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- ItemEmbargoAlterações testiculares causadas por antagonista de receptores H2 (cimetidina) e efeito benéfico da vitamina B12 sobre o epitélio seminífero de ratos adultos(Universidade Federal de São Paulo (UNIFESP), 2014) Beltrame, Flavia Luciana [UNIFESP]; Cerri, Estela Sasso [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Introdução: A cimetidina, um antagonista de receptores H2 utilizado no tratamento de ulceras gastricas, parece interferir na absorcao de vitamina B12. Em pacientes do sexo masculino, este farmaco apresenta uma acao antiandrogenica e, em testiculos de ratos adultos, causa alteracoes nos tubulos seminiferos, incluindo as celulas germinativas, celulas de Sertoli e celulas mioides peritubulares. Objetivos: Considerando a presenca de receptores H2 e de androgenos (AR) nos vasos sanguineos, foi proposto avaliar se o tratamento com cimetidina causa alteracoes estruturais na microvascularizacao testicular. Com base nos resultados deste estudo, um segundo estudo foi realizado a fim de verificar se as alteracoes vasculares poderiam estar relacionadas a possiveis danos estruturais e funcionais nas celulas de Leydig (CL). Em um terceiro e quarto estudos, foi proposto confirmar se a cimetidina promove defiCiência de vitamina B12 em ratos adultos. Alem disso, foi proposto verificar se as alteracoes causadas pela cimetidina no epitelio seminifero sao amenizadas pela suplementacao com esta vitamina. Material e metodos: Ratos adultos receberam, durante 50 dias, injecoes intraperitoneais de cimetidina (GCMT), cimetidina e vitamina B12 (GCMT/B12), vitamina B12 (GB12) e solucao salina (GC). Os testiculos foram processados para analises ao microscopio de luz e eletronico de transmissao (MET). A fim de avaliar o efeito da cimetidina na microvascularizacao testicular, cortes foram submetidos ao metodo do PAS, e a densidade microvascular (MVD) e a area da luz vascular (ALV) foram obtidas. Para avaliar o efeito do tratamento nas celulas de Leydig, foi realizada a dosagem das concentracoes sericas de testosterona, e os cortes testiculares foram submetidos ao metodo do TUNEL e a reacoes imuno-histoquimicas (IH) para deteccao de: 1) caspase-3; 2) 17β-HSD6 (para quantificacao das CL); 3) 17β-HSD6+TUNEL (para verificar CL em processo de morte celular); 4) CD163 (para deteccao de macrofagos residentes u ED2); 5) CD163+TUNEL e 17β-HSD6+ED2 (para verificar atividade fagocitica dos macrofagos ED2); 6) PK-1 (para analisar a expressao de EG-VEGF); 7) p65 (para analisar a expressao de NF-κB) e 8) AR. A fim de verificar se a cimetidina causa defiCiência de vitamina B12 nos ratos, e se as alteracoes causadas por este farmaco sao amenizadas pelo suplemento com esta vitamina, foram analisados os seguintes parametros: 1) concentracoes plasmaticas de vitamina B12 (Vit B12) e homocisteina total (Hcy); 2) IHC para deteccao de PCNA (antigeno nuclear de proliferacao celular); 3) numero de celulas de Sertoli (CS); 4) frequencia de tubulos com nucleos de CS e de celulas germinativas na luz tubular; 5) frequencia de tubulos em estagios especificos do ciclo do epitelio seminifero e 6) numero de espermatogonias e espermatocitos. Resultados e conclusoes: No tecido intersticial, foi observada uma reducao significante na MVD e na ALV, indicando atrofia vascular. A presenca de celulas vasculares positivas ao metodo do TUNEL e as caracteristicas ultraestruturais confirmaram a morte destas celulas por apoptose. Os niveis plasmaticos de testosterona diminuiram significantemente no GCMT, em comparacao ao GC. Alem disso, foram observadas celulas intersticiais positivas a caspase-3, bem como uma significante diminuicao no numero de CL positivas a 17β-HSD6. A presenca de celulas positivas a 17β-HSD6+TUNEL indicaram apoptose, a qual foi confirmada pela MET. No GCMT, as CL tambem apresentaram uma intensa imunoexpressao citoplasmatica de NF-κB e uma menor expressao de AR. Estes