benazepril and Disease-Models--Animal

LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNi), is reported to play a cardioprotective role after acute myocardial infarction (AMI). Angiotensin-converting enzyme inhibitors(ACEIs) have similar roles. However, it is unclear whether the combination of the two drugs has a better protective effect. The purpose of this study was to investigate the effect of this combination therapy after AMI.. Male C57BL/6 J mice subjected to ligation of left anterior descending artery were treated for 4 weeks with LCZ696, ACEI(benazepril), or both(combination therapy) after induction of MI. Cardiac function, hemodynamics, and inflammatory factors were evaluated at 1 st day, 14th day, and 28th day. Heart weight and myocardial fibrosis were measured at the end of the experiment.. Blood pressure was lower in all treatment groups than in the control group. The combination therapy group had the strongest antihypertensive effect. Compared with LCZ696 or benazepril, treatment with combination therapy increased ejection fraction, fractional shortening, and cardiac output and decreased N-terminal pro-B-type natriuretic peptide(NT-proBNP). The ratios of heart weight to body weight in all treatment groups were less than that in the control group. Compared with the control and LCZ696 group, the fibrotic area in the combination therapy group was suppressed and had a lower level of TGF-β1 in the left ventricle. The plasma concentration of bradykinin and renin in the combination therapy group were highest among groups at 14th and 28th day.. LCZ696 in combination with benazepril showed better positive effects in modulating heart failure and myocardial fibrosis after acute AMI in mice and affect some inflammatory markers.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Biphenyl Compounds; Disease Models, Animal; Drug Combinations; Drug Therapy, Combination; Fibrosis; Heart Failure; Hemodynamics; Inflammation Mediators; Male; Mice, Inbred C57BL; Myocardial Contraction; Myocardial Infarction; Myocardium; Neprilysin; Protease Inhibitors; Renin; Tetrazoles; Transforming Growth Factor beta1; Valsartan; Ventricular Function, Left

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Chronic heart failure (CHF) is the end-stage of many cardiovascular diseases and severely affects the patients' lifespan. Inhibiting ventricular remodeling is thus a primary treatment target for CHF patients. Astragaloside IV (AS-IV) can improve cardiac function and protect myocardial cells. The study aims to investigate the effects of AS-IV on ventricular remodeling and explore its role in regulating energy metabolism using a rat CHF model. Sprague-Dawley rats were divided into five groups (

Topics: Animals; Benzazepines; Chronic Disease; Chymases; Disease Models, Animal; Energy Metabolism; Fatty Acids; Heart Failure; Heart Ventricles; Humans; Myocardium; Myocytes, Cardiac; PPAR alpha; Rats; RNA, Messenger; Saponins; Triterpenes; Ventricular Remodeling

This study aimed to investigate the effects of benazepril hydrochloride (BH) on proteinuria and ANGPTL-4 expression in a diabetic nephropathy (DN) rat model.. A total of 72 Wistar male rats were randomly divided into three groups: normal control (NC), DN group and BH treatment (BH) groups. The DN model was induced by streptozotocin (STZ). Weight, glucose, proteinuria, biochemical indicators and the kidney weight index were examined at 8, 12 and 16 weeks. In addition, ANGPTL-4 protein and mRNA expressions were assessed by immunohistochemistry and qRT-PCR, respectively. Relationships between ANGPTL-4 and biochemical indicators were investigated using Spearman analysis.. Weight was significantly lower but glucose levels were significantly higher in both the DN and BH groups than in the NC group (P < 0.05). Compared with the DN group, proteinuria, urea, creatinine, triglycerides and total cholesterol levels were decreased, whereas the albumin level was increased after BH treatment (all P < 0.05). Furthermore, BH diminished kidney volume and ameliorated the pathological changes associated with DN. ANGPTL-4 expression was significantly decreased after BH treatment, and ANGPTL-4 expression was highly correlated with biochemical indicators of DN (P < 0.05).. Benazepril hydrochloride improves DN and decreases proteinuria by decreasing ANGPTL-4 expression.

