ABSTRACT
This study aimed to investigate the mechanism of fluorofenidone (AKF-PD) in treating renal interstitial fibrosis in rats with unilateral urinary obstruction (UUO). Thirty-two male Sprague-Dawley rats were randomly divided into sham, UUO, UUO + enalapril, and UUO + AKF-PD groups. All rats, except sham, underwent left urethral obstruction surgery to establish the animal model. Rats were sacrificed 14 days after surgery, and serum was collected for renal function examination. Kidneys were collected to observe pathological changes. Immunohistochemistry was performed to assess collagen I (Col I) protein expression, and terminal deoxynucleotidyl transferase-mediated nick end-labeling staining to observe the apoptosis of renal tubular epithelial cells. The expression of Fas-associated death domain (FADD), apoptotic protease activating factor-1 (Apaf-1), and C/EBP homologous protein (CHOP) proteins was evaluated by immunohistochemistry and western blot analysis. AKF-PD showed no significant effect on renal function in UUO rats. The pathological changes were alleviated significantly after enalapril or AKF-PD treatment, but with no significant differences between the two groups. Col I protein was overexpressed in the UUO group, which was inhibited by both enalapril and AKF-PD. The number of apoptotic renal tubular epithelial cells was much higher in the UUO group, and AKF-PD significantly inhibited epithelial cells apoptosis. The expression of FADD, Apaf-1, and CHOP proteins was significantly upregulated in the UUO group and downregulated by enalapril and AKF-PD. In conclusion, AKF-PD improved renal interstitial fibrosis by inhibiting apoptosis of renal tubular epithelial cells in rats with UUO.
Subject(s)
Animals , Male , Pyridones/pharmacology , Ureteral Obstruction/pathology , Apoptosis/drug effects , Epithelial Cells/drug effects , Kidney Diseases/pathology , Pyridones/metabolism , Blood Urea Nitrogen , Fibrosis , Angiotensin-Converting Enzyme Inhibitors/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Enalapril/metabolism , Enalapril/pharmacology , Random Allocation , Rats, Sprague-Dawley , Creatinine/blood , Collagen Type I/drug effects , Collagen Type I/metabolism , Disease Models, Animal , Transcription Factor CHOP/drug effects , Apoptotic Protease-Activating Factor 1/drug effects , Apoptotic Protease-Activating Factor 1/metabolism , Fas-Associated Death Domain Protein/drug effects , Fas-Associated Death Domain Protein/metabolismABSTRACT
Inhibition of angiotensin converting enzyme(EC 3.4,15.1, ACE) in presence of captopril, lisinopril and enalapril were investigated in kidney, lung and serum of sheep using Hip-His-Leu(HHL) as substrate. The activity in kidney, lung and serum was inhibited at HHL concentration above 5 mM. The inhibitory constants (IC50) ranged between 5.6 nM for serum ACE with lisinopril and 70000 nM for renal ACE with enalapril while Ki ranged from 1.0 nM for serum ACE with lisinopril to 12000 nM for kidney ACE with enalapril. Differences in inhibition observed in different tissues suggest that the inhibitors may block function(s) of ACE to varying degrees in each tissue.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/metabolism , Animals , Captopril/metabolism , Enalapril/metabolism , Kidney/enzymology , Kinetics , Lisinopril/metabolism , Lung/enzymology , Oligopeptides , Peptidyl-Dipeptidase A/blood , SheepABSTRACT
Se estudia la eficacia del enalapril en una población de 29 hipertensos primarios que permanecían con presiones diastólicas iguales o superiores a 115 mmHg a pesar de terapia controlada con 3 ó 4 drogas de acuerdo al esquema clásico. La utilización de la droga en monoterpia simple de 40 mg diarios permitió normalizar al 31% de los casos. Asociada a hidroclorotiazida su eficacia fue de 65% y alcanzó al 89% con diltiazem como tercera droga. El objetivo terapéutico de la totalidad de los casos se logró utilizando pequeñas dosis de clonidina como cuarta droga (3 pacientes, 10,4%). Durante las 16 semanas de seguimiento la aceptación del medicamento fue óptima y no se demostró efectos adversos sobre glicemia, colesterol sérico, función renal, examen de orina, hemogiama, potasio plasmático y electrocardiograma de reposo