OBJECTIVEMatrine has an anti-fibrosis effect, such as hepatic cirrhosis and derma fibrosis, while its effect on glomerulosclerosis is unknown. The purpose of this study was to analyze the renoprotective effects of matrine on experimental glomerulosclerosis in rats and inquire into its mechanisms.

METHODSThe rats were randomly assigned to following groups: normal control group, model control group, benazepril treatment group, matrine 100 mg/kg treatment group and matrine 50 mg/kg treatment group. The rats of normal control group were subjected to sham operation and were injected with normal saline via the tail vein one week later. The rats of the other groups were uninephrectomized and injected with adriamycin (5 mg/kg) via the tail vein one week later. The dose of benazepril was 6 mg/kg. Both matrine and benazepril were given by gastric perfusion from the first day after the operation. The level of urinary protein was measured at the 2nd, 4th and 6th week after the operation. The serum total protein and albumin, serum creatinine, blood urea nitrogen (BUN) were tested only at the 6th week after operation. Renal pathology changes were evaluated at the 6th week as well. Immunohistochemistry was used to detect the expression of fibronectin (FN), laminin (LN), connective tissue growth factor (CTGF) and transforming growth factor-beta1 (TGF-beta1) in glomeruli.

RESULTSMatrine and benazepril not only reduced the excretion of urinary protein and the level of serum creatinine and BUN, but also significantly ameliorated glomerular mesangial proliferation and glomerular sclerosis (P < 0.05, respectively). Immunohistochemical staining indicated that there was an increasing FN, LN, CTGF and TGF-beta1 expression in model control group as compared to the three treatment groups (P < 0.05). Matrine 100 mg/kg treatment group and benazepril treatment group showed much more advantages than matrine 50 mg/kg treatment group (P < 0.05), but there was no significant difference between the former two groups (P > 0.05).

CONCLUSIONMatrine has a renoprotective effect on experimental glomerulosclerosis in rats, the possible mechanism might relate to the reduction of the TGF-beta1 negative function via CTGF, which will inhibit the activation and proliferation of glomerular intrinsic cells, decrease the secretion of ECM accordingly.

Alkaloids ; pharmacology ; Animals ; Benzazepines ; pharmacology ; Kidney ; drug effects ; Kidney Diseases ; prevention & control ; Kidney Glomerulus ; drug effects ; Protective Agents ; pharmacology ; Quinolizines ; pharmacology ; Rats ; Renal Agents ; pharmacology

OBJECTIVETo study the effect of peroxisome proliferator activated receptor γ (PPAR-γ) agonist on the angiotensin converting enzyme 2 (ACE2) mRNA expression in monocyte-derived macrophages of essential hypertensive patients.

METHODSTotally 57 essential hypertensive patients were randomly divided into three groups: conventional treatment group (n=18), telmisartan group (n=19), and benazepril group (n=20); 20 patients with normal blood pressure were also selected as the control group. Monocyte-derived macrophages were isolated from blood samples of patients in all four groups. The expression of ACE2 mRNA in monocyte-derived macrophages was detected by RT-PCR before treatment and 4 and 12 weeks after treatment.

RESULTSFour and 12 weeks after treatment, the systolic pressure and diastolic pressure of telmisartan group and benazepril group were significantly lower than that of the conventional treatment group (all P<0.01), and the systolic pressure and diastolic pressure of telmisartan group were significantly lower than that of the benazepril group(both P<0.01) .The expression of ACE2 mRNA in monocyte-derived macrophages were significantly lower in essential hypertensive patients than that in control group (P<0.01). After having been treated for 4 weeks and 12 weeks, the expression of ACE2 mRNA in monocyte-derived macrophages of hypertensive patients in telmisartan and benazepril groups were significantly higher than that in conventional treatment group (all P<0.01), and the expression of ACE2 mRNA in telmisartan group was significantly higher than that in benazepril group (both P<0.01).

CONCLUSIONPPAR-γ agonist could increase the ACE2 mRNA expression in monocyte-derived macrophages of essential hypertensive patients.

Aged ; Benzazepines ; pharmacology ; Benzimidazoles ; pharmacology ; Benzoates ; pharmacology ; Female ; Humans ; Hypertension ; drug therapy ; enzymology ; Macrophages ; enzymology ; Male ; Middle Aged ; PPAR gamma ; agonists ; Peptidyl-Dipeptidase A ; genetics ; metabolism ; RNA, Messenger ; genetics

