STUDY ON THE ENANTIO-SELECTIVITY OF S(+)-KETAMINE ON THE REGULATION OF CIRCULATION

本研究的目的是阐明硬膜外注射外消旋氯胺酮和S（+）-氯胺酮对全身麻醉时循环系统影响的机制。对于整个动物研究，使用用1%（0.5MAC）异氟烷麻醉的兔。外消旋氯胺酮和S（+）-氯胺酮0.5 mg/kg和1.0 mg/kg下胸段硬膜外给药均能显著降低动脉压和肾交感神经活动。然而，既没有剂量依赖性也没有对映体选择性。毒蕈碱M2受体和一氧化氮可能不参与这种血流动力学变化。需要高浓度的外消旋氯胺酮或S（+）-氯胺酮（IC 50约为300 μ M）来抑制心肌收缩性。这种作用源于这些药物的钠通道阻断作用。同样，高浓度的氯胺酮在神经束膜可能会阻止交感神经的传播，因此没有检测到两种药物之间的差异。分离和培养的细胞从脊髓中的中间外侧细胞柱是困难的。相反，大鼠小胶质细胞系是可用的，所以我们对这些细胞进行膜片钳研究。临床相关浓度的硫喷妥钠增强P2 X7受体电流，但临床相关浓度的氯胺酮（100 M）没有显着改变P2 X7受体电流。利用对ATP具有高灵敏度和高选择性的生物传感器，对脊髓中ATP作为细胞外递质进行实时测量。采用缺氧等方法造成神经损伤，测定脊髓ATP含量和交感神经活性，并研究S（+）-氯胺酮和外消旋氯胺酮的作用。然而，在各种条件下从未观察到ATP浓度的增加。有必要重新评估ATP生物传感器的可靠性。

The purpose of this study was to elucidate the mechanism on circulatory effects of epidural administration of racemic ketamine and S(+)-ketamine during concomitant use of general anesthesia. For whole animal study, rabbits anesthetized with 1 % (0.5MAC) isoflurane were used. Low thoracic epidural administration of racemic ketamine and S(+)-ketamine, 0.5 mg/kg and 1.0 mg/kg, both significantly reduced arterial pressure, renal sympathetic nerve activity. However, neither dose-dependency nor enantio-selectivity was demonstrated. Muscarinic M2 receptors and nitric oxide may not be involved in this hemodynamic change. High concentration of racemic ketamine or S(+)-ketamine (IC50 was approximately 300 uM) was required to suppress myocardial contractility. This effect is originated from the sodium channel blocking effects of these drugs. Similarly, high concentrations of ketamine at the perineurium may have blocked sympathetic nerve propagation thus no difference between the two drugs was detected.Separation and culture of the cells from the intermediolateral cell columns in the spinal cord was difficult. Instead, rat microglial cell line was available so we did patch clamp study on these cells. Clinically relevant concentrations of thiopental enhanced P2X7 receptor currents, but clinically relevant concentrations of ketamine (100 M) did not significantly change P2X7 receptor currents. Real-time measurement of ATP as an extracellular transmitter was performed in the spinal cord using a biosensor which has high sensitivity and selectivity to ATP. Neural damage was induced by hypoxic challenge etc. ATP concentrations in the spinal cord and sympathetic nerve activity were measured and effects of S(+)-ketamine and racemic ketamine were studied. However, inclease in ATP concentrations was never observed with various conditions. Reevaluation of the reliability of the ATP biosensor was necessary.