Hsiao George, Shen Ming-Yi, Chou Duen-Suey, Chang Yi, Lee Lin-Wen, Lin Chien-Huang, Sheu Joen-Rong
Graduate Institute of Pharmacology, Taipei Medical University, Taipei, Taiwan.
Eur J Pharmacol. 2004 Mar 8;487(1-3):159-66. doi: 10.1016/j.ejphar.2004.01.026.
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 microM) inhibited platelet aggregation in washed human platelets stimulated by thrombin (0.05 U/ml). Midazolam (15 and 30 microM) also inhibited phosphoinositide breakdown and intracellular Ca(+2) mobilization in platelets stimulated by thrombin (0.05 U/ml). In addition, midazolam (15 and 30 microM) 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 microM). 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 microM). Midazolam (30 microM) 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 microg/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.
咪达唑仑被广泛用作镇静剂和麻醉诱导剂。本研究的目的是系统地研究咪达唑仑抑制血小板聚集的机制。在本研究中，咪达唑仑浓度依赖性地（15和30微摩尔）抑制由凝血酶（0.05单位/毫升）刺激的洗涤人血小板的聚集。咪达唑仑（15和30微摩尔）还抑制由凝血酶（0.05单位/毫升）刺激的血小板中的磷脂酰肌醇分解和细胞内钙离子动员。此外，咪达唑仑（15和30微摩尔）增加环磷酸腺苷的形成，但不增加环磷酸鸟苷或一氧化氮的形成。在存在咪达唑仑（15和30微摩尔）的情况下，凝血酶引起的细胞内pH值升高受到明显抑制。分子量为47,000（P47）的血小板蛋白的快速磷酸化是蛋白激酶C激活的标志，由凝血酶（0.05单位/毫升）触发。这种磷酸化受到咪达唑仑（15和30微摩尔）的明显抑制。咪达唑仑（30微摩尔）并没有显著降低活化血小板中羟自由基的电子自旋共振信号强度。在体内研究中，静脉注射咪达唑仑（10微克/克）显著延长了肠系膜小静脉中诱导血小板栓形成的潜伏期。这些结果表明，咪达唑仑可以显著预防体内血栓形成。其抗血小板活性可能与抑制磷脂酶C和钠/氢交换体的激活以及增加环磷酸腺苷的形成有关。这些导致细胞内钙离子动员降低和P47磷酸化。
