Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben Gurion University, Beer Sheva, Israel.
Anesth Analg. 2010 Dec;111(6):1497-504. doi: 10.1213/ANE.0b013e3181fc0112. Epub 2010 Nov 3.
Glutamate neurotoxicity is determined by the balance between glutamate release within the brain and efflux of excess glutamate from the brain. Brain-to-blood efflux of glutamate is increased by decreasing the concentration of glutamate in blood. Little is known about the effect of hyperthermia on blood glutamate concentrations, and the effectiveness of blood glutamate-decreasing mechanisms in these conditions. Although hyperthermia is hypothesized to decrease blood glutamate concentrations by activation of stress mechanisms, blunting the stress response by blocking β-adrenergic receptors should prevent this decrease. Furthermore, during hyperthermia there should be a concurrent process of leakage of glutamate from muscle tissue into blood, resulting in a contradictory increase of blood glutamate concentrations. In this study we investigated the effects of hyperthermia on blood glutamate levels and studied the effects of the β-adrenergic receptor antagonist propranolol on stress-induced changes in glutamate levels. We then studied the effectiveness of the blood glutamate scavenger oxaloacetate on hyperthermia-induced increases of glutamate levels.
Twenty-four rats were randomly divided into 3 groups. Rats' body temperatures were increased (by 1°C every 40 minutes) from 37°C to 42°C. The first group received 1 mL per 100 g of isotonic saline (control). The second group received 1 mL per 100 g of 1M oxaloacetate when the temperature reached 39°C. The third group received 10 mg/kg of propranolol before initiation of the warming.
Warming the rats from 37°C to 39°C decreased the blood glutamate levels in the control group (P < 0.01) and oxaloacetate treatment group (P < 0.0001), whereas further increases in temperature from 40°C to 42°C increased the blood glutamate levels (P < 0.01 and P < 0.0001, respectively). Pretreatment with propranolol prevented the decrease in blood glutamate concentrations seen in mild hyperthermia and did not affect the increase in blood glutamate levels seen at temperatures of 41°C and 42°C (P < 0.005).
The results of this study demonstrated that hyperthermia leads to decreases in glutamate levels in the blood, presumably by activation of the sympathetic nervous system. Oxaloacetate, previously reported to reduce blood glutamate levels at 37°C, was ineffective at temperatures over 40°C. Propranolol pretreatment blunted the initial decrease in blood glutamate, and thereafter had no effect when compared with control and treatment groups. Understanding the mechanisms underlying glutamate regulation in the blood during states of hyperthermia and stress has important clinical implications in treating neurodegenerative conditions.
谷氨酸神经毒性取决于脑内谷氨酸的释放平衡与脑内多余谷氨酸的流出。通过降低血液中谷氨酸的浓度，可以增加脑向血液的谷氨酸流出。关于高热对血液谷氨酸浓度的影响以及这些条件下降低血液谷氨酸机制的有效性，我们知之甚少。尽管高热通过激活应激机制被假设为降低血液谷氨酸浓度，但通过阻断β-肾上腺素能受体来钝化应激反应应该可以防止这种降低。此外，在高热期间，谷氨酸应该会从肌肉组织漏入血液，导致血液谷氨酸浓度出现相反的增加。在这项研究中，我们研究了高热对血液谷氨酸水平的影响，并研究了β-肾上腺素能受体拮抗剂普萘洛尔对谷氨酸水平应激诱导变化的影响。然后，我们研究了血液谷氨酸清除剂草酰乙酸对高热引起的谷氨酸水平升高的有效性。
24 只大鼠被随机分为 3 组。将大鼠体温从 37°C 升高（每 40 分钟升高 1°C）至 42°C。第一组接受 100g 体重 1mL 的等渗盐水（对照）。第二组在温度达到 39°C 时接受 1M 草酰乙酸 1mL。第三组在开始升温前给予 10mg/kg 普萘洛尔。
将大鼠从 37°C 升温至 39°C 会降低对照组（P < 0.01）和草酰乙酸处理组（P < 0.0001）的血液谷氨酸水平，而从 40°C 进一步升温至 42°C 会增加血液谷氨酸水平（P < 0.01 和 P < 0.0001，分别）。普萘洛尔预处理可防止轻度高热时血液谷氨酸浓度的降低，并且不影响 41°C 和 42°C 时血液谷氨酸水平的升高（P < 0.005）。
本研究结果表明，高热导致血液谷氨酸水平降低，推测是通过激活交感神经系统。先前报道在 37°C 时降低血液谷氨酸水平的草酰乙酸在 40°C 以上时无效。普萘洛尔预处理可减弱血液谷氨酸的初始降低，并且与对照组和处理组相比，此后无影响。了解高热和应激状态下血液中谷氨酸调节的机制在治疗神经退行性疾病方面具有重要的临床意义。