resultados sugerem uma possivel interferencia da cimetidina na translocacao deste fator para o nucleo. A imunoexpressao de EG-VEGF nas CL tambem reduziu no GCMT. Portanto, as alteracoes funcionais e apoptose nestas celulas podem ser, pelo menos em parte, responsaveis pelas alteracoes vasculares causadas pela cimetidina. As dosagens de Vit B12 e Hcy, nos animais do GCMT, nao revelaram nenhuma diferenca entre os grupos GC e GCMT, indicando que a cimetidina nao foi capaz de causar defiCiência de vitamina B12 nos ratos. O estudo sobre o efeito da vitamina B12 nos tubulos seminiferos dos animais tratados com cimetidina mostrou uma reducao significante na area tubular, bem como no numero de celulas de Sertoli, de espermatogonias e de espermatocitos. Entretanto, a suplementacao vitaminica foi capaz de amenizar tais alteracoes nos animais tratados. Este efeito deve-se ao aumento no numero de CS e espermatogonias nos animais do GCMT/B12, em comparacao ao GCMT, e indica que a vitamina B12 estimula o processo mitotico (fase de sintese) destas celulas
- ItemEmbargoAvaliação morfológica e morfométrica do epitélio seminífero e da vascularização testicular de ratos tratados com cimetidina e suplementados com vitamina B12(Universidade Federal de São Paulo (UNIFESP), 2009-08-26) Beltrame, Flavia Luciana [UNIFESP]; Sasso-Cerri, Estela [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Introduction: Cimetidine, an H2 receptor antagonist used for treatment of gastric ulcer, reduces the acid secretion and interferes in the vitamin B12 absorption. Studies in male patients revealed that cimetidine is an antiandrogenic drug; some authors have demonstrated that this drug also exerts a potent antiangiogenic action. In the male genital tract of rats, cimetidine cause testicular alterations, mainly in the seminiferous tubules and interstitial vascularization. Objectives: Regarding the important role of vitamin B12 for testicular function, the aim of the present study was to verify if the testicular alterations caused by cimetidine are attenuated by vitamin B12. In addition, the main cause of the vascular alterations and a possible interference of cimetidine on Leydig cells were also investigated. Material and methods: Twenty adult male rats were divided into four groups: Cimetidine (CMTG), Cimetidine/vitamin B12 (CMT/B12G), vitamin B12 (B12G) and Control (CG). The animals from CMTG received daily intraperitoneal injections of cimetidine (100 mg/kg b.w.) for 50 days. The animals from CMT/B12G received doses of solution containing cimetidine (100mg/Kg) and 3ìg of vitamin B12. The animals from B12G received doses of 3ìg of vitamin B12 and the animals from CG received doses of saline solution. The right and left testes were removed, fixed in 4% formaldehyde (pH 7.2) and Bouin liquid, respectively, and processed for embedding in historesin and parafin. The historesin sections were stained with Hematoxylin and Eosin (HE) for morphological analysis and submitted for Periodic-Acid Schiff (PAS) method for the following morphometrical analyses: areas of both seminiferous tubule and epithelium, number of blood vessels/mm2 of testicular tissue and area of vascular luminal area. The paraffin sections were submitted to TUNEL method for detection of vascular cell death. With the aim to verify the vascular alterations as well as the ultrastructural aspects of Leydig cells, some testicular fragments were processed for analysis under transmission electron microscope (TEM). Results: In the testes of all animals from CMTG, seminiferous tubules apparently reduced and irregularly outlined were usually observed; in these tubules, the germ cell layers were disorganized. In the interstitial tissue, collapsed blood vessels and TUNEL-labeled vascular cells were usually observed. Adjacent to these altered vessels, TUNEL-positive interstitial cells, probably Leydig cells, were also found. The morphometric results revealed, in CMTG, a significant