Topics: Angiopoietin-Like Protein 4; Animals; Antihypertensive Agents; Benzazepines; Blood Glucose; Cholesterol; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Male; Organ Size; Proteinuria; Rats; Rats, Wistar; RNA, Messenger; Serum Albumin; Triglycerides; Up-Regulation; Urea

To observe the effect of Shenkang Injection on the blood pressure, metabolism, blood biochemistry and renal pathology in hypertension renal damge rats, then to provide theoretical basis for clinical trials.. 75 spontaneously hypertensive nephropathy rats were randomly divided into five groups with 15 rats in each group: model group (SHR group) rats were intragastrically treated with the vehicle (4 mL/kg normal saline per day) of Shenkang Injection per day; Benazepril group( positive control group, 8 mg/ kg Benazepril per day) ;Shenkang Injection low-dose group (6.7 mL/kg Shenkang Injection per day); middle-dose group (13.3 mL/kg Shenkang Injection per day); high-dose group (26.6 mL/kg Shenkang Injection per day); and WKY rats were normal control group (n = 15) (4 mL/kg normal saline per day).. After 3 months intraperitoneal injection treatment, SHR rats blood pressure were in- hibited; the levels of microalbumin (m-ALB), total protein (U-TP), serum creatinine (Ser) and urea nitrogen (BUN) were decreased significantly in Shenkang Injection treated groups rats. Shenkang Injection significantly improved the levels of creatinine clearance rate (Ccr), serum albumin (ALB) and superoxide dismutase (SOD), decreased the content of methane dicarboxylic aldehyde (MDA), aldosterone (Ald), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), transforming growth factor-β1 (TGF-β1) and C-reactive protein (CRP), and had histologic improvement compared with model group.. Shenkang Injection can improve the kidney function, decrease the levels of serum inflammatory factors,improve the oxidative status and reduce the degree of hypertensive renal damage.

Topics: Animals; Benzazepines; Blood Pressure; C-Reactive Protein; Disease Models, Animal; Drugs, Chinese Herbal; Hypertension; Interleukin-6; Kidney; Kidney Diseases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

1. Advanced glycation end-products (AGE) and their receptors (RAGE) have been implicated in renal damage in diabetes. The aim of the present study was to investigate the effects of benazepril, an angiotensin-converting enzyme inhibitor (ACEI), on the formation of AGE, the expression RAGE and other associated components in the oxidative stress pathway in spontaneously hypertensive rats (SHR). 2. Groups of SHR were treated with or without 10 mg/kg per day benazepril for 12 weeks. Systolic blood pressure (SBP) and angiotensin (Ang) II levels were evaluated in SHR and control Wistar-Kyoto (WKY) rats. Renal function was investigated by determining levels of proteinuria and glomerulosclerosis. Furthermore, reactive oxygen species (ROS) in the rat renal cortex were analysed using an H(2)O(2)-based hydroxyl radical-detection assay and the renal content of AGE, RAGE, NADPH oxidase p47phox, nuclear factor (NF)-kappaB p65, phosphorylated (p-) NF-kappaB p65, vascular cell adhesion molecule (VCAM)-1 and transforming growth factor (TGF)-beta1 was determined by immunohistochemistry, quantitative real-time polymerase chain reaction and western blot analysis. 3. Treatment with benazepril inhibited the formation of AngII, reduced SBP and alleviated renal lesions in SHR compared with both untreated SHR and control WKY rats. Benazepril treatment significantly suppressed the accumulation of AGE and expression of RAGE in the kidney of SHR. In addition, benazepril treatment reduced the upregulation of NADPH oxidase p47phox, ROS generation and NF-kappaB p65, p-NF-kappaB p65, VCAM-1 and TGF-beta1 expression in the kidney of SHR compared with both untreated SHR and control WKY rats. 4. The results of the present study provide new insights into the regulation by the renin-angiotensin system of AGE-RAGE, oxidative stress and nephropathy, increasing our understanding of the role of the RAS in nephropathy.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzazepines; Blood Pressure; Disease Models, Animal; Female; Glycation End Products, Advanced; Hypertension; Kidney Cortex; Kidney Diseases; Male; NADPH Oxidases; Oxidative Stress; Phosphorylation; Platelet-Derived Growth Factor; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Signal Transduction; Transcription Factor RelA; Transforming Growth Factor beta1; Vascular Cell Adhesion Molecule-1