OBJECTIVES: Investigate the influence of benazepril and amlodipine on the expression of secretin (PZ) and somatostatin (SS) in spontaneously hypertensive rats (SHR). METHODS: Forty-five SHRs (14 weeks old, male) were randomly assigned into 3 groups (=15):SHR group, Benazepril group (which was given benazepril 0.90 mg·kg·d) and Amlodipine group (SHRs were given amlodipine 0.45 mg· kg·d), taking WistarKyoto(WKY) as normal control (=15), meanwhile, rats in SHR group and WKY group were given the same volume of distilled water. After 8 weeks of intervention, the expression of protein and mRNA of PZ in duodenum and SS in sinuses ventriculi was detected by enzyme-linked immunoassay and RT-PCR. RESULTS: After 8 weeks of intervention, compared with the WKY group, the expression of protein and mRNA of PZ in duodenum and SS in sinuses ventriculi was increased significantly in SHR group (<0. 05). Compared with SHR group, the expression of PZ in duodenum and SS in sinuses ventriculi was decreased significantly in Benazepril group and Amlodipine group (<0.05). Compared with Benazepril group, in Amlodipine group the expression of PZ mRNA in duodenum and SS mRNA in sinuses ventriculi was decreased more significantly (<0.05). CONCLUSIONS The regulation disorder of PZ in duodenum and SS in sinuses ventriculi exists in SHR. The antihypertensive effect of benazepril and amlodipine may be realized by regulating the expression of PZ and SS, while the regulation of amlodipine is more obvious than benazepril.
Amlodipine ; pharmacology ; Animals ; Antihypertensive Agents ; pharmacology ; Benzazepines ; pharmacology ; Blood Pressure ; Hypertension ; drug therapy ; Male ; Random Allocation ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Secretin ; metabolism ; Somatostatin ; metabolism

To explore the role of D(1)-dopamine receptor in the modulation of basic respiratory rhythm, neonatal (0-3 d) Sprague-Dawley rats of either sex were used. The medulla oblongata slice was prepared and the surgical procedure was performed in the modified Kreb's solution (MKS) with continuous ventilating 95% O2 and 5% CO2 and ended in 3 min. A 600-700 mum single transverse slice containing the hypoglossal nerve roots and some parts of the ventral respiratory group was cut. The preparation was quickly transferred to a recording chamber and continuously perfused with oxygen-saturated MKS at a rate of 4-6 mL/min at 27-29 degrees C. Ten medulla oblongata slice preparations were randomly divided into two groups. In group I, the preparations were perfused with perfusion solution containing D(1)-dopamine receptor specific agonist cis-(+/-)-1-(Aminomethyl)-3,4-dihydro-3-phenyl-1H-2-Benzopyran-5,6-Diolhy-drochlo-ride (A68930, 5 mumol/L) for 10 min first; after washing out, the preparations were then perfused with perfusion solution containing D(1)-dopamine receptor specific antagonist R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390, 2 mumol/L) for 10 min. In group II, after perfusion with A68930 for 10 min, the preparations were perfused with additional A68930 + SCH-23390 for 10 min. Respiratory rhythmical discharge activity (RRDA) of the rootlets of hypoglossal nerve was recorded by suction electrodes. The results showed that A68930 shortened the respiratory cycle (RC) and expiratory time (TE) with an increase in the integral amplitude (IA). However, SCH-23390 significantly prolonged RC and TE, and decreased IA with a decrease in inspiratory time (TI). Moreover, the effect of A68930 on the respiratory rhythm was partially reversed by additional application of A68930 + SCH-23390. These results indicate that D(1)-dopamine receptor is possibly involved in the modulation of the RRDA in the isolated neonatal rat brainstem slice.
Animals ; Animals, Newborn ; Benzazepines ; pharmacology ; Biological Clocks ; Chromans ; pharmacology ; Female ; In Vitro Techniques ; Male ; Medulla Oblongata ; physiology ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine ; physiology ; Respiration

Neuropeptide Y (NPY) receptors are present in cardiac membranes. However, its physiological roles in the heart are not clear. The aim of this study was to define the direct effects of pancreatic polypeptide (PP) on atrial dynamics and atrial natriuretic peptide (ANP) release in perfused beating atria. Pancreatic polypeptides, a NPY Y4 receptor agonist, decreased atrial contractility but was not dose-dependent. The ANP release was stimulated by PP in a dose-dependent manner. GR 23118, a NPY Y4 receptor agonist, also increased the ANP release and the potency was greater than PP. In contrast, peptide YY (3-36) (PYY), an NPY Y2 receptor agonist, suppressed the release of ANP with positive inotropy. NPY, an agonist for Y1, 2, 5 receptor, did not cause any significant changes. The pretreatment of NPY (18-36), an antagonist for NPY Y3 receptor, markedly attenuated the stimulation of ANP release by PP but did not affect the suppression of ANP release by PYY. BIIE0246, an antagonist for NPY Y2 receptor, attenuated the suppression of ANP release by PYY. The responsiveness of atrial contractility to PP or PYY was not affected by either of the antagonists. These results suggest that NPY Y4 and Y2 receptor differently regulate the release of atrial ANP.
Animals ; Arginine/analogs & derivatives/pharmacology ; Atrial Natriuretic Factor/*metabolism ; Benzazepines/pharmacology ; Gene Expression Regulation ; Pancreatic Polypeptide/pharmacology ; Peptide YY/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Neuropeptide Y/agonists/antagonists & inhibitors/*metabolism

