RESUMEN
BACKGROUND: Abnormalities of the L-arginine-nitric oxide pathway induce hypertension. 5-Lipoxygenase (5-LO) is the key enzyme involved in synthesis of leukotrienes (LTs). However, whether nitricoxide synthase dysfunction induces hypertensive vascular remodeling by regulating 5-LO activity and its downstream inflammatory metabolites remains unknown. METHODS AND RESULTS: Six-week L-NAME treatment significantly induced hypertension and vascular remodeling in both wild-type (WT) and 5-LO-knockout (5-LO-KO) mice, and blood pressure in caudal and carotid arteries was lower in 5-LO-KO than WT mice with L-NAME exposure. On histology, L-NAME induced less media thickness, media-to-lumen ratio, and collagen deposition and fewer Ki-67-positive vascular smooth muscle cells (VSMCs) but more elastin expression in thoracic and mesenteric aortas of 5-LO-KO than L-NAME-treated WT mice. L-NAME significantly increased LT content, including LTB4 and cysteinyl LT (CysLTs), in plasma and neutrophil culture supernatants from WT mice. On immunohistochemistry, L-NAME promoted the colocalization of 5-LO and 5-LO-activating protein on the nuclear envelope of cultured neutrophils, which was accompanied by elevated LT content in culture supernatants. In addition, LTs significantly promoted BrdU incorporation, migration and phenotypic modulation in VSMCs. CONCLUSION: L-NAME may activate the 5-LO/LT pathway in immune cells, such as neutrophils, and promote the products of 5-LO metabolites, including LTB4 and CysLTs, which aggravate vascular remodeling in hypertension. 5-LO deficiency may protect against hypertension and vascular remodeling by reducing levels of 5-LO downstream inflammatory metabolites.
Asunto(s)
Araquidonato 5-Lipooxigenasa/genética , Hipertensión/prevención & control , Remodelación Vascular , Animales , Aorta/metabolismo , Aorta/patología , Araquidonato 5-Lipooxigenasa/deficiencia , Presión Sanguínea/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Hipertensión/inducido químicamente , Hipertensión/patología , Leucotrieno A4/sangre , Leucotrieno A4/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/citología , Músculo Liso Vascular/metabolismo , NG-Nitroarginina Metil Éster/metabolismo , NG-Nitroarginina Metil Éster/toxicidad , Neutrófilos/inmunología , Neutrófilos/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Ratas Sprague-Dawley , Remodelación Vascular/efectos de los fármacosRESUMEN
OBJECTIVE: To optimize the matrix formulation of compound Die Da Zhen Tong cataplasm. METHODS: The optimal preparation was selected by U17 (17(16)) uniform design, independent variables were the percentage ratio of the matrix formulation component part in compound Die Da Zhen Tong cataplasm,and the viscosity, continued viscosity and overall desirability used as indexes were dependent variables. RESULTS: The percentage of the matrix formulation component part in compound Die Da Zhen Tong cataplasm was, NP-700: carbomer 980: PVP K-90: dihydroxy aluminum: tartaric: kaolinite: sorbitol: glycerin = 5: 1. 2: 2.5: 0.25: 0.15:4: 12: 5. CONCLUSION: The optimized cataplasm has good viscosity, continued viscosity and high overall desirability.
