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Inhibition of Human Platelet Aggregation and Thromboxane-B₂ Production by Melatonin: Evidence for a Diurnal Variation^*

MARIA DE LAS M. DEL ZAR, MARTA MARTINUZZO, CRISTINA FALCÓN, DANIEL P. CARDINALI, LUIS O. CARRERAS and MARIA I. VACAS

Departamento de Fisiologia, Facultad de Medicina (M.D.Z., D.P.C., M.I.V.), and Sectión Hemostasia y Trombosis, División Hematologia, Hospital de Clinicas José de San Martin (M.M., C.F., L.O.C.), Uniuersidad de Buenos Aires Buenos Aires, Argentina

Address all correspondence and requests for reprints to: Maria I. Vacas, Departamento de Fisiologia, Facultad de Medicina-UBA, CC 243,1425 Buenos Aires, Argentina.

The effects of melatonin on platelet aggregation and thromboxane-B₂ (TxB₂) production induced by 1–4 x 10–^–6 M adenosine diphosphate (ADP) or 0.6 x 10^–3 M arachidonic acid (AA) were assessed in platelet-rich plasma (PRP). Micromolar concentrations of melatonin inhibited in a dose-dependent way ADP-induced platelet aggregation with individual inhibitions 40% or more at 10^–6–10^–5 M. A significant depression of AA-induced platelet aggregation was observed only at 10^–5–10^–4 M melatonin. Morning (0830 h)-evening (1800 h) studies of ADP-induced platelet aggregation in seven normal men showed a higher sensitivity at 1800 h when analyzed as a global inhibitory effect of melatonin (P < 0.01). Moreover, only during the evening hours did melatonin induce reversible aggregation, an index of inhibition of the platelet secretory process elicited by ADP exposure. No diurnal variability in melatonin inhibition of AA-induced aggregation was detected. TxB₂ production elicited by AA in the evening was inhibited significantly in a concentration-related manner by a 2-min preincubation with 10^–9–10^–5 M melatonin, while during the morning hours the inhibition was significant only at 10^–6 M or higher melatonin concentrations. In the case of ADP, the inhibition of TxB₂ release attained significance at 10^–5-M (0830 h) or 10^–6-M concentrations (1800 h). In the presence of either stimulatory agent, melatonin depression of TxB₂ generation was about 2-fold greater at 1800 h than at 0830 h. The diurnal changes in melatonin effect on TxB₂ production were also observed in thrombin-stimulated washed platelets. The present data indicate the existence of circadian variations in platelet responsiveness to melatonin in humans.

^* This work was supported in part by grants from Fondation Sanofi Thrombose pour la Recherche, France (to L.O.C.), and Consejo Nacional de Investigaciones Cientificas y Técnicas de la República Argentina (to D.P.C., M.I.V., and L.O.C.).

Research Fellow, Universidad de Buenos Aires, Buenos Aires, Argentina.

Received February 3, 1989.