Contribution of L-type Voltage Sensitive Ca^<2+> Channels to Mechanism of General Anesthesia

【体外实验】采用K^+诱发的神经递质（去甲肾上腺素[NA]、多巴胺和谷氨酸）从大鼠脑片释放模型，研究静脉麻醉药对电压敏感Ca^<2+>通道（VSCCs）的影响。首先，我们发现释放主要通过P/Q-VSCCs介导。其次，除氯胺酮外，静脉麻醉药物以浓度依赖的方式显著抑制释放。因此，这些麻醉剂可能抑制VSCC。然而，双管碱，一种GABA_A受体拮抗剂，逆转了静脉麻醉剂的抑制作用。因此，这些麻醉剂激活GABA_A受体可能会降低VSCC的活性。【体内】采用微透析方法，研究了全麻药物对脑区NA释放的影响。我们发现抑制NMDA受体的麻醉剂增加NA的释放，而激活GABA_A受体的麻醉剂则减少NA的释放。同时具有这两种特性的异氟醚减少了大脑皮层的释放，增加了下丘脑前部视前区的释放。由于诱导睡眠的NAergic神经元存在，NMDA拮抗剂如麻醉剂增加NA释放可能有助于激活诱导睡眠的NAergic神经元。相比之下，GABA_A激动剂如麻醉剂减少NA的释放可能导致觉醒诱导的NAergic神经元的抑制。

[In Vitro] We used model of K^+-evoked neurotransmitter (noradrebaline [NA], dopamine and glutamate) release from rat brain slices to study effects of iv anesthetic agents on voltage sensitive Ca^<2+> channels (VSCCs). First, we found that the release is mediated mainly via P/Q-VSCCs. Second, iv anesthetic agents except ketamine significantly inhibit the release in a concentration dependent manner. Thus, these anesthetic agents may inhibit VSCC.However, bicuculline, a GABA_A receptor antagonist, reversed the inhibitory effects of iv anesthetic agents. Therefore, it is likely that activation of GABA_A receptors by these anesthetic agents may reduce VSCC activities.[In Vivo] Using microdialysis method, we studied effects general anesthetic agents on NA release from several brain regions. We found that anesthetics inhibiting NMDA receptor increase NA release, whereas anesthetics activating GABA_A receptor reduce the release. Isoflurane that has both characters decreases the release in the cerebrocortex and increases in the preoptic area of anterior hypothalamus. As sleep-inducing NAergic neurons exist, increase in NA release by NMDA antagonist like anesthetics may contribute to activating sleep-inducing NAergic neurons. In contrast, decrease in NA release by GABA_A agonist like anesthetics may induces inhibition of wakefulness-inducing NAergic neurons.