Bumetanide increases manganese accumulation in the brain of rats with liver damage

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• 作者：Sergio Montes^a ; ^{smontes@innn.edu.mx" class="auth_mail" title="E-mail the corresponding author} ; Armando Castro-Chá ; vez^b ; ^{armado_cruzazul@hotmail.com" class="auth_mail" title="E-mail the corresponding author} ; Circe Florian-Soto^b ; ^{circevi.floso@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Yessica Heras-Romero^c ; ^{sarehy@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Camilo Rí ; os^a ; ^{crios@correo.xoc.uam.mx" class="auth_mail" title="E-mail the corresponding author} ; Susana Rivera-Mancí ; a^b ; ¹ ; ^{syriverama@conacyt.mx" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Bumetanide (PubChem CID ; 2471) ; ammonium acetate (PubChem CID ; 517165) ; manganous chloride (PubChem CID ; 24480) ; glutamine (PubChem CID ; 5961)
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：5 March 2016
• 年：2016
• 卷：774
• 期：Complete
• 页码：127-134
• 全文大小：1063 K

文摘

Hepatic encephalopathy is a common complication in cases of liver damage; it results from several factors, including the accumulation of toxic substances in the brain, e.g. manganese, ammonia and glutamine. We have previously reported that manganese favors ammonia and glutamine accumulation in the brain of cirrhotic rats, and we suggested that such effect could be mediated by manganese-elicited activation of the NKCC1 (Na⁺/K⁺/2Cl^– cotransporter 1). To test this hypothesis, we used bumetanide, an NKCC1 blocker prescribed to treat ascites in cirrhotic patients; we expected that if NKCC1 was responsible for manganese-mediated ammonia buildup and the subsequent glutamine accumulation, bumetanide could counteract such effect and improve motor coordination. In addition, we considered essential to test the effect of bumetanide on manganese brain levels. We used a model of liver damage in rats, consisting in bile-duct ligation. Animals were exposed to manganese in the drinking water (1 mg/ml) for two weeks and ammonia in the food (20% w/w of ammonia acetate) during the second week after surgery. Bumetanide was administered intraperitoneally in the course of the ammonia treatment. We measured glutamine and manganese in three brain regions: frontal cortex, striatum and cerebellum. Bumetanide produced no effect on glutamine accumulation; however, because of bumetanide treatment, manganese was increased in the brain, and also the activity of gamma-glutamyl transferase in plasma; thus, we consider that the influence of bumetanide and similar diuretics on liver function and manganese homeostasis should be further studied.