Oxidative and nitrosative stress contribute to ammonia-induced astrocytic dysfunction and swelling, the primary causes of lethal brain edema associated with hepatic encephalopathy (HE). Treatment of cultured astrocytes with 5 mmol/L ammonium chloride (“ammonia”) increased the production of reactive oxygen species (ROS), including the NADPH oxidase reaction product, .O2-. Atrial natriuretic peptide (ANP), natriuretic peptide C (CNP) and a selective NPR-C ligand, cANP(4-23), each decreased formation of ROS measured as the sum of different species both in control cells and cells treated with ammonia. However, attenuation of .O2- by ANP and cANP(4-23) was observed in ammonia-treated cells only. In contrast to ANP, cANP(4-23) did not elevate the cGMP content in astrocytes, indicating the absence of its interaction with the NPR-A or NPR-B receptors, which are coupled to guanylate cyclase activity. However, cANP(4-23) decreased cAMP content and reduced the expression of Giα-2, the NADPH oxidase-regulatory protein. The results show the presence of functional NPR-C in astrocytes, activation of which i) attenuates basal ROS production, ii) prevents excessive accumulation of the toxic ROS species, .O2- by ammonia. Ammonia, ANP and cANP(4-23) added separately, each stimulated formation of NO (nitrates+nitrites). However, the effect of ammonia on NO was not augmented by co-addition of ANP, and was reduced to the control level by co-addition of cANP(4-23), indicating that activation of NPR-C may also reduce nitrosative stress. Preliminary results indicate that cANP(4-23) attenuates ammonia-induced cell volume increase of astrocytes, which indicates the potential future use of cANP(4-23) or other NPR-C agonists in HE therapy. Supported by Ministry of Science and Education grants S005/PN/2007/01 (JA) and NN 401 0550 33 (MZ)
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