New Engl J Med 1990; 322(22): 1549-1554.

    Google Scholar 

  9. Sylven C, Hagerman I, Karlberg KE, et al. Platelet and leukocyte activation after myocardial infarction. Influence of enalapril. Eur Heart J 1995; 16(12): 1800-1806.

    PubMed  Google Scholar 

  10. Matsuno H, Kozawa O, Niwa M, UematsuT. Inhibition of von Willebrand factor binding to platelet GP lb by a fractionated aurintricarboxylic acid prevents restenosis after vascular injury in hamster carotid artery. Circulation 1997; 96(4): 1299-1304.

    PubMed  Google Scholar 

  11. Ishiwata S, Tukada T, Nakanishi S, Nishiyama S, Seki A. Postangioplasty restenosis: Platelet activation and the coagulation-fibrinolysis system as possible factors in the pathogenesis of restenosis. AmHeart J 1997; 133(4): 387-392.

    Google Scholar 

  12. Keidar S, Oiknine J, Leiba A, Shapira C, Leiba M, Aviram M. Fosinopril reduces ADP-induced platelet aggregation in hypertensive patients. J Cardiovasc Pharmacol 1996; 27 183-186.

    PubMed  Google Scholar 

  13. Brezinski DA, Tofler GH, Muller JE, et al. Morning increase in platelet aggregability. Association with assumption of the upright posture. Circulation 1988; 78(1): 35-40.

    PubMed  Google Scholar 

  14. Thibonnier M, Woloschak M. Platelet aggregation and vasopressin receptors in patients with diabetes mellitus. Proc Soc Exp Biol Med 1988; 188(2): 149-152.

    PubMed  Google Scholar 

  15. Flores NA, Sheridan DJ. The pathophysiological role of platelets during myocardial ischaemia. Cardiovasc Res 1994; 28: 295-302.

    PubMed  Google Scholar 

  16. Investigators RVAPT. Randomized trial of ridogrel, a combined thromboxane A2 synthase inhibitor and tromboxane A2/prostaglandin endoperoxide receptor antagonist, versus asperin as adjunct to thrombolysis in patients with acutre myocardial infarction. Circulation 1994; 89: 588-595.

    Google Scholar 

  17. Fitzgerald GA, Oates JA, Hawiger J, Maas RL, Roberts LJ, Brash AR. Endogenous prostacyclin biosynthesis and platelet function during chronic aspirin adminstration in man. J Clin Invest 1993; 71: 676-688.

    Google Scholar 

  18. D'souza D, Wu KK, Hellums JD, Phillips MD. Platelet activation and arterial thrombosis. Lancet 1994; 334: 991-995.

    Google Scholar 

  19. Tazawa S, Nakane T, Chiba S. Angiotensin II type 1 receptor blockade prevents upregulation of angiotensin II type 1A receptors in rat injured artery. J Pharmacol Exp Ther 1999; 288(2): 898-904.

    PubMed  Google Scholar 

  20. Pawlak MA, Macdonald GJ. Altered number of platelet angiotensin II receptors in relation to plasma agonist concentrations in normal and hypertensive pregnancy. J Hypertens 1992; 10(8): 813-819.

    PubMed  Google Scholar 

  21. Nickenig G, Strehlow K, Roeling J, Zolk O, Knorr A, Bohm M. Salt induces vascularAT1 receptor overexpression in vitro and in vivo. Hypertension 1998; 31(6): 1272-1277.

    PubMed  Google Scholar 

  22. Gyurko R, Tran D, Phillips MI. Time course of inhibition of hypertension by antisense oligonucleotides targeted to AT1 angiotensin receptor mRNA in spontaneously hypertensive rats. Am J Hypertens 1997; 10(5, Pt. 2): 56S-62S.

    PubMed  Google Scholar 

  23. Warnholtz A, Nickenig G, Schulz E, et al. Increased NADHoxidase-mediated superoxide production in the early stages of atherosclerosis-evidence for involvement of the reninangiotensin system. Circulation 1999; 99(15): 2027-2033.

    PubMed  Google Scholar 

  24. Griendling KK, Ushio-Fukai M, Lassegue B, Alexander RW. Angiotensin II signaling in vascular smooth muscle. New concepts. Hypertension 1997; 29(1, Pt. 2): 366-373.

    PubMed  Google Scholar 

  25. Makaritsis KP, Gavras H, Du Y, Chobanian AV, Brecher P. Alphal-adrenergic plus angiotensin receptor blockade reduces atherosclerosis in apolipoprotein E-deficient mice. Hypertension 1998; 32(6): 1044-1048.

    PubMed  Google Scholar 

  26. de Zeeuw D, Gansevoort RT, de Jong PE. Losartan in patients with renal insufficiency. Can J Cardiol 1995; 11(Suppl F): 41F-44F.

