Please use this identifier to cite or link to this item: http://repositorio.unifesp.br/11600/15366
Title: Vias metabólicas na degradação da bradicinina e influência de inibidores de cininases
Authors: Lindsey, Charles Julian [UNIFESP]
Houch, Jurema Maria Dalle Lucca [UNIFESP]
Keywords: Peptidil Dipeptidase A
Carboxipeptidases
Bradicinina
Issue Date: 1997
Publisher: Universidade Federal de São Paulo (UNIFESP)
Citation: HOUCH, Jurema Maria Dalle Lucca. Vias metabólicas na degradação da bradicinina e influência de inibidores de cininases. Dissertação (Mestrado em Ciências) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 1997.
Abstract: A contribuicao de diferentes atividades cininasicas no metabolismo da bradicinina na circulacao arterial foi avaliada na preparacao de leito vascular mesenterico de rato. Os peptideos bradicinina (BK1-9), BK1-8 e BK1-7 foram injetados na preparacao na presenca e ausencia de inibidores de cininases e os produtos de degradacao analisados por HPLC. A potenciacao do efeito vasodilatador da bradicinina por inibidores de cininases foi tambem estudada nesta preparacao. Os resultados mostraram que 30% da bradicinina foram metabolizadas apos passagem pelo leito vascular mesenterico, sendo BK1-7, BK1-5 e BK1-8 os principais produtos gerados. O inibidor da enzima conversora de angiotensina, enalaprilato, inibiu a formacao de BK1-7 e BK1-5 e aumentou a recuperacao de BK1-8. O inibidor da carboxipeptidase M, MGTA, reduziu a formacao de BK1-8. Phosphoramidon, inibidor da endopeptidase neutra 24.11, reduziu fortemente a recuperacao de BK1-7. A recuperacao de BK1-5 e BK1-8 foi altamente dependente do pH diminuindo com o aumento do mesmo. A administracao prolongada do inibidor da ECA, ramipril, levou a um aumento significativo das atividades AmP/DAPIV na circulacao pulmonar de ratos. Nossos resultados mostram que as principais cininases ativas no catabolismo da bradicinina no leito vascular mesenterico sao NEP, ECA e carboxipeptidase M, que agem na porcao C-terminal da molecula. Alem disso, nossos resultados mostram tambem que a inibicao cronica da atividade da ECA leva a uma estimulacao da atividade de outras cininases na circulacao pulmonar, evidenciando a necessidade do desenvolvimento de inibidores de outras cininases para o uso clinico no tratamento de doencas cardiovasculares
The contribution of different kininases to the degradation of bradykinin in the arterial circulation was evaluated by examining bradykinin metabolism in the rat mesenteric vascular bed preparation. The peptides bradykinin (BK1-9), BK1-8 and BK1-7 were injected into the preparation in the presence and absence of kininase inhibitors and HPLC was used to analyse the breakdown products. The potentiation of the vasodilatory effect of bradykinin by kininase inhibitors was also estimated in this preparation. Our results show that approximately 30% of bradykinin was metabolized by passage through the mesenteric vascular bed and the main products detected were BK1-7, BK1-5 and BK1-8. Enalaprilat, an inhibitor of kininase II, inhibited the formation of BK1-7 and BK1-5 and increased the recovery of BK1-8. The carboxypeptidase M inhibitor, MGTA, reduced the recovery of BK1-8. Phosphoramidon, an inhibitor of the neutral endopeptidase (EP24.11), strongly reduced the recovery of BK1-7. The recovery of BK1-5 and BK1-8 were increased at pH 7.2 with respect to pH 7.4 or 7.8. Experiments in the perfused mesenteric artery showed that the kininase inhibitors phosphoramidon, MGTA and enalaprilat added to the perfusion medium caused 4-5 fold potentiation of the vascular effect of bradykinin. Chronic inhibition of kininase II with ramipril caused a significant increase in the activity of AmP/DAPIV in the rat pulmonar circulation. Our results show that the main kininases active in bradykinin catabolism in the mesenteric vascular bed are NEP, kininase II and carboxypeptidase M, which act on the C-terminus of bradykinin. Furthermore, our results also show that chronic inhibition of ACE activity leads to a stimulation of other kininase activities in the pulmonary circulation, pointing to the importance of development of mixed inhibitors for the treatment of cardiovascular diseases.
URI: http://repositorio.unifesp.br/handle/11600/15366
Appears in Collections:Dissertação de mestrado

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