Nitric oxide-dependent antiplatelet action of AT1-receptor antagonists in a pulmonary thromboembolism in mice.
The aim of this study was to determine whether AT1-receptor antagonists could inhibit platelet activation-dependent pulmonary thromboembolism in mice and to investigate the involvement of nitric oxide in this action. Losartan, its active metabolite EXP3174, and valsartan given intraperitoneally 1 hour before the thrombotic challenge (in doses of 3, 10, or 30 mg/kg) protected mice from death or hind-limb paralysis in response to intravenous injection of a mixture of collagen and epinephrine; losartan was effective in all doses used, whereas EXP3174 and valsartan reduced mortality only in the two higher doses. The protective action of EXP3174 and valsartan was abolished when nitric oxide synthase was inhibited with l-NAME, whereas that of losartan was only partially reduced. Moreover, only losartan protected mice from death caused by intravenous injection of the thromboxane A2 mimetic U46619 and this action was preserved in l-NAME-pretreated animals. Our results demonstrate the ability of AT1-receptor antagonists to inhibit platelet activation in vivo in a nitric oxide-dependent mechanism. Stronger antiplatelet activity of losartan, most likely due to its blockade of thromboxane A2/prostaglandin H2 receptor, could be of potential clinical relevance, particularly in conditions in which synthesis of endogenous nitric oxide is impaired.
Matys
Tomasz
T
Department of Pharmacodynamics, Medical University of Bialystok, Poland.
Kucharewicz
Iwona
I
Pawlak
Robert
R
Chabielska
Ewa
E
Domaniewski
Tomasz
T
Buczko
Wlodzimierz
W
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D007093:Imidazoles / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D019808:Losartan / Q000627:therapeutic use*; D051379:Mice; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011655:Pulmonary Embolism / Q000517:prevention & control*; D051381:Rats; D013777:Tetrazoles / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D000068756:Valsartan; C066026:losartan carboxylic acid; D014633:Valine; D019808:Losartan