    PubMed  Google Scholar 

  27. Ferri C, De Angelis C, Del Porto MA, et al. Blood platelets and angiotensin II: Angiotensin II release after platelet aggregation. J Hypertens 1988; 6: S69-S71.

    Google Scholar 

  28. Touyz RM, Schiffrin EL. Effects of angiotensin II and endothelin-1 on platelet aggregation and cytosolic pH and free Ca2+ concentrations in essential hypertension. Hypertension 1993; 22: 853-862.

    PubMed  Google Scholar 

  29. Swartz SL, Moore TJ. Effect of angiotensin II on collagen-induced platelet activation in normotensive subjects. Thromb Haemostas 1990; 63(1): 87-90.

    Google Scholar 

  30. Chabielska E, Pawlak R, Buczko W. Losartan does not influence the blood platelet aggregation in normotensive rats. Acta Physiol Hungarica 1996; 84(3): 271-272.

    Google Scholar 

  31. Levy P, Yunis C, Owen J, Brosnihan B, Smith R, Ferrario CM. Inhibition of platelet aggregability by losartan in essential hypertension. Am J Cardiol 2000; 86: 1188-1192.

    PubMed  Google Scholar 

  32. Pawlak R, Chabielska E, Golatowski J, Azzadin A, Buczko W. Nitric oxide and prostacyclin are involved in antithrombotic Losartan Inhibits Platelets: Role of TxA2 307 action of captopril in venous thrombosis in rats. Thromb Haemostas 1998; 79(6): 1208-1212.

    Google Scholar 

  33. Li P, Ferrario CM, Brosnihan KB. Losartan inhibits thromboxane A2-induced platelet aggregation and vascular constriction in spontaneously hypertensive rats. J Cardiovasc Pharmacol 1998; 32(2): 198-205.

    PubMed  Google Scholar 

  34. Moser L, Callahan KS, Cheung AK, Stoddard GJ, Munger MA.ACEinhibitor effects on platelet function in stages I-II hypertension. J Cardiovasc Pharmacol 1997; 30(4): 461-467.

    PubMed  Google Scholar 

  35. Owens P, Kelly L, Nallen R, Ryan D, Fitzgerald D, O'Brien E. Comparison of antihypertensive and metabolic effects of losartan and losartan in combination with hydrochlorothiazide-a randomized controlled trial. J Hypertens 2000; 18(3): 339-345.

    PubMed  Google Scholar 

  36. Nishikibe M, Ikemoto F. Pharmacological properties and its significance in clinical practice. Nippon Rinsho-Japanese Journal of Clinical Medicine 1999; 57(5): 1124-1129, (in Japanese).

    PubMed  Google Scholar 

  37. Liu EC, Hedberg A, Goldenberg HJ, Harris DN, Webb ML. DuP 753, the selective angiotensin II receptor blocker, is a competitive antagonist to human platelet thromboxane A2/prostaglandin H2 (TP) receptors. Prostaglandins 1992; 44(2): 89-99.

    PubMed  Google Scholar 

  38. Li P, Ferrario CM, Brosnihan KB. Nonpeptide angiotensin II antagonist losartan inhibits thromboxane A2-induced contractions in canine coronary arteries. Journal of Pharmacology & Experimental Therapeutics 1997; 281(3): 1065-1070.

    Google Scholar 

  39. Li P, Fukuhara M, Diz DI, Ferrario CM, Brosnihan KB. Novel angiotensinAT(1) receptor antagonist irbesartan prevents thromboxane A(2)-induced vasoconstriction in canine arteries and human platelet aggregation. J Pharmacol Exp Ther 2000; 292(1): 238-246.

    PubMed  Google Scholar 

  40. Freeman EJ, Ruehr ML, Dorman RV. ANG II-induced translocation of cytosolic PLA2 to the nucleus in vascular smooth muscle cells. Am J Physiol 1998; 274(1, Pt. 1): C282-C288.

    PubMed  Google Scholar 

  41. Lokuta AJ, Cooper C, Gaa ST, Wang HE, Rogers TB. Angiotensin II stimulates the release of phospholipidderived second messengers through multiple receptor subtypes in heart cells. J Biol Chem 1994; 269(7): 4832-4838.

    PubMed  Google Scholar 

  42. Ivanova K, Schaefer M, Drummer C, Gerzer R. Effects of nitric oxide-containing compounds on increases in cytosolic ionized Ca2+ and on aggregation of human platelets. Eur J Pharmacol Mol Pharmacol 1993; 244: 37-47.