To investigate the effect of benazepril on atrial cytoskeleton remodeling in atrial fibrillation (AF) canines induced by chronic rapid atrial pacing (RAP).. Twenty canines were randomly divided into 3 groups: (1) Sham-operated group without RAP; (2) AF group: AF established by RAP at 600 beats per minute for 6 weeks; (3) Benazepril group: benazepril was dosed from 1 week pre-pacing to 6 weeks post-pacing. The diameter of atrial cardiomyocyte was measured, collagen volume fraction (CVF) analyzed by Masson staining and the expression and distribution of desmin were assayed by immunohistochemistry. RT-PCR method was used to semi-quantify the mRNA expression of beta-tubulin and desmin.. The diameter of atrial cardiomyocyte increased in AF group [LA:(27.9 +/- 3.8) microm; RA: (26.8 +/- 3.2) microm] and benazepril group[LA: (25.1 +/- 3.4) microm; RA: (25.2 +/- 3.5) microm] than sham-operated group [LA: (19.6 +/- 2.9) microm; RA: (18.7 +/- 2.6) microm] (P < 0.01). CVF increased in AF group than sham-operated group [LA: (16.9 +/- 1.1)% vs (9.2 +/- 0.9)%, RA: (15.7 +/- 2.3)% vs (9.3 +/- 0.8)%, P < 0.01] and it decreased in benazepril group than AF group [LA: (11.3 +/- 0.8)% vs (16.9 +/- 1.1)%, RA: (10.9 +/- 0.8)% vs (15.7 +/- 2.3)%, P < 0.01]. Normal desmin cross-striations were lost in atrial cardiomyocyte and the desmin organization became irregular in AF group. The A values analyzed by immunohistochemistry of desmin increased in AF group than sham-operated group and they decreased in benazepril group than AF group (P < 0.01). The expression of mRNA level of desmin and beta-tubulin were up-regulated in AF group than sham-operated group, (LA:1.0 +/- 0.3 vs 0.6 +/- 0.3, 0.9 +/- 0.4 vs 0.6 +/- 0.3; RA: 1.0 +/- 0.6 vs 0.6 +/- 0.2, 1.1 +/- 0.3 vs 0.7 +/- 0.4, P < 0.01) and they were down-regulated in benazepril group than AF group (LA:0.8 +/- 0.4 vs 1.0 +/- 0.3, 0.7 +/- 0.3 vs 0.9 +/- 0.4; RA:0.7 +/- 0.3 vs 1.0 +/- 0.6, 0.7 +/- 0.3 vs 1.1 +/- 0.3, P < 0.01).. Benazepril can favorably improve atrial cytoskeleton remodeling in the canine atrial fibrillation model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Fibrillation; Benzazepines; Cytoskeleton; Desmin; Disease Models, Animal; Dogs; Heart Atria; Myocytes, Cardiac; RNA, Messenger; Tubulin

Ventricular remodeling is an important pathologic progress in almost all end stage heart failure (HF), and it is characterized by ventricular thickening and cardiac fibrosis with poor prognosis. The connective tissue growth factor (CTGF), a new growth factor with multi-function, has an important role in fibrosis of tissue and organs. It has been demonstrated that angiotensin-converting enzyme inhibitor (ACEI) can prevent the development of cardiomyocyte from remodeling and improve cardiac function. Researchers try to test the hypothesis that cardiac function improvement attributable to ACEI is associated with inhibiting expression of CTGF in patients with HF. The aim of this study was to observe changes in CTGF expression in cardiomyocyte of young rats with HF and effect of benazepril on CTGF.. The animal model of HF was established by constriction of abdominal aorta. Five weeks old rats were randomly divided into 3 groups after 6 weeks of operation: (1) HF group without treatment (n = 15); (2) HF group where rats were treated with benazepril (n = 15); (3) sham-operated group (n = 15) where rats were administered benazepril through direct gastric gavage. After 4 weeks of treatment, the high frequency ultrasound was performed. The expression of CTGF was detected by immunohistochemistry and semi-quantative reverse transcription-polymerase chain reaction.. Compared with the sham-operated group, left ventricular diastolic dimension (LVEDD), left ventricular systolic dimension (LVESD), interventricular septal thickness at end-diastole (IVSTd), interventricular septal thickness at end-systole (IVSTs), left ventricular posterior wall thickness at end-diastole (LVPWTd), left ventricular posterior wall thickness at end-systole (LVPWTs), left ventricular relative weight (LVRW), and right ventricular relative weight (RVRW) were all increased (P < 0.01), but ejection fraction (EF) and fractional shortening (FS) were decreased (P < 0.01). CTGF positive cells and expression of CTGF mRNA (0.609 +/- 0.065 vs 0.117 +/- 0.011, P < 0.01) were increased in HF group without treatment. LVESD, IVSTd, IVSTs, LVPWTd, LVPWTs, LVRW and RVRW were all decreased (P < 0.01), but FS and EF were increased (P < 0.01) in cases of HF treated with benazepril when compared with HF group without treatment. LVESD, IVSTd, IVSTs, LVPWTd, LVPWTs, LVRW and RVRW were higher (P < 0.01), EF and FS were lower (P < 0.01), CTGF positive cells and expression of CTGF mRNA were higher (P < 0.01) in HF group treated with benazepril than those of sham-operated group.. The expression of CTGF was increased in the cardiomyocyte of young rats with HF and benazepril could prevent left ventricular from remodeling partly and improve cardiac function by inhibiting the expression of CTGF in cardiomyocyte in cases of HF.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Connective Tissue Growth Factor; Disease Models, Animal; Heart Failure; Immunohistochemistry; Male; Myocytes, Cardiac; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Ultrasonography; Ventricular Dysfunction, Left; Ventricular Remodeling

