TY - JOUR
T1 - Mechanisms involved in the antiplatelet activity of midazolam in human platelets
AU - Sheu, Joen R.
AU - Hsiao, George
AU - Luk, Hsiung N.
AU - Chen, Yi W.
AU - Chen, Ta L.
AU - Lee, Lin W.
AU - Lin, Chien H.
AU - Chou, Duen S.
PY - 2002
Y1 - 2002
N2 - Background: Midazolam is widely used as a sedative and anesthetic induction agent. The aim of this study was to systematically examine the inhibitory mechanisms of midazolam in platelet aggregation. Methods: The inhibitory mechanisms of midazolam in platelet aggregation were explored by means of analysis of the platelet glycoprotein IIb-IIIa complex, phosphoinositide breakdown, intracellular Ca +2 mobilization, measurement of membrane fluidity, thromboxane B 2 formation, and protein kinase C activity. Results: In this study, midazolam dose-dependently (6-26 μM) inhibited platelet aggregation in human platelets stimulated by agonists. Midazolam also dose-dependently inhibited phosphoinositide breakdown and intracellular Ca +2 mobilization in human platelets stimulated by collagen. Midazolam (6-26 μM) significantly inhibited thromboxane A 2 formation stimulated by collagen in human platelets. Moreover, midazolam (15 and 26 μM) dose-dependently decreased the fluorescence of platelet membranes tagged with diphenylhexatriene. Rapid phosphorylation of a platelet protein of Mr 47,000 (P47), a marker of protein kinase C activation, was triggered by collagen (2 μg/ml). This phosphorylation was markedly inhibited by midazolam (26 μM). Conclusions: These results indicate that the antiplatelet activity of midazolam may be involved in the following pathways: the effects of midazolam may initially be caused by induction of conformational changes in platelet membrane, leading to a change in the activity of phospholipase C, and subsequent inhibition of phosphoinositide breakdown and thromboxane A 2 formation, thereby leading to inhibition of both intracellular Ca +2 mobilization and phosphorylation of P47 protein.
AB - Background: Midazolam is widely used as a sedative and anesthetic induction agent. The aim of this study was to systematically examine the inhibitory mechanisms of midazolam in platelet aggregation. Methods: The inhibitory mechanisms of midazolam in platelet aggregation were explored by means of analysis of the platelet glycoprotein IIb-IIIa complex, phosphoinositide breakdown, intracellular Ca +2 mobilization, measurement of membrane fluidity, thromboxane B 2 formation, and protein kinase C activity. Results: In this study, midazolam dose-dependently (6-26 μM) inhibited platelet aggregation in human platelets stimulated by agonists. Midazolam also dose-dependently inhibited phosphoinositide breakdown and intracellular Ca +2 mobilization in human platelets stimulated by collagen. Midazolam (6-26 μM) significantly inhibited thromboxane A 2 formation stimulated by collagen in human platelets. Moreover, midazolam (15 and 26 μM) dose-dependently decreased the fluorescence of platelet membranes tagged with diphenylhexatriene. Rapid phosphorylation of a platelet protein of Mr 47,000 (P47), a marker of protein kinase C activation, was triggered by collagen (2 μg/ml). This phosphorylation was markedly inhibited by midazolam (26 μM). Conclusions: These results indicate that the antiplatelet activity of midazolam may be involved in the following pathways: the effects of midazolam may initially be caused by induction of conformational changes in platelet membrane, leading to a change in the activity of phospholipase C, and subsequent inhibition of phosphoinositide breakdown and thromboxane A 2 formation, thereby leading to inhibition of both intracellular Ca +2 mobilization and phosphorylation of P47 protein.
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U2 - 10.1097/00000542-200203000-00022
DO - 10.1097/00000542-200203000-00022
M3 - Article
C2 - 11873041
AN - SCOPUS:0036184121
SN - 0003-3022
VL - 96
SP - 651
EP - 658
JO - Anesthesiology
JF - Anesthesiology
IS - 3
ER -