臺灣博碩士論文加值系統

研究顯示酒精的攝取會影響許多生理功能，尤其是對中樞神經系統和心血管系統。在急性過量攝取酒精(酒精中毒)的情況下，可能造成心血管功能失常，如低血壓、血管擴張與心動過速。許多研究也證實酒精會與神經傳遞物質、神經調節因子和細胞訊息分子相互作用，而導致酒精造成的生理或行為上的改變。但是，急性過量的酒精攝取影響心血管功能的機制卻尚未明確。本研究假設急性過量的攝取酒精，會透過影響中樞神經系統調節心血管功能的核區而產生降壓反應。並探討N-methyl-D-aspartate (NMDA) 受體、一氧化氮 (nitric oxide, NO)、γ-氨基丁酸 (γ-aminobutyric acid, GABA) 的訊息路徑及蛋白質激酶A (protein kinase A, PKA) 與蛋白質激酶C (protein kinase C, PKC) 訊息傳遞因子是否參與酒精所引起的心血管反應。
本實驗使用Sprague-Dawley (SD) 品系大鼠，腹腔注射酒精，在麻醉下測量血壓和心跳的變化。用微量注射的方式，將代謝型谷氨酸受體第五型(metabotropic glutamate receptor type 5, mGluR5)、NMDA受體、GABA受體、PKA或一氧化氮合成酶 (NO synthase)的抑制劑、注射進入腦室中(intracerebroventricular, ICV)、脊髓鞘內 (intrathecal)或前腹外側延腦核 (RVLM) 中。以及進行腦部微量透析，偵測前腹外側延腦核中的glutamate、NO和GABA的變化量。
研究結果發現，麻醉大鼠腹腔注射不同濃度 (20%和40%) 但劑量相同的酒精 (3.2 g/kg)，會產生血壓與心跳下降的反應。腦室內注射DL-AP5 (NMDA受體拮抗劑)，荷包牡丹鹼 (bicuculline ; GABA受體拮抗劑) 會減弱酒精產生的降壓作用，但此作用無法被MPEP (mGluR5拮抗劑)，KT5720 (PKA抑製劑) 影響。而KT5720或MPEP以鞘內注射到脊髓腔中，卻可以減弱酒精造成的降壓反應。RVLM給予氯胺酮 (ketamine ; NMDA受體拮抗劑)，N-nitro-L-Arginine (L-NNA ; NO合成酶抑製劑) 或bicuculline也能減弱酒精引發的低血壓作用。在微透析的研究結果，在酒精引發降血壓作用的期間，RVLM中glutamate，NO和GABA的量顯著升高。而RVLM注射ketamine會阻斷NO和GABA的量增加; RVLM 注射L-NNA則會阻斷GABA的量增加。由我們的研究結果推論，乙醇造成的降壓作用可能與乙醇增強RVLM中的glutamate釋放，進而透過NMDA受體/ NO / GABA訊息路徑影響RVLM神經元活性有關。此外，位於脊髓的交感節前神經元中的PKA以及mGluR5路徑亦可能參與酒精的降壓作用。

Background: Consumption of ethanol (alcohol) has many effects on physiological functions, particularly those in the central nervous system (CNS) and cardiovascular system. Acute excessive intake of ethanol (alcohol intoxication) may cause cardiovascular dysfunction, such as hypotension, vasodilation, and tachycardia. Many studies have revealed that ethanol interacts with variety neurotransmitters, neuromodulators or cellular signals, leading to physiological or behavioral changes caused by ethanol. However, the precise mechanisms by which acute excessive ethanol modulates cardiovascular function remain undefined. We hypothesized that the nucleus in CNS related to cardiovascular regulation may be affected by acute excessive ethanol, leading to hypotension. We examine the mechanistic involvement of glutamatergic NMDA receptors, nitric oxide (NO) and γ-aminobutyric acid (GABA) pathways, and the protein kinase A (PKA) and protein kinase C (PKC), in the CNS in acute ethanol-induced cardiovascular effects.

Methods: Ethanol was administered by intraperitoneal (IP) injection in Sprague Dawley (SD) rats. The blood pressure (BP) and heart rate (HR) were measured in urethane-anesthetized rats. Inhibitors of metabotropic glutamate receptor type 5 (mGluR5), NMDA receptor, GABA receptor, PKA or nitric oxide synthase (NOS) were applied by intracerebroventricular (ICV) injection, intrathecal injection or by microinjection into the RVLM. Microdialysis was used to determine the level of glutamate, NO, and GABA in the RVLM.

