PATHOGENESIS OF HEPATIC COMA

拟议的研究重点是氨作为神经系统疾病的主要原因。 急性和慢性肝病引起的并发症。 我们的假设 是患病肝脏不能从循环中清除氨 导致中枢神经系统神经递质（乙酰胆碱、谷氨酸、GABA）异常 功能、能量代谢和还原当量的细胞内转运 通过苹果酸-天冬氨酸穿梭从细胞质到胞浆。 进一步 提出，随着时间的推移，高氨血症导致蛋白质周转抑制 在脑中，血脑屏障功能异常， 大脑对氨，缺氧和其他叠加的“敏感性”增加 代谢应激 氨对这些重要的神经化学物质的干扰 过程被认为是引起典型的神经病理学图片， 慢性肝性脑病 为了验证这些假设，我们选择了一个 多方面的方法：1）检查脑摄取和代谢的 门腔静脉分流大鼠和患者中的13 N-氨和13 N-氨基酸 肝病; 2）确定急性和慢性 高氨血症，伴或不伴叠加缺氧或氨负荷， 脑血流量、氧化能量偶联、碳水化合物代谢，以及 乙酰胆碱周转; 3）阐明α-酮戊二酸和 与实验性肝昏迷症状相关的其他α-酮酸; 和4）评估慢性门体分流的影响， 高氨血症对脑中蛋白质合成和降解速率的影响， 血脑屏障对氨基酸和其他物质的渗透性。 它 预计这些调查将澄清 氨引起神经毒性，并将建议更有效的方法来预防 这种毒性在肝病患者中。

The proposed research focuses upon ammonia as a prime cause of the neurological complications arising from both acute and chronic liver desease. Our hypothesis is that failure of the diseased liver to remove ammonia from the circulation causes CNS abnormalities of neurotransmitter (acetylcholine, glutamate, GABA) function, energy metabolism, and intracellular transport of reduced equivalents from cytoplasm to mitochondrion via the malate-aspartate shuttle. It is further proposed that, with time, hyperammonemia leads to inhibition of protein turnover in brain, abnormalities of blood-brain barrier function, and the development of an increased cerebral "sensitivity" to ammonia, hypoxia, and other superimposed metabolic stresses. Interference by ammonia with these vital neurochemical processes is believed to give rise to the typical neuropathological picture of chronic hepatic encephalopathy. To test these hypotheses, we have chosen a multifaceted approach: 1) To examine the cerebral uptake and metabolism of 13N-ammonia and 13N-amino acids in rats with portacaval shunts and in patients with liver disease; 2) To determine the effect of acute and chronic hyperammonemia, with and without superimposed hypoxia or ammonia loading, upon cerebral blood flow, oxidative energy coupling, carbohydrate metabolism, and acetylcholine turnover; 3) To clarify the role of alpha-ketoglutaramate and of other alpha-keto acids in relation to the symptoms of experimental hepatic coma; and 4) To assess the effects of chronic portal-systemic shunting and hyperammonemia on the rates of protein synthesis and degradation in brain and on the permeability of the blood-brain barrier to amino acids and other agents. It is anticipated that these investigations will clarify the mechanisms by which ammonia causes neurotoxicity and will suggest more effective methods to prevent this toxicity in patients with liver disease.