    Google Scholar 

  43. Grynkiewicz G, Poenie M, Tsien RY. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 1985; 260: 3440-3450.

    PubMed  Google Scholar 

  44. Hale LP, Craver KT, Berrier AM, Sheffield MV, Case LD, Owen J. Combination of fosinopril and pravastatin decreases platelet response to thrombin receptor agonist in monkeys. Arterioscler Thromb Vasc Biol 1998; 18(10): 1643-1646.

    PubMed  Google Scholar 

  45. Chabielska E, Pawlak R, Wollny T, Rolkowski R, Buczko W. Antithrombotic activity of losartan in two kidney, one clip hypertensive rats. A study on the mechanism of action. J Physiol Pharmacol 1999; 50(1): 99-109.

    PubMed  Google Scholar 

  46. Guerra-Cuesta JI, Monton M, Rodriguez-Feo JA, et al. Effect of losartan on human platelet activation. J Hypertens 1999; 17(3): 447-452.

    PubMed  Google Scholar 

  47. Tripodi F, Stanke-Labesque F, Devillier P, Chavanon O, Sessa C, Bessard G. Antagonistic effects of losartan on thromboxane A2-receptors in human isolated gastroepiploic artery and saphenous vein. Journal of CardiovascularPharmacology 1999; 34(5): 734-740.

    Google Scholar 

  48. Guerra-Cuesta JI, Monton M, Rodriguez-Feo JA, et al. Effect of losartan on human platelet activation. Journal of Hypertension 1999; 17(3): 447-452.

    PubMed  Google Scholar 

  49. Li P, Fukuhara M, Diz DI, Ferrario CM, Brosnihan KB. The AT1 receptor antagonist irbesartan inhibits thromboxane-A2-induced human platelet aggregation and vasoconstriction in canine coronary arteries. Circulation 1999; 100(18): 808.

    Google Scholar 

  50. Corriu C, Bernard S, Schott C, Stoclet JC. Effects of losartan on contractile responses of conductance and resistance arteries from rats. Journal of Cardiovascular Pharmacology 1995; 26(5): 688-692.

    PubMed  Google Scholar 

  51. Aoki T, Tomiyama Y, Honda S, et al. Difference of (Ca2+)i movements in platelets stimulated by thrombin and TRAP: The involvement of alpha(IIb)beta3-mediatedTXA2 synthesis. Thromb Haemostas 1998; 79(6): 1184-1190.

    Google Scholar 

  52. Heemskerk JW, Feijge MA, Sage SO, Farndale RW. Human platelet activation is inhibited upstream of the activation of phospholipase A2 by U73343. Biochem Pharmacol 1997; 53(9): 1257-1262.

    PubMed  Google Scholar 

  53. Turini ME, Holub BJ. The cleavage of plasmenylethanolamine by phospholipase A2 appears to be mediated by the low affinity binding site of the TxA2/PGH2 receptor in U46619-stimulated human platelets. Biochem Biophys Acta 1994; 1213(1): 21-26.

    PubMed  Google Scholar 

  54. Balestrieri ML, Malik KU, Balestrieri C, Lee TC. Types of purinoceptors and phospholipase A2 involved in the activation of the platelet-activating factor-dependent transacetylase activity and arachidonate release by ATP in endothelial cells. Prostagland Lipid Mediat 1998; 56(56): 363-375.

    Google Scholar 

  55. Kim S, Tokuyama M, Hosoi M, Yamamoto K. Adrenal and circulating renin-angiotensin system in strokeprone hypertensive rats. Hypertension 1992; 20(3): 280-291.

    PubMed  Google Scholar 

  56. Droste DW, Siemens HJ, Sonne M, Kaps M, Wagner T. Hemostaseologic and hematologic parameters with aspirin and ticlopidine treatment in patients with cerebrovascular disease: A cross-over study. J Cardiovasc Pharmacol 1996; 28(4): 591-594.

    PubMed  Google Scholar 

  57. Williams B. Mechanical influences on vascular smooth muscle cell function. J Hypertens 1998; 16(12, Pt. 2): 1921-1929.

    PubMed  Google Scholar 

  58. Shibata H, Suzuki H, Murakami M, Sato A, Saruta T. Angiotensin II type 1 receptor messenger RNA levels in human blood cells of patients with primary and secondary hypertension: Reference to renin profile. J Hypertens 1994; 12(11): 1275-1284.

    PubMed  Google Scholar 

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  1. Institute of Applied Physiology, Albert-Ludwigs University, Freiburg, Germany

    Michael Schwemmer, Olaf Sommer & Eberhard Bassenge

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Schwemmer, M., Sommer, O. & Bassenge, E. Angiotensin Receptor Blocker Losartan Suppresses Platelet Activity by Interfering with Thromboxane Signaling. Cardiovasc Drugs Ther 15, 301–307 (2001). https://doi.org/10.1023/A:1012750430056

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