[Effect of losartan on human platelet activation by thromboxane A2].
OBJECTIVE
Previous studies have demonstrated that losartan, an AT-1 receptor antagonist of angiotensin II (Ang II) could block the receptor of thromboxane A2 (TXA2) in the vascular wall. The aim of the present study was to assess the effect of losartan on human platelet activation.


METHODS
Platelets were obtained from 15 healthy men between the age 26 and 40. Platelet activation was measured by changes in the light transmission of platelet-rich plasma stimulated by a synthetic TXA2 analogue, U46619 (5 x 10(-6) mol/l).


RESULTS
The U46619-stimulated platelet aggregation was significantly inhibited by losartan in a dose-response manner. Only a high dose of EXP 3174 (5 10-5 mol/l), the in vivo active metabolite of losartan, was able to attenuate U46619-induced platelet activation. Captopril, an angiotensin I-converting inhibitor failed to modify U46619-induced platelet aggregation. Despite the platelets expressing AT-1 type receptors, of Ang II exogenous Ang II did not modify platelet aggregation induced by U46619. The binding of U46619 to platelets was competitively inhibited by losartan in dose-dependent manner. However, only a high dose of EXP 3174 reduced the binding of U46619. Captopril failed to modify the binding of U46619 to platelets.


CONCLUSIONS
Losartan decreased platelet aggregation by a TXA2-dependent mechanism. EXP 3174 showed a lesser potency than losartan to reduce TXA2-platelet activation. Captopril and exogenous angiotensin II had no effect on human platelet activation. These results suggest that losartan reduced TXA2-dependent platelet activation independently of the blockade of AT-1 receptors.
Guerra
J I
JI
Laboratorio de Investigación Cardiovascular e Hipertensión. Fundación Jiménez Díaz. Madrid.
Montón
M
M
Rodríguez-Feo
J A
JA
Farré
J
J
Jiménez
A M
AM
Núñez
A
A
Gómez
J
J
Rico
L
L
Marcos
P
P
Castilla
C
C
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 / Q000494:pharmacology; D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D015539:Platelet Activation / Q000187:drug effects*; D017482:Receptors, Thromboxane / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology; D013928:Thromboxane A2 / Q000502:physiology*
D007093:Imidazoles; D017482:Receptors, Thromboxane; D013777:Tetrazoles; D000804:Angiotensin II; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C066026:losartan carboxylic acid; D019808:Losartan