Neuropeptide Y (NPY), a sympathetic neurotransmitter, is highly associated with baroreflex dysfunction and multiple cardiac diseases such as diabetic myocardiopathy. In the present study, we aimed to explore the role of peripheral NPY Y1 receptor (Y1R) and Y2 receptor (Y2R), which are dominantly present in peripheral cardiovascular control, in baroreflex sensitivity (BRS) of streptozotocin (STZ)-induced diabetic rats. Peripheral Y1R and Y2R were antagonized by specific antagonists (BIBP 3226 and BIIE 0246, respectively) from subcutaneously implanted ALZET mini-osmotic pump in STZ-induced diabetic rats for 4 weeks. Then baseline systolic blood pressure, heart rate, cardiac function, BRS, plasma NPY and lipid levels were evaluated. We found that STZ led to increased plasma NPY and lipid level. And the STZ-increased lipid levels were reduced by BIBP 3226 and BIIE 0246. BIBP 3226 ameliorated the aberrant BRS, but had little effect on the impaired cardiac function of the STZ rats. BIIE 0246 alleviated sodium nitroprusside (SNP)-induced but not phenylephrine (PE)-induced aberrant baroreflex control of heart rate in the STZ rats. In addition, BIIE 0246 alleviated the bradycardia, but further impaired cardiac contractility in the STZ rats. These results suggest that peripheral Y1R and Y2R play different roles in STZ-induced impairment of BRS.
Animals ; Arginine ; analogs & derivatives ; pharmacology ; Baroreflex ; Benzazepines ; pharmacology ; Blood Pressure ; Bradycardia ; Diabetes Mellitus, Experimental ; drug therapy ; physiopathology ; Heart Rate ; Myocardial Contraction ; Neuropeptide Y ; blood ; Rats ; Receptors, Neuropeptide Y ; antagonists & inhibitors ; Streptozocin

AIMTo investigate the effects of angiotensin converting enzyme inhibitor (ACEI) on apoptosis and the expression of Fas and Fas-L in the kidney of diabetic rats.

METHODSUninephrectomized Spraque-Dawley rats were used to induce diabetes by intraperitoneal injection of streptozotocin (65 mg.kg-1). Benazepril (10 mg.kg-1) was given daily by gavage from the next day of the induction to diabetes for 12 weeks. Apoptosis was evaluated by means of terminal-deoxynucleotidyl transferase mediated d-UTP nick end labeling (TUNEL). Flow cytometry and immunohistochemistry were used to detect the expression of Fas and Fas-L.

RESULTSCompared with those in the kidneys of control group, apoptotic cells were more in number and the expression of Fas and Fas-L was higher in the diabetic kidneys (P < 0.05). The number of apoptotic cells and the level of expression of Fas and Fas-L were reduced by benazepril treatment (P < 0.05).

CONCLUSIONAngiotensin converting enzyme inhibitor benazepril showed some renal protective effect on diabetic nephropathy, partly through inhibiting apoptosis by down-regulating Fas and Fas-L expression.

Angiotensin-Converting Enzyme Inhibitors ; pharmacology ; Animals ; Apoptosis ; Benzazepines ; pharmacology ; Diabetes Mellitus, Experimental ; metabolism ; pathology ; Diabetic Nephropathies ; metabolism ; pathology ; Fas Ligand Protein ; Kidney ; metabolism ; pathology ; Male ; Membrane Glycoproteins ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; fas Receptor ; metabolism

OBJECTIVETo study the renal protective effect of Xinganbao Capsule on rats with adriamycin induced nephropathy (AIN).

METHODSForty male SD rats were randomly divided into four groups, i.e., the normal control group (N), the AIN model group (M), the Benazepril group (B),and the Xinganbao Capsule group (X). AIN rat model was established by left unilateral nephrectomy and repeated caudal vein injection of adriamycin. Gastric perfusion of xinganbao Capsule (at the dose of 500 mg/kg per day) and Benazepril (at the dose of 4 mg/kg per day) was given to rats in the X group and the B group respectively one week after nephrectomy. Rats were sacrificed at the 8th week after medication. The 24-h urinary protein excretion (24 h-UP) and blood biochemical indices were determined. Renal tissues were collected for pathological changes under light and electron microscopes. Expressions of fibronection (FN), collagen IV (COL-IV), and osteopontin (OPN) in renal tissues were detected by immunohistochemistry. mRNA levels of transforming growth factor-beta 1 (TGF-beta1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and plasminogen activator inhibitor-1 (PAI-1) were measured by fluorescent Real-time PCR.

