(Circulation. 1995;91:2080-2088.)
© 1995 American Heart Association, Inc.
Articles |
Effects of Aspirin on Platelet-Neutrophil Interactions
Role of Nitric Oxide and Endothelin-1
From Laboratorio de Nefrologia-Hipertensión, Instituto de Investigaciones Médicas, Fundación Jiménez Díaz, Facultad de Medicina, Universidad Autónoma, Madrid, Spain.
Correspondence to Carlos Caramelo, MD, Instituto de Investigaciones Médicas, Fundación Jiménez Díaz, Facultad de Medicina, Universidad Autónoma de Madrid, Avda Reyes Católicos, 2, 28040 Madrid, Spain.
Background In recent studies, the hypothesis has been raised that the mechanisms by which aspirin acts as a protective anti-ischemic agent exceed the inhibition of platelet thromboxane A2 synthesis. Recently, new data have been obtained disclosing a platelet-antiaggregating effect by neutrophils, which occurs through a nitric oxide (NO)/cGMP-dependent pathway.
Methods and Results The present study, using platelets and neutrophils from normal subjects, was undertaken to assess the putative effect of aspirin on the neutrophil-mediated, platelet-inactivating effect. Aspirin facilitated the inhibitory effect of neutrophils on platelet activation by thrombin, ADP, or epinephrine. This effect was equally evident in vitro and in blood samples of normal individuals taking aspirin. A significant stimulation of NO-mediated mechanisms in the presence of aspirin was disclosed by different methods, as follows: (1) the increased metabolism of arginine to citrulline, (2) the increase of cGMP in the platelet/neutrophil system, and (3) the inhibitory action of the L-arginine (L-Arg)–competitive analogue L-NMMA, which was reversed by L-Arg. The effect of aspirin appeared to be related to cyclooxygenase inhibition, since it was reproduced by using indomethacin. The vasoconstricting peptide endothelin-1 (ET-1) reversed the effect of aspirin through the endogenous production of platelet-activating factor (PAF) by neutrophils, as judged by the marked inhibitory effect of the PAF antagonist BN-52021.
Conclusions Our results show that a significant part of the effect of aspirin on platelet activation involves a neutrophil-mediated, NO/cGMP-dependent mechanism. The presence of ET-1 counterbalances these effects of neutrophils on platelet activation, therefore acting as an indirect proactivating agent. These results add new elements for interpreting the effects of aspirin on the interactions between blood cells, with special reference to high endothelin states (for example, ischemia/reperfusion processes).
Key Words: aspirin • platelets • endothelin
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