Accumulating evidence shows that inhibition of the vascular renin-angiotensin system results in suppression of injury-elicited neointima formation. We attempted to determine whether or not combined treatment with an angiotensin II type 1 receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) has an additive inhibitory effect on balloon-injury-elicited neointima formation in the carotid artery. Male Sprague-Dawley rats were treated with an ARB (valsartan: 3 mg/kg/day) and/or an ACEI (benazepril: 0.3 mg/kg/day) from 1 week before until 2 weeks after balloon injury. Experiments were also conducted with one-third of the dose combination used in the original experiments. Both ARB and ACEI inhibited neointima formation without any blood pressure changes. The full-dose combination lowered blood pressure and suppressed neointima formation significantly compared with the levels in the groups treated with either ACEI or ARB alone. The low-dose combination without blood pressure reduction also inhibited neointima formation to a similar extent as the full-dose combination. We measured 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a marker of oxidative stress, and nitrite and nitrate (NOx), an index of nitric monoxide production, in media conditioned by the injured artery. NOx production was lower and 8-iso-PGF2alpha was higher in the media of the injured artery, compared with those in the normal artery. ACEI restored NOx production more dramatically than ARB, and ARB suppressed 8-iso-PGF2alpha markedly compared with ACEI. These results suggest that the combination of an ARB and an ACEI exerts an additive inhibitory effect, presumably through an increase in production and bioavailability of NO from the endothelium.

Topics: Angioplasty, Balloon; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzazepines; Blood Pressure; Carotid Artery Injuries; Disease Models, Animal; Hypertension; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Tetrazoles; Tunica Intima; Valine; Valsartan

To investigate the trend and potential pathogenic role of nuclear factor (NF)-kappaB P(65)/Rel-A mRNA and angiotensin-II (AngII) receptor type 1 (AT(1)) proteins expression, and the relativity between them in early stage of renal tubulointerstitial lesions in young rats with adriamycin nephrosis and the interfering effects of treatment with angiotensin converting enzyme inhibitor (ACEI) benazepril and ACEI combined with AngII type 1 receptor antagonist (AT(1)RA) Losartan.. Male young Wistar rats with adriamycin nephrosis were used as experimental models. At different time points (weeks 1, 2, and 3 in early nephritic phase, the urinary protein and blood biochemical parameters were measured, and P(65)/Rel-A mRNA was detected; AT(1) protein expression was determined by in situ hybridization and immunohistochemical methods. The relativity between them was evaluated.. In the early phase of tubulointerstitial lesions, following adriamycin injection and proteinuria aggravated progressively, at week 3, the proteinuria level had reached heavy proteinuria (123.2 +/- 7.7 mg/24 h). The serum parameters reflecting renal function were elevated. The inflammatory cells infiltrated into renal tissues, especially in tubulointerstitial regions, were increased markedly. Swelling of tubular epithelial cells, broadened tubulointerstitial areas, and protein casts in tubule were observed. In situ hybridization and immunochemical staining showed that AT(1) protein was expressed in tubular epithelial cell cytoplasm and on nuclear membranes (AT(1): 1st week 19.8 +/- 1.1%, 2nd week 25.0 +/- 2.6%, 3rd week 37.1 +/- 1.0% (control: 10.3 +/- 0.8%, 10.4 +/- 1.6%, 10.2 +/- 1.5%); and P(65)/Rel-A mRNA expression in the same locations was upregulated. P(65)/Rel-A translocation from cytoplasm into nucleus increased markedly simultaneously. The positive signal of hybridization dominated in cytoplasm gradually became dominant in the nuclei as the pathological changes progressed. The semiquantitative expression of P(65)/Rel-A was 24.0 +/- 3.3% at week 1, 34.2 +/- 2.4% at week 2, 39.9 +/- 6.4% at week 3, while the values of controls were 8.5 +/- 0.4%, 8.7 +/- 1.0%, and 8.4 +/- 0.9%, respectively. There was a positive correlation between AT(1) and P(65)/Rel-A expression in localization and time phase (r = 0.857, P < 0.01). However, the tendency of those factor's expression was all decreased in each treated group, the semiquantitative results were AT(1): 14.6 +/- 2.1%, 13.7 +/- 2.3%, 11.4 +/- 1.1%; P(65)/Rel-A: 18.5 +/- 3.4%, 22.8 +/- 1.6%, 26.7 +/- 4.9% at 1, 2, 3 weeks in ACEI treated group; AT(1): 12.4 +/- 1.5%, 11.1 +/- 1.0%, 10.3 +/- 0.8%; P(65)/Rel-A: 17.9 +/- 5.0%, 21.3 +/- 6.0%, 22.5 +/- 2.5% in AT(1)RA (Losartan) group, respectively. The significant difference were observed between all groups in different time points (P < 0.05).. The present study suggested that NF-kappaB (P(65)/Rel-A) mRNA expression and its activity was enhanced significantly that synchronized with aggravating injures in tubulointerstitial lesions initial period induced by proteinuria-loading in nephrotic young rats. This tendency was related with AngII and its receptors system that may accelerate lesions progressing in many renal diseases.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Benzazepines; Biopsy; Disease Models, Animal; Doxorubicin; Gene Expression Regulation; Immunohistochemistry; In Situ Hybridization; Kidney; Losartan; Male; Nephrosis; NF-kappa B; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Transcription Factor RelA

