Abstract

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.

Original languageEnglish
Pages (from-to)651-658
Number of pages8
JournalAnesthesiology
Volume96
Issue number3
DOIs
Publication statusPublished - 2002

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Midazolam
Blood Platelets
Thromboxanes
Phosphatidylinositols
Platelet Aggregation
Collagen
Phosphorylation
varespladib methyl
Protein Kinase C
Diphenylhexatriene
Integrin beta3
Platelet Glycoprotein GPIIb-IIIa Complex
Membrane Fluidity
Membranes
Type C Phospholipases
Hypnotics and Sedatives
Anesthetics
Proteins
Fluorescence

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Mechanisms involved in the antiplatelet activity of midazolam in human platelets. / Sheu, Joen R.; Hsiao, George; Luk, Hsiung N.; Chen, Yi W.; Chen, Ta L.; Lee, Lin W.; Lin, Chien-Huang; Chou, Duen S.

In: Anesthesiology, Vol. 96, No. 3, 2002, p. 651-658.

Research output: Contribution to journalArticle

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abstract = "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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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-Huang

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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