Abstract

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. In this study, midazolam concentration- dependently (15 and 30 μM) inhibited platelet aggregation in washed human platelets stimulated by thrombin (0.05 U/ml). Midazolam (15 and 30 μM) also inhibited phosphoinositide breakdown and intracellular Ca+2 mobilization in platelets stimulated by thrombin (0.05 U/ml). In addition, midazolam (15 and 30 μM) increased the formation of cyclic AMP but not cyclic GMP or nitric oxide. The thrombin-evoked increase in pHi was markedly inhibited in the presence of midazolam (15 and 30 μM). Rapid phosphorylation of a platelet protein of molecular weight (Mr.) 47,000 (P47), a marker of protein kinase C activation, was triggered by thrombin (0.05 U/ml). This phosphorylation was markedly inhibited by midazolam (15 and 30 μM). Midazolam (30 μM) did not significantly reduce the electron spin resonance signal intensity of hydroxyl radicals in activated platelets. In the vivo study, intravenous injection of midazolam (10 μg/g) significantly prolonged the latent period of inducing platelet plug formation in mesenteric venules. These results indicate that midazolam can significantly prevent thrombus formation in vivo. Its antiplatelet activity may be involved in the inhibition of the activation of phospholipase C and the Na+/H+ exchanger and increased cyclic AMP formation. These lead to lower intracellular Ca +2 mobilization and phosphorylation of P47.

Original languageEnglish
Pages (from-to)159-166
Number of pages8
JournalEuropean Journal of Pharmacology
Volume487
Issue number1-3
DOIs
Publication statusPublished - Mar 8 2004

Fingerprint

Midazolam
Blood Platelets
Thrombin
Phosphorylation
Platelet Aggregation
Cyclic AMP
In Vitro Techniques
Sodium-Hydrogen Antiporter
Venules
Cyclic GMP
Electron Spin Resonance Spectroscopy
Type C Phospholipases
Phosphatidylinositols
Hypnotics and Sedatives
Intravenous Injections
Hydroxyl Radical
Protein Kinase C
Anesthetics
Nitric Oxide
Thrombosis

Keywords

  • Cyclic AMP
  • Midazolam
  • Na /H exchanger
  • Phospholipase C
  • Platelet aggregation
  • Thrombosis

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Mechanisms of antiplatelet and antithrombotic activity of midazolam in in vitro and in vivo studies. / Hsiao, George; Shen, Ming Yi; Chou, Duen Suey; Chang, Yi; Lee, Lin Wen; Lin, Chien-Huang; Sheu, Joen Rong.

In: European Journal of Pharmacology, Vol. 487, No. 1-3, 08.03.2004, p. 159-166.

Research output: Contribution to journalArticle

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abstract = "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. In this study, midazolam concentration- dependently (15 and 30 μM) inhibited platelet aggregation in washed human platelets stimulated by thrombin (0.05 U/ml). Midazolam (15 and 30 μM) also inhibited phosphoinositide breakdown and intracellular Ca+2 mobilization in platelets stimulated by thrombin (0.05 U/ml). In addition, midazolam (15 and 30 μM) increased the formation of cyclic AMP but not cyclic GMP or nitric oxide. The thrombin-evoked increase in pHi was markedly inhibited in the presence of midazolam (15 and 30 μM). Rapid phosphorylation of a platelet protein of molecular weight (Mr.) 47,000 (P47), a marker of protein kinase C activation, was triggered by thrombin (0.05 U/ml). This phosphorylation was markedly inhibited by midazolam (15 and 30 μM). Midazolam (30 μM) did not significantly reduce the electron spin resonance signal intensity of hydroxyl radicals in activated platelets. In the vivo study, intravenous injection of midazolam (10 μg/g) significantly prolonged the latent period of inducing platelet plug formation in mesenteric venules. These results indicate that midazolam can significantly prevent thrombus formation in vivo. Its antiplatelet activity may be involved in the inhibition of the activation of phospholipase C and the Na+/H+ exchanger and increased cyclic AMP formation. These lead to lower intracellular Ca +2 mobilization and phosphorylation of P47.",
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AU - Shen, Ming Yi

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AU - Lee, Lin Wen

AU - Lin, Chien-Huang

AU - Sheu, Joen Rong

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N2 - 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. In this study, midazolam concentration- dependently (15 and 30 μM) inhibited platelet aggregation in washed human platelets stimulated by thrombin (0.05 U/ml). Midazolam (15 and 30 μM) also inhibited phosphoinositide breakdown and intracellular Ca+2 mobilization in platelets stimulated by thrombin (0.05 U/ml). In addition, midazolam (15 and 30 μM) increased the formation of cyclic AMP but not cyclic GMP or nitric oxide. The thrombin-evoked increase in pHi was markedly inhibited in the presence of midazolam (15 and 30 μM). Rapid phosphorylation of a platelet protein of molecular weight (Mr.) 47,000 (P47), a marker of protein kinase C activation, was triggered by thrombin (0.05 U/ml). This phosphorylation was markedly inhibited by midazolam (15 and 30 μM). Midazolam (30 μM) did not significantly reduce the electron spin resonance signal intensity of hydroxyl radicals in activated platelets. In the vivo study, intravenous injection of midazolam (10 μg/g) significantly prolonged the latent period of inducing platelet plug formation in mesenteric venules. These results indicate that midazolam can significantly prevent thrombus formation in vivo. Its antiplatelet activity may be involved in the inhibition of the activation of phospholipase C and the Na+/H+ exchanger and increased cyclic AMP formation. These lead to lower intracellular Ca +2 mobilization and phosphorylation of P47.

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