ABSTRACT
PURPOSE: To evaluate the ocular surface toxicity of two nitric oxide donors in ex vivo and in vivo animal models: S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylcysteine (SNAC) in a hydroxypropyl methylcellulose (HPMC) matrix at final concentrations 1.0 and 10.0 mM. METHODS: Ex vivo GSNO and SNAC toxicities were clinically and histologically analyzed using freshly excised pig eyeballs. In vivo experiments were performed with 20 albino rabbits which were randomized into 4 groups (5 animals each): Groups 1 and 2 received instillations of 150 µL of aqueous HPMC solution containing GSNO 1.0 and 10.0 mM, respectively, in one of the eyes; Groups 3 and 4 received instillations of 150 µL of aqueous HPMC solution-containing SNAC 1.0 and 10.0 mM, respectively, in one of the eyes. The contralateral eyes in each group received aqueous HPMC as a control. All animals underwent clinical evaluation on a slit lamp and the eyes were scored according to a modified Draize eye test and were histologically analyzed. RESULTS: Pig eyeballs showed no signs of perforation, erosion, corneal opacity or other gross damage. These findings were confirmed by histological analysis. There was no difference between control and treated rabbit eyes according to the Draize eye test score in all groups (p>0.05). All formulations showed a mean score under 1 and were classified as "non-irritating". There was no evidence of tissue toxicity in the histological analysis in all animals. CONCLUSION: Aqueous HPMC solutions containing GSNO and SNAC at concentrations up to 10.0 mM do not induce ocular irritation.
OBJETIVO: Avaliar a toxidade na superfície ocular de dois compostos doadores de óxido nítrico em modelos ex vivo e in vivo: S-nitrosoglutationa (GSNO) e S-nitroso-N-acetilcisteína (SNAC), em uma matriz de hidroxipropil metilcelulose (HPMC) nas concentrações finais de 1,0 and 10,0 mM. MÉTODOS: As toxicidades de GSNO e SNAC foram avaliadas clinicamente e histologicamente em modelo ex vivo usando globos oculares porcinos recém excisados. Experimentos in vivo foram realizados com 20 coelhos albinos que foram randomizados em 4 grupos (5 animais em cada): Os grupos 1 e 2 receberam instilações de 150 µL de solução aquosa de HPMC contendo GSNO 1,0 e 10,0 mM, respectivamente, em um dos olhos; Os grupos 3 e 4 receberam instilações de 150 µL de solução aquosa de HPMC contendo SNAC 1,0 and 10,0 mM, respectivamente, em um dos olhos. Os olhos contralaterias em cada grupo receberam solução aquosa de HPMC como controle. Todos os animais foram clinicamente avaliados em lâmpada de fenda e os olhos foram pontuados de acordo com o teste de Draize modificado e analisados histologicamente. RESULTADOS: Os globos oculares porcinos não apresentaram sinais de perfuração, erosão, opacidade da córnea ou outros danos graves. Esses resultados foram confirmados pela análise histológica. Não houve diferença entre os olhos dos coelhos tratados e controles de acordo com a pontuação do teste de Draize em todos os grupos (p>0,05). Todas as formulações apresentaram um escore médio menor do que 1 e foram classificadas como "não-irritantes". Não houve evidência de toxicidade tecidual nas análises histológicas em todos os animais. CONCLUSÃO: Soluções aquosas de HPMC contendo GSNO e SNAC em concentrações até 10,0 mM não induzem irritação ocular.
Subject(s)
Animals , Male , Rabbits , Acetylcysteine/analogs & derivatives , Eye/drug effects , Nitric Oxide Donors/toxicity , S-Nitrosoglutathione/toxicity , Acetylcysteine/administration & dosage , Acetylcysteine/toxicity , Dose-Response Relationship, Drug , Eye/pathology , Instillation, Drug , Nitric Oxide Donors/administration & dosage , Random Allocation , S-Nitrosoglutathione/administration & dosage , SwineABSTRACT
BACKGROUND: Steatosis is currently the most common chronic liver disease and it can aggravate ischemia-reperfusion (IR) lesions. We hypothesized that S-nitroso-N-acetylcysteine (SNAC), an NO donor component, can ameliorate cell damage from IR injury. In this paper, we report the effect of SNAC on liver IR in rats with normal livers compared to those with steatotic livers. METHODS: Thirty-four rats were divided into five groups: I (n=8), IR in normal liver; II (n=8), IR in normal liver with SNAC; III (n=9), IR in steatotic liver; IV (n=9), IR in steatotic liver with SNAC; and V (n=10), SHAN. Liver steatosis was achieved by administration of a protein-free diet. A SNAC solution was infused intraperitoneally for one hour, beginning 30 min. after partial (70 percent) liver ischemia. The volume of solution infused was 1 ml/100 g body weight. The animals were sacrificed four hours after reperfusion, and the liver and lung were removed for analysis. We assessed hepatic histology, mitochondrial respiration, oxidative stress (MDA), and pulmonary myeloperoxidase. RESULTS: All groups showed significant alterations compared with the group that received SHAN. The results from the steatotic SNAC group revealed a significant improvement in liver mitochondrial respiration and oxidative stress compared to the steatotic group without SNAC. No difference in myeloperoxidase was observed. Histological analysis revealed no difference between the non-steatotic groups. However, the SNAC groups showed less intraparenchymal hemorrhage than groups without SNAC (p=0.02). CONCLUSION: This study suggests that SNAC effectively protects against IR injury in the steatotic liver but not in the normal liver.