Results: IP injection of different concentration (20% (v/v) and 40% (v/v)) but same dose of ethanol (3.2 g/kg), caused a significant decrease in BP and HR in anesthetized rats. The ethanol-induced depressor effects of ethanol were significantly attenuated by ICV injection of DL-AP5 (an NMDA receptor antagonist), bicuculline (a GABA receptor antagonist) but not by MPEP (a mGluR5 antagonist) or KT5720 (a PKA inhibitor). The depressor effects of ethanol were attenuated when KT5720 or MPEP was applied intrathecally 5 min after ethanol injection. Post-treatment with ketamine (an NMDA receptor antagonist), L-NNA (a NO synthase inhibitor), or bicuculline into RVLM also reduced the hypotensive responses induced by ethanol. A microdialysis study showed that ethanol caused an increase in the level of glutamate, NO, and GABA in the RVLM during the hypotensive responses. RVLM post-treatment with ketamine blocked the increase in NO and GABA levels; post-treatment with L-NNA blocked the increase in GABA level.

Conclusions: Our results demonstrated that ethanol augmentation of glutamatergic NMDA receptors/NO/GABA pathways in the RVLM may participate in the hypotensive effects induced by acute administration of ethanol. In addition, PKA and mGluR5 signals in sympathetic preganglionic neurons in spinal cord may also be involved in ethanol hypotensive effects.

Table of Contents
ABSTRACT IN CHINESE 4
ABSTRACT 6
ABBREVIATIONS 8
1. General introduction 9
1.1 Acute ethanol intoxication (Alcohol intoxication) 9
1.2 Ethanol pharmacokinetic and the effects of ethanol in the brain 9
1.3 Ethanol effect on cardiovascular function and brain function 10
1.4 Cardiovascular and autonomic influences on blood pressure (BP) 11
1.5 Rostral ventrolateral medulla (RVLM) and control of blood pressure 12
1.6 The sympathetic preganglionic neurons (SPNs) 14
1.7 Neural transmission of glutamate and GABA 15
1.8 Nitric oxide and nitric oxide synthase 21
2. Purpose of the study 26
3. Materials and methods 27
3.1 Research process design 27
3.2 Animals 27
3.3 Intracerebroventricular cannula implantation 27
3.4 Intrathecal microinjection 28
3.5 RVLM microinjections 29
3.6 Blood pressure measurement 30
3.7 RVLM microdialysis 30
3.8 Determination of total NO metabolite levels 31
3.9 Determination of the level of glutamate and GABA 32
3.10 Determination of blood ethanol levels 32
3.11 Materials 33
3.12 Statistical analysis 34
4. Results 35
4.1 Acute ethanol exposure increased blood ethanol concentrations (BEC) to an intoxication level 35
4.2 High dose of ethanol-induced hypotensive and bradycardic effects in anesthetized rats. 35
4.3 Effect of blockade of NMDA receptors, mGluR5, protein kinase A and GABA receptors in CNS on ethanol-induced hypotensive effects 36
4.4 Blockade of NMDA receptors, NOS activity or GABA receptors but not PKA activity in RVLM attenuated the hypotensive effects of ethanol 37
4.5 Increased release of NOx, glutamate, and GABA in the RVLM following ethanol treatment 38
5. Discussion 40
5.1 Ethanol intoxication induced hypotension and bradycardia 40
5.2 The role of NMDA receptor, mGluR5, GABA receptor and PKA in the CNS in ethanol-induced hypotensive effects 43
5.3 The role of glutamate, NO and GABA in RVLM in ethanol-induced blood pressure effects 46
6. Conclusion 51
7. Recommendations for future research 52
FIGURE 1 71
FIGURE 2 72
FIGURE 3 74
FIGURE 4 75
FIGURE 5 76
FIGURE 6 77
FIGURE 7 78
FIGURE 8 79
FIGURE 9 80
FIGURE 10 81
FIGURE 11 82
FIGURE 12 84
FIGURE 13 85
FIGURE 14 86
FIGURE 15 88

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