reduction in the epithelial and total tubular areas as well as in the number of blood vessels and in the vascular luminal area. Moreover, a significant increase in the collapsed blood vessels was observed in this group. In CMT/B12G, both tubular and epithelial areas were not changed. Although the vascular luminal area was significantly reduced in this group, the number of blood vessels was unaltered, in comparison to CG. Additionally, the vitamin supplement reduced the frequency of collapsed blood vessels. The analysis of CMTG under TEM revealed endothelial and vascular muscle cells with irregular nuclei, condensed chromatin in the nuclear periphery and nuclear fragments with strong eletrondensity, suggesting apoptosis. Adjacent to these altered vessels, Leydig cells with apoptotic features were also observed. Conclusions: The results revealed that vitamin B12 plays an efficient role on the spermatogenic process and avoids the alterations caused by cimetidine on the seminiferous tubules. Cimetidine interferes significantly in the testicular vascularization, leading to vascular atrophy and reduction in the number of blood vessels. These alterations are due to endotheliocytes and vascular muscle cells apoptosis. In the animals from CMT/B12G, the vitamin supplement was not able to avoid cimetidine action on the vascular luminal area. However, the total number of vessels was not affected, suggesting that vascular alterations were attenuated by vitamin supplement, possibly due to its angiogenic action. Leydig cells were also affected by the treatment with cimetidine and undergo apoptosis. The presence of apoptotic Leydig cells adjacent to altered blood vessels suggests that vascular atrophy can be due to the interference of cimetidine on Leydig cells.
- ItemSomente MetadadadosEfeito da cimetidina sobre a espermatogênese de ratos albinos tratados na fase intra-uterina(Universidade Federal de São Paulo (UNIFESP), 2005) Braga, Alessandra Tobias [UNIFESP]; Miraglia, Sandra Maria [UNIFESP]
- ItemSomente MetadadadosEstudo morfológico e morfométrico de testículo de ratos sob efeito antiandrogênico da cimetidina(Universidade Federal de São Paulo (UNIFESP), 1995) Cerri, Estela Sasso [UNIFESP]; Hayashi, Hisakazu [UNIFESP]
- ItemAcesso aberto (Open Access)Interferência da cimetidina na histofisiologia androgênica de epidídimos de ratos(Universidade Federal de São Paulo (UNIFESP), 2017-03-29) Santi, Fabiane de [UNIFESP]; Cerri, Estela Sasso [UNIFESP]; http://lattes.cnpq.br/4455630076841302; http://lattes.cnpq.br/6811833354624192; Universidade Federal de São Paulo (UNIFESP)Hormonal disorders and changes in the reproductive tract have been related to antiandrogenic effect of cimetidine. Thus, androgen-dependent structural and functional parameters of epididymis were investigated. Male rats received 100mg/kg cimetidine (CMTG) or saline (CG) for 50 days, and the epididymal cauda region was processed for light and transmission electron microscopy. Epididymal duct diameter and stromal collagen were evaluated. TUNEL-labeled epithelial cells, and AR, KPNA and SHBG immunolocalization were analyzed. In CMTG, the duct diameter reduced and a high number of TUNEL-labeled cells was associated to apoptotic features. In the epithelium, a weak/absent AR nuclear immunofluorescence was observed in contrast to enhanced AR-immunolabeled cytoplasm and reduced KPNA immunoreactivity. The collagen and SHBG levels reduced in the stroma. Cimetidine induced epithelial androgenic dysfunction due to impairment of AR nuclear import. These changes may be result of androgen unavailability in the stroma and/or to a direct cimetidine antiandrogenic effect on epithelial cells.
- ItemSomente MetadadadosMorfologia comparativa da mucosa gástrica do rato albino no início da recuperação da cirurgia, sob efeito da pentagastrina, cimetidina e etanol(Universidade Federal de São Paulo (UNIFESP), 1996) Giovanoni, Marisa [UNIFESP]; Hayashi, Hisakazu [UNIFESP]