Comparative effects of angiotensin II AT-1-type receptor antagonists in vitro on human platelet activation.
A recent study has shown that losartan, an AT-1-receptor antagonist, interacts with thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptors in human platelets. The aim of this study was to analyze the ability of different angiotensin II (Ang II) AT-1-receptor antagonists to inhibit TxA2-dependent human platelet activation. Platelets were obtained from healthy volunteers. Platelets were stimulated with the TxA2 analogue, U46619 (10(-6) M). U46619-stimulated platelet activation was significantly reduced by both losartan and irbesartan in a dose-dependent manner. Only maximal doses of valsartan (5 x 10(-6) M) and the main metabolite of losartan, EXP3174 (5 x 10(-6) M), reduced U46619-induced platelet activation. Whereas the active form of candesartan cilexetil (candesartan, CV-11974) failed to modify platelet activation involved by TxA2, telmisartan showed a higher effect than valsartan and EXP3174 but lower than either losartan and irbesartan. Losartan or irbesartan reduced the binding of [3H]-U46619 to platelets, an effect that was observed with lower ability with the other AT-1 antagonists. Although platelets expressed AT-1-type receptors, exogenous Ang II did not modify platelet activation. This effect was not modified by blocking the AT-2 receptor with PD123319. These results suggest that some AT-1-receptor antagonists reduce TxA2-dependent activation independent of Ang II involvement.
Montón
M
M
Cardiovascular Research and Hypertension Laboratory, Fundación Jiménez Díaz, Madrid, Spain.
Jiménez
A
A
Núñez
A
A
López-Blaya
A
A
Farré
J
J
Gómez
J
J
Zalba
L R
LR
Sánchez de Miguel
L
L
Casado
S
S
López-Farré
A
A
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000378:metabolism / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D000077405:Irbesartan; D019808:Losartan / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000276:immunology; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology; D013928:Thromboxane A2 / Q000494:pharmacology; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
D057911:Angiotensin Receptor Antagonists; D000911:Antibodies, Monoclonal; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000068756:Valsartan; C066026:losartan carboxylic acid; D014633:Valine; D000077405:Irbesartan; D019808:Losartan; C081643:candesartan; D000077333:Telmisartan