To explore the changes of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenesis, and the effects of bFGF, angiotensin converting enzyme inhibiter(ACEI) benazepril on the angiogenesis in acute myocardial infarction (AMI) model of rabbits, and to provide a probable evidence for the treatment of AMI.. AMI model was established by ligating anterior descending branch of coronary artery of Japan-Sino hybridization white rabbits. The postoperative rabbits were randomly divided into 6 groups and each group was treated with different drugs. Groups 1 and 2 were treated with normal saline (NS) for 28 and 14 days (d), group 3 and 4 with bFGF for 28 and 14 d, groups 5 with benazepril for 14 d, and group 6 with benazepril and bFGF for 14 d respectively. The rabbits were killed on the 14th or 28th d and their hearts were excised, sectioned and stained with HE, Masson trichrome to observe VEGF, bFGF and CD(34) under a microscope, which were quantified with a computer-assisted morphometry.. Compared with group 1, the granulation tissue of infarction zone (IZ) in group 2 freshened up, and the capillary density (CD) in IZ was increased (P = 0.002). The CD in the IZ as well as VEGF and bFGF in groups 3 and 4 were increased respectively (P = 0.011-0.037). In group 5 the changes of VEGF and bFGF were not found in the IZ and the border zone (BZ) while CD was significantly increased (35.4% and 25.6%, P = 0.036 and 0.037). Compared with group 2, the CD in the IZ and BZ of group 6 was significantly increased (63.4% and 44.3% P = 0.007 and 0.007), meanwhile VEGF and bFGF were increased. Compared with group 5, only VEGF was increased.. Intravenous bFGF may increase VEGF and bFGF significantly, thus promoting the angiogenesis in the IZ and BZ in cardiac infarction as VEGF and bFGF are the potent angiogenic growth factors. Benazepril may promote angiogenesis in the IZ and BZ in cardiac infarction, but its mechanism is irrelative to the expression of VEGF and bFGF. The combination of benazepril and bFGF may promote, to some extent, the expression of VEGF and bFGF, but their effect on angiogenesis has not been found.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Coronary Circulation; Coronary Vessels; Disease Models, Animal; Fibroblast Growth Factor 2; Myocardial Infarction; Neovascularization, Physiologic; Rabbits; Time Factors; Vascular Endothelial Growth Factor A

Inhibition of the renin-angiotensin system with an angiotensin-converting enzyme inhibitor (ACEi) is an effective therapy in hypertension. Vasopeptidase inhibition was initially proposed with compounds inhibiting both angiotensin-converting enzyme and neutral endopeptidase (omapatrilat), but clinical trials revealed that reducing angiotensin II while blocking the degradation of vasodilatory peptides was not without concerns. We have previously investigated the combination of an ACEi with an endothelin-converting enzyme inhibitor (ECEi); now we add a neutral endopeptidase inhibitor (NEPi) toward triple vasopeptidase inhibition. Male spontaneously hypertensive rats were surgically implanted with a vascular catheter and treated with an ACEi (benazepril), a NEPi (CGS 24592) and an ECEi (CGS 35066) (continuous intra-arterial infusion at 1 or 5 mg/kg/day x 5 days each). After 15 days, drugs administration was stopped for 3 days. ACEi (1 mg/kg per day) reduced the mean arterial blood pressure by 8.4%. The addition of a NEPi and an ECEi at the same dose did not shown any added benefit. The mean arterial blood pressure came back to baseline upon cessation of treatment. ACEi (5 mg/kg per day) reduced the mean arterial blood pressure by 28%. The mean arterial blood pressure remained attenuated by 21% and 19% with the addition of the NEPi and the ECEi. Again, the mean arterial blood pressure rose back to 148 +/- 4 mmHg following cessation of treatment. Daily biochemical and hematological analysis of plasma did not reveal any signs of toxicity, except for a rapid elevation in K (40%) after 1 day of ACEi. Thus, angiotensin II inhibition plays a primary role in controlling the blood pressure of spontaneously hypertensive whereas additional NEPi and ECEi did not provide further benefits under the present dose combinations. The normalizing effect of the higher dose of ACEi by itself made it impossible to discriminate the role of neutral endopeptidase and endothelin-converting enzyme-modulated peptides and to further define the paradigm of triple vasopeptidase inhibition toward better control of vascular hemodynamics. Additional studies are underway.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aspartic Acid Endopeptidases; Benzazepines; Benzofurans; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelin-Converting Enzymes; Heart Rate; Hypertension; Infusions, Intra-Arterial; Male; Metalloendopeptidases; Neprilysin; Organophosphonates; Phenylalanine; Rats; Rats, Inbred SHR; Time Factors