RESULTSWhen compared with the model group, 24 h-UP, blood urea nitrogen (BUN), and serum creatinine (SCr), and blood lipids levels were significantly lowered in the X group. The mesangial matrix percentage was less in the X group than in the M group. Renal FN, COL-IV, and OPN expressions more significantly decreased in the X group than in the M group. Similarly mRNA expressions of TGF-beta1,, TIMP-1, PAl-1 in renal tissues obviously decreased.

CONCLUSIONXinganbao Capsule could exert its renal protective action possibly through reducing the urinary protein excretion, correcting lipid metabolic disturbance, inhibiting excessive accumulation of extracellular matrix, decreasing the expression of fibrosis factors, and improving the pathological damage of kidneys in the AIN rat model.

Animals ; Benzazepines ; pharmacology ; therapeutic use ; Doxorubicin ; adverse effects ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Fibrosis ; Kidney ; drug effects ; metabolism ; pathology ; Kidney Diseases ; chemically induced ; drug therapy ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley

OBJECTIVE: To explore the effect of benazepril (one of angiotesin converting enzymes) on the expression of vascular endothelial growth factor (VEGF) and the change of microvessel density (MVD) in the remnant kidney of rats that undergone 5/6 subtotal nephrectomy (STNx). METHODS: The male Sprague-Dawley (SD) rats were performed 5/6 nephrectomy to produce chronic renal failure, and randomly divided into a model group (STNx group), a STNx combined with benazepril group (Benazepril group), and a sham group that served as normal controls. Pathological changes of the remnant kidney were evaluated at the 8th week after gastric gavage. Immunohistochemistry Methods were used to examine the expression of VEGF and MVD in the remnant kidney, and the correlation was determined between VEGF, MVD and glomerulosclerosis index (GSI), tubulointerstitial score (TIS), BUN, and creatinine (Cr). RESULTS: UP, BUN, Cr, GSI, and TIS significantly decreased in the benazepirl group (P<0.05); and the expression of VEGF and MVD significant increased (P<0.05). The expression of VEGF was positively related to MVD (P<0.05), and there was negative correlation between VEGF, MVD and GSI, TIS, BUN, Cr (P<0.05). CONCLUSION The decrease of the expression of VEGF and MVD in the remnant kidney may be involved in the progressive remnant kidney fibrosis and renal function. Benazepril can significantly relieve the remnant kidney fibrosis and protect the renal function by increasing the expression of VEGF and MVD in the remnant kidney.
Angiotensin-Converting Enzyme Inhibitors ; pharmacology ; Animals ; Benzazepines ; pharmacology ; Capillaries ; drug effects ; Kidney ; blood supply ; Male ; Nephrectomy ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Renal Insufficiency ; prevention & control ; Vascular Endothelial Growth Factor A ; biosynthesis ; genetics

OBJECTIVETo study the effects of low concentration dopamine(DA) on hydrogen peroxide-induced apoptosis in cultured rat cardiomyocytes as well as the possible molecular mechanisms.

METHODSCultured neonatal rat cardiomyocytes were randomly divided into the following groups: control group (control), hydrogen peroxide group (H2O2), pretreated with low concentration dopamine ( DA + H2O2), dopamine receptor l(DR1) antagonist group (DR1 + DA + H2O2), dopamine receptor 2(DR2) antagonist group (DR2 + DA + H2O2). The cell apoptosis was then assessed by MTT and flow cytometry. The cellular ultrastructure changes were observed by transmission electron micro- scope. The activity of lactate dehydrogenase(LDH )and superoxide dismutase (SOD) in cell medium was analyzed by colorimetry. The protein expressions of Cytochrone c, Caspase 3 and Caspase 9 were obtained by Western blot.

RESULTSCompared with hydrogen peroxide group, low concentration dopamine(10 µmol/L) decreased the apoptosis rate and the expression of protein of apoptosis related protein, enhanced SOD activity, decreased LDH activity. DR1 antagonist SCH-23390 treatment inhibited dopamine induced cardiac protective effect. DR2 antagonist haloperido treatment had no changes compared with dopamine group.

CONCLUSIONAbove findings indicate that low concentration dopanine inhibits apoptosis induced by hydrogen peroxide in neonatal rat cardiomyocytes, which is partly associated with the activation of DR1.

Animals ; Apoptosis ; Benzazepines ; Caspase 3 ; metabolism ; Caspase 9 ; metabolism ; Cells, Cultured ; Dopamine ; pharmacology ; Hydrogen Peroxide ; L-Lactate Dehydrogenase ; metabolism ; Myocytes, Cardiac ; drug effects ; Rats ; Rats, Wistar ; Receptors, Dopamine D1 ; metabolism ; Superoxide Dismutase ; metabolism