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Władysław Buczko, Tomasz Matys, Robert Pawlak, Iwona Kucharewicz, Ewa Chabielska
Med Sci Monit 2001; 7(4): BR600-605
Background: In our previous experiments we showed that the prototype memberof the AT1 receptor antagonists (AT1-As) family, losartan, prevented the development of arterial andvenous thrombosis in rats. Recent studies have demonstrated that apart from blocking AT1 receptor, losartanis also a competitive antagonist to thromboxane A2/prostaglandin H[sub]2[/sub] receptor (TP receptor). Thus, wedecided to assess if this feature could contribute to the antithrombotic action of losartan.
Material and methods: We compared the influence losartan, its active metabolite EXP3174 and valsartan on rat plateletadhesion to fibrillar collagen and platelet aggregation in response to thromboxane A2 analogue, U46619.We also assessed the efficacy of these drugs in platelet-dependent pulmonary thrombosis in mice as wellas preventive and therapeutic models of venous thrombosis in rats.
Results: All the three compounds,given in a single dose, inhibited rat platelet adhesion to fibrillar collagen and platelet aggregationinduced with U46619 in vitro and ex vivo, with the action of losartan being much more pronounced thanthat of EXP3174 or valsartan. Losartan also more effectively protected mice from death in response tothe intravenous injection of collagen / epinephrine and it was the only compound which reduced mice mortalityafter the intravenous injection of U46619. In contrast, all the three AT1 receptor antagonists exerteda similar thrombolytic action and comparably decreased the thrombus weight in the therapeutic and preventivemodel of venous thrombosis, although in the latter case a high dose of losartan was slightly more effectivethan a corresponding dose of EXP3174 and valsartan.
Conclusions: Since losartan is endowed with a relativelylow affinity towards the AT1 receptor, we conclude that its superiority over EXP 3174 and valsartan ininhibiting thrombocyte function and platelet-dependent thrombosis could result from its stronger actionon the TP receptor. This feature seems to be less important in the thrombolytic effect of AT1-As andin the inhibition of the venous thrombosis development, in which platelets play only a minor role.