Although recent clinical studies have indicated that angiotensin II receptor blocker is as effective in treating heart failure as an angiotensin-converting enzyme inhibitor, it is unknown whether their effects are different. Dahl salt-sensitive rats were treated with an angiotensin-converting enzyme inhibitor benazepril, and an angiotensin II receptor blocker candesartan from 11 weeks old. We examined cardiac geometry and function by echocardiography, and histology and gene expression by high-density oligonucleotide arrays using Affymetrix U34 (Affymetrix, Santa Clara, CA, U.S.A.). Dahl salt-sensitive rats fed a high salt diet showed a marked increase in blood pressure and developed concentric hypertrophy at 11 weeks, followed by left ventricle dilation and congestive heart failure by 20 weeks after birth. Although both medications had only a mild antihypertensive effect, they strongly suppressed the development of cardiac hypertrophy, fibrosis and heart failure to the same extent. Gene expression pattern examined by Affymetrix GeneChip (Affymetrix) is quite different between the two drug groups, indicating that angiotensin II receptor blocker and angiotensin-converting enzyme inhibitor prevent heart failure by different mechanisms.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Benzimidazoles; Biphenyl Compounds; Disease Models, Animal; Echocardiography; Fibrosis; Gene Expression; Gene Expression Profiling; Heart Failure; Hypertension; Hypertrophy, Left Ventricular; Infusions, Parenteral; Male; Oligonucleotide Array Sequence Analysis; Organ Size; Rats; Rats, Inbred Dahl; Receptors, Angiotensin; Sodium Chloride, Dietary; Subcutaneous Tissue; Tetrazoles; Time Factors; Ventricular Function, Left

The mechanism and treatment of diastolic heart failure are poorly understood. We compared the effects of an ACE inhibitor, an angiotensin receptor blocker (ARB), and their combination on diastolic heart failure in Dahl salt-sensitive (DS) rats.. DS rats fed an 8% NaCl diet from 7 weeks of age were treated with benazepril 10 mg/kg alone, valsartan 30 mg/kg alone, or combined benazepril and valsartan at 5 and 15 mg/kg, respectively, or at 1 and 3 mg/kg, respectively. At 16 weeks of age, DS rats exhibited prominent concentric left ventricular (LV) hypertrophy and diastolic dysfunction with preserved systolic function, as estimated by echocardiography. Despite comparable hypotensive effects among all drug treatments, the combination of benazepril 5 mg/kg and valsartan 15 mg/kg improved diastolic dysfunction and survival in DS rats more effectively than ACE inhibitor or ARB alone. Furthermore, the increase in LV endothelin-1 levels and hydroxyproline contents in DS rats was significantly suppressed only by combined benazepril and valsartan, and LV atrial natriuretic peptide mRNA upregulation in DS rats was suppressed to a greater extent by the combination therapy than monotherapy.. The combination of ACE inhibitor and ARB, independently of the hypotensive effect, improved LV phenotypic change and increased LV endothelin-1 production and collagen accumulation, diastolic dysfunction, and survival in a rat heart failure model more effectively than either agent alone, thereby providing solid experimental evidence that the combination of these 2 agents is more beneficial than monotherapy for treatment of heart failure.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzazepines; Blood Pressure; Catecholamines; Collagen; Diastole; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Endothelin-1; Gene Expression; Heart Failure; Heart Function Tests; Hydroxyproline; Myocardium; Myosin Heavy Chains; Organ Size; Rats; Rats, Inbred Dahl; Receptors, Angiotensin; RNA, Messenger; Sodium Chloride, Dietary; Survival Rate; Tetrazoles; Valine; Valsartan; Ventricular Remodeling

