Chandler L J, Guzman N J, Sumners C, Crews F T
Department of Pharmacology, University of Florida College of Medicine, Gainesville.
J Pharmacol Exp Ther. 1994 Oct;271(1):67-75.
The coupling of calcium mobilizing receptors to nitric oxide (NO) formation was examined in cerebral cortical cultures. Of the various agents tested, only glutamate, depolarization with KCl and the calcium ionophore ionomycin stimulated nitric oxide synthase (NOS) activity. Characterization of the glutamate response revealed that the ionotropic glutamate receptor agonists N-methyl-D-aspartate (NMDA), kainate and alpha-amino-3-hydroxy-5-methyl-4-isoxalone propionic all stimulated NOS activity with a relative maximal efficacy of NMDA > kainate > alpha-amino-3-hydroxy-5-methyl-4-isoxalone propionic. Ethanol, Mg++ and Zn++ produced a concentration-dependent inhibition of NMDA stimulation of NOS. The Mg++ inhibition was reversed by increasing concentrations of NMDA, whereas Zn++ inhibition was not. Ethanol (100 mM) produced an apparent competitive type inhibition as seen by a parallel right-shift in the NMDA concentration-response curve. However, ethanol inhibition was dependent upon the presence of Mg++ and/or Zn++ in a concentration-related manner. Whereas 100 mM ethanol did not significantly inhibit NMDA stimulation of NOS activity in the absence of Mg++ and Zn++, inclusion of a combination of these cations increased the sensitivity to ethanol such that the NMDA response was completely blocked by 100 mM ethanol (IC50 approximately 30 mM). The potency for inhibition of NMDA stimulation of NOS by several short-chain alcohols followed their hydrophobicity profile and showed a similar dependency upon Mg++ for inhibition, alpha-amino-3-hydroxy-5-methyl-4-isoxalone propionic, but not kainate, stimulation of NOS was also inhibited by ethanol (100 mM).(ABSTRACT TRUNCATED AT 250 WORDS)
在大脑皮层培养物中研究了钙动员受体与一氧化氮（NO）生成的偶联。在测试的各种试剂中，只有谷氨酸、氯化钾去极化和钙离子载体离子霉素刺激一氧化氮合酶（NOS）活性。对谷氨酸反应的表征显示，离子型谷氨酸受体激动剂N-甲基-D-天冬氨酸（NMDA）、海人酸和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸均刺激NOS活性，相对最大效力为NMDA>海人酸>α-氨基-3-羟基-5-甲基-4-异恶唑丙酸。乙醇、Mg++和Zn++对NMDA刺激NOS产生浓度依赖性抑制。Mg++的抑制作用可通过增加NMDA浓度来逆转，而Zn++的抑制作用则不能。乙醇（100 mM）产生明显的竞争性抑制类型，如NMDA浓度-反应曲线平行右移所示。然而，乙醇抑制作用以浓度相关的方式依赖于Mg++和/或Zn++的存在。在没有Mg++和Zn++的情况下，100 mM乙醇不会显著抑制NMDA对NOS活性的刺激，而加入这些阳离子的组合会增加对乙醇的敏感性，使得100 mM乙醇完全阻断NMDA反应（IC50约为30 mM）。几种短链醇对NMDA刺激NOS的抑制效力遵循其疏水性特征，并且对Mg++的抑制作用表现出类似的依赖性，乙醇（100 mM）也抑制α-氨基-3-羟基-5-甲基-4-异恶唑丙酸对NOS的刺激，但不抑制海人酸的刺激。（摘要截短于250字）
