Antiplatelet action of losartan involves TXA(2) receptor antagonism but not TXA(2) synthase inhibition

Various AT(1) receptor antagonists including losartan are known to inhibit human platelet activation by antagonising TXA(2)/PGH(2) receptors (TP recep tors). Presently, we check a hypothesis that losartan, an imidazole derivat ive in contrast with valsartan, a non-imidazole compound, may inhibit human platelet activation also through inhibition of TXA(2) synthesis. Inhibitor y action of losartan (2-n butyl-4-chloro-5-hydroxymethyl-1-beta (2'-(1H-tet razol-5yl)biphenyl-4-yl)methyl] imidazole), its active metabolite EXP 3174 (2-n-butyl-4-chloro-1-beta (2-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl]imid azole-5-carboxylic acid) and valsartan ((S)-N-valeryl-N-(beta2'-(1H-tetrazo l-5-yl)biphenyl-4-yl]methyl]valine), on collagen-induced platelet aggregati on and TXA(2) generation was compared to effects achieved by each compound on U46619-induced aggregation in aspirinized platelets. Losartan and aspiri n inhibited collagen-induced platelet aggregation with approximately the sa me potency, whereas EXP 3174 and valsartan showed much weaker antiplatelet effects. Interestingly, losartan, EXP 3174 and valsartan displayed similar potencies as inhibitors of U46619-induced aggregation in asprinized platele ts as in collagen-induced aggregation in non-aspirinized platelets. None of the above three AT antagonists, up to concentration of 300 muM, did influe nce collagen-induced TXA(2) synthesis in human platelets. In conclusion, an tiplatelet effects of AT antagonists, irrespective of the presence or absen ce of non-condensed imidazole in their chemical structure, involve antagoni sm of TP receptors but not inhibition of TXA(2) synthesis in platelets.