The purpose of this study was to determine whether an angiotensin converting enzyme (ACE) inhibitor, benazepril, and an angiotensin receptor antagonist, valsartan, would decrease atherosclerotic severity in cholesterol-fed rabbits. Male rabbits were fed either: (a) normal rabbit chow; (b) 2% cholesterol diet; (c) 2% cholesterol diet supplemented by benazepril (3 mg/kg per day, subcutaneous injection); or (d) 2% cholesterol diet supplemented by valsartan (1 mg/kg per day, subcutaneous injection). After 12 weeks, the arteries were harvested for histomorphometry and immunohistochemistry. We observed that decreases in serum triglyceride (TG) and total cholesterol (TC) and ACE activity with benazepril-treatment were more than 60, 30, and 84%, respectively, in comparison with the cholesterol group; with valsartan-treatment, TG levels were 53% lower than in the cholesterol group, however, there was no significant difference in TC and ACE activity. The percentage of aortic surface atherosclerotic area, intimal thickness and the ratio of aortic intimal area to medial area were about 40% lower in the benazepril-treated group in comparison with those of the cholesterol group; the difference was more than 60% in the thoracic aorta. The valsartan-treated group had 23% less atherosclerotic area, less effective than benazepril treatment. The percent of PCNA-positive cells and the number of intimal proliferative cells/mm2 were significantly less in the benazepril-treated group compared with the cholesterol group (by 55 and 63%); these parameters were 35 and 17% lower, respectively, with valsartan. The ratio of proliferating macrophages to smooth muscle cells (SMCs) was 3:1 in the cholesterol group, 1:1 in the benazepril and 2:1 in the valsartan-treated group. These results indicate that benazepril could reduce atherosclerotic progression by decreasing macrophage proliferation and accumulation in the arterial wall. The mechanisms for reducing atherosclerotic progression by benazepril and valsartan may be related to reduction of TG and blockade of the angiotensin II action.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta, Thoracic; Arteriosclerosis; Benzazepines; Cholesterol, Dietary; Disease Models, Animal; Endothelium, Vascular; Immunohistochemistry; Male; Muscle, Smooth, Vascular; Rabbits; Reference Values; Tetrazoles; Valine; Valsartan

Angiotensin converting enzyme inhibitors have uniformly been shown to prevent the development both of proteinuria and of glomerulosclerosis in rats with a remnant kidney. Conversely, dihydropyridine calcium antagonists (DCA) have failed to demonstrate such a benefit in spite of causing an equivalent reduction in blood pressure.. To test the hypothesis that concomitant administration of an angiotensin converting enzyme inhibitor and a DCA would lead to a smaller increase both in proteinuria and in glomerulosclerosis relative to that caused by administration of a DCA alone at similar levels of blood pressure.. Experiments were carried out using Sprague-Dawley rats that had been subjected to five-sixths renal ablation. Animals were allocated randomly to one of four groups: control (no treatment), amlodipine (A rats), benazepril (B rats), or a combination of benazepril and amlodipine (B + A rats). We implanted intraperitoneal sensors for telemetric monitoring of the animal's blood pressure. Other parameters measured at baseline included proteinuria and inulin clearance. After approximately 7 weeks all of the parameters were remeasured and animals killed for morphologic assessment of the kidney.. The B + A rats had lower levels of proteinuria than did the rats in group A (21 +/- 12 mg/day for B + A rats versus 59 +/- 24 mg/day for A rats, P < 0.05). The degree of glomerulosclerosis in the B + A rats was also reduced markedly compared with that in A rats (12 +/- 4% for B + A rats versus 43 +/- 12% for A rats, P < 0.05). Moreover, the results on proteinuria and glomerulosclerosis of B + A rats were similar to those for B rats. These differences could not be explained totally in terms of differences in blood pressure control (144 +/- 12 mmHg in A rats versus 132 +/- 13 mmHg in B + A rats, NS).. The results were consistent with the observation that a combination of benzepril and amlodipine provides additional protection against renal injury compared with that provided by amlodipine alone. The mechanism for this benefit is not known.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Blood Pressure; Calcium Channel Blockers; Disease Models, Animal; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Kidney; Male; Nephrectomy; Proteinuria; Random Allocation; Rats; Rats, Sprague-Dawley

