| Summary: | 博士 === 慈濟大學 === 藥理暨毒理學碩士班/博士班 === 106 === 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.
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