We investigated the role of vascular angiotensin-converting enzyme (ACE) activity, cell proliferation, and the effect of different doses of benazepril on intimal hyperplasia after angioplasty in rabbits. Angioplasty was performed in all left iliac arteries in 28 rabbits. Benazepril was administrated to treatment groups in low (1 mg/kg/day) and high (10 mg/kg/day) doses. Two weeks after angioplasty, vascular ACE activity of the angioplasty subgroup was significantly higher than that of the nonangioplasty subgroup (from 0.44 to 1.19 nmol His-Leu/mg/min; p < 0.01). Strong correlation was demonstrated between vascular ACE activity and intimal area (r = 0.708; p < 0.01). Suppression of vascular ACE activity (59% decrease) and inhibition of intimal hyperplasia (43% decrease) was observed in the high-dose subgroup compared with the angioplasty subgroup without drug intervention (p < 0.01). But in the low-dose subgroup, the level of vascular ACE activity decreased moderately (24.4%; p < 0.05), and the intimal area did not alter significantly. Both the low and high dosage of benazepril resulted in a significant decrease in blood pressure (31 and 44 mm Hg, respectively). Striking correlation was displayed between proliferating-cell nuclear antigen (PCNA)-positive cell percentage and intimal area (r = 0.716; p < 0.01). These results indicated that with excessive expression of vascular ACE, intimal cellular proliferation may play a potential role in restenosis after angioplasty. Benazepril could inhibit intimal hyperplasia by suppressing vascular-tissue ACE.

Topics: Analysis of Variance; Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Biomarkers; Blood Pressure; Cell Division; Coronary Disease; Coronary Vessels; Disease Models, Animal; Hyperplasia; Male; Peptidyl-Dipeptidase A; Proliferating Cell Nuclear Antigen; Rabbits; Tunica Intima

Endothelial regulation of peripheral vascular resistance is impaired in hypertension. We studied the effects of different antihypertensive therapies on endothelial function in perfused mesenteric resistance arteries. Spontaneously hypertensive rats (SHR) aged 7 weeks were treated with either the nonpeptidic angiotensin II (AII) receptor antagonist CGP 48369, the angiotensin-converting enzyme (ACE) inhibitor benazepril HCl, or the calcium antagonist nifedipine (each 10 mg/kg/day orally, p.o.) for 8 weeks. All forms of therapy inhibited the increase in systolic blood pressure (SBP) to a comparable degree (18-23 mm Hg) and reduced but did not normalize medial hypertrophy in SHR. Changes in intraluminal vascular diameter to acetylcholine (ACh), norepinephrine (NE), and endothelin-1 (ET-1) were measured. Impaired endothelium-dependent relaxations to intraluminal ACh improved or normalized with all therapies, whereas the response to extraluminal ACh (which was unimpaired in SHR) remained unaffected. The endothelium-dependent inhibition of contractions to NE was lost in untreated SHR and improved or restored by antihypertensive therapy. In SHR, the sensitivity but not the maximal response of vascular smooth muscle (VSM) to ET-1 was paradoxically decreased. Antihypertensive therapy with CGP 48369, nifedipine, or benazepril HCl restored or increased the sensitivity to ET-1. Thus, chronic blockade of the renin-angiotensin system or voltage-operated calcium channels reduces BP and improves endothelial dysfunction in the resistance circulation of SHR. This may contribute to normalization of peripheral vascular resistance during antihypertensive treatment and improve local blood flow to vital organs.

Topics: Acetylcholine; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzazepines; Blood Pressure; Disease Models, Animal; Endothelins; Endothelium, Vascular; Hypertension; In Vitro Techniques; Male; Mesenteric Arteries; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Nifedipine; Norepinephrine; Potassium Chloride; Pyrimidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; Tetrazoles; Vascular Resistance

Male Munich-Wistar rats were subjected to 1 2/3 nephrectomy. One group received no therapy (C). A second group received daily doses of methylprednisolone (MP). A third group received MP plus the angiotensin I converting enzyme inhibitor (CEI) benzazepril. A fourth group received CEI alone. Half of the rats in each group underwent micropuncture study 2 weeks after ablation. Untreated rats exhibited systemic hypertension and elevation of the single nephron glomerular filtration rate (SNGFR), due to glomerular capillary hyperperfusion and hypertension. Administration of MP resulted in comparable systemic hypertension with further elevation of SNGFR due to even higher values for glomerular perfusion and hydraulic pressure (PGC). Concurrent treatment with CEI-controlled systemic and glomerular hypertension despite equivalent renal ablation and comparable doses of MP. After 12 weeks untreated rats demonstrated continued systemic hypertension, progressive proteinuria, and eventual glomerular sclerosis. Addition of MP dramatically accelerated the development of proteinuria and glomerular sclerosis, while CEI afforded striking protection against disease progression. Thus, potent vasodilator glucocorticoids may amplify hemodynamically mediated glomerular injury, whereas control of systemic and glomerular hypertension prevents this undesirable consequence of chronic steroid therapy.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Disease Models, Animal; Glomerular Filtration Rate; Glucocorticoids; Hypertension, Renal; Kidney Glomerulus; Male; Methylprednisolone; Nephrectomy; Nephrons; Proteinuria; Rats; Rats, Inbred Strains; Renal Circulation