enalapril and Fibrosis

Chronic unilateral ureteral obstruction results in interstitial fibrosis of the affected kidney. Both an angiotensin-converting enzyme inhibitor, enalapril, and an angiotensin II receptor antagonist, SC-51316, ameliorate the increased production of extracellular matrix protein in the tubulointerstitium of the obstructed kidney. Blockade of angiotensin II synthesis or inability of angiotensin II to bind to its receptor lessened the increased levels of mRNA for transforming growth factor-beta and collagen IV found in the obstructed kidney of untreated rats. A monocyte/macrophage infiltration was present in the obstructed kidney of untreated rats or rats treated with the angiotensin II receptor antagonists. In contrast, this infiltrate was almost completely absent in the obstructed kidney of rats treated with enalapril. The reason for this different effect of enalapril compared with the angiotensin II receptor antagonist on the macrophage infiltrate seen in obstructive nephropathy has not been elucidated. We conclude that both an angiotensin-converting enzyme inhibitor (enalapril) and a receptor antagonist of angiotensin II ameliorate the tubulointerstitial fibrosis that follows complete unilateral ureteral obstruction in the rat. We suggest that an increased level of angiotensin II has a major role in the development of tubulointerstitial fibrosis following ureteral obstruction.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Collagen; Enalapril; Extracellular Matrix Proteins; Fibrosis; Kidney; Kidney Diseases; Kidney Tubules; Macrophages; Monocytes; Rats; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Triazoles; Ureteral Obstruction

Myocyte growth is seen in all forms of myocardial hypertrophy. In certain disease states, particularly arterial hypertension, components of the hypertrophic remodelling process, other than myocyte growth, distort myocardial structure and thereby adversely alter its mechanical behaviour. Such a pathologic structural remodelling includes a perivascular and interstitial fibrosis that impairs myocardial stiffness and a medial thickening of intramyocardial coronary arteries that attenuates its vasodilator reserve to ischaemic and pharmacologic provocation. The concept of cardioreparation embodies both a regression in myocyte hypertrophy and the pathologic components of the structurally remodelled myocardium and in so doing restores structure and function to normal. Implicit in this concept is the supposition that heart failure will be reversible. The concept of reparation was tested in 14-week-old male spontaneously hypertensive rats having left ventricular hypertrophy, diastolic dysfunction with myocardial fibrosis, and impaired coronary vascular reserve to adenosine, using the angiotensin-converting enzyme inhibitor lisinopril. A regression in left ventricular hypertrophy, perivascular and interstitial fibrosis, and medial thickening of intramural vessels were obtained after 12 weeks of oral lisinopril administration. It would now seem logical to determine whether cardioreparation can be achieved with lisinopril in patients with hypertension and left ventricular hypertrophy, in whom pathologic remodelling of the myocardium is responsible for symptomatic heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Vessels; Cardiomegaly; Enalapril; Fibrosis; Heart; Humans; Hypertension; Lisinopril; Myocardium

To compare the effects of the angiotensin II receptor antagonist candesartan with the angiotensin-converting enzyme inhibitor enalapril on myocardial fibrosis evaluated by echoreflectivity analysis.. Hypertensive patients (n = 196) with echocardigraphically documented left ventricular hypertrophy were randomized to candesartan 8-16 mg/day (n = 91) or enalapril 10-20 mg/day (n = 105) with possible addition of hydrochlorothiazide (12.5-25 mg/day) for 48 weeks. Echoreflectivity analysis was performed on ultrasound two-dimensional tracings of the midapex septum with a specifically designed and validated software. Colour histograms were obtained; the primary outcome variable was the treatment-related change in histogram width (broadband), previously shown to correlate with collagen volume on endomyocardial biopsy; changes in mean colour scale were secondary outcome variable.. Echoreflectivity analysis was feasible in 84 patients (48 candesartan, 36 enalapril). Broadband decreased significantly in the candesartan (-8.0 colour levels) and in the enalapril group (-12.9 colour levels) with no significant difference between treatments (P = 0.409); no significant changes occurred in mean colour scale. Patients under monotherapy (n = 46) showed similar trends as the larger intention to treat cohort, without significant difference between treatments.. In hypertensive patients with left ventricular hypertrophy, both candesartan and enalapril induce a moderate but statistically significant reduction in an echoreflectivity index of myocardial fibrosis.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Enalapril; Female; Fibrosis; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Myocardium; Tetrazoles; Treatment Outcome; Ultrasonography

Myocardial fibrosis commonly occurs in patients with end-stage renal disease (ESRD) and has proven to be an important predictor for cardiovascular events. In experimental settings, angiotensin II type 1 receptor (AT1-R) antagonists have been shown to have anti-fibrotic effects on the myocardium independent of their antihypertensive effects. In this study, to investigate whether the AT1-R antagonist losartan would have such anti-fibrotic effects in patients, we administered losartan or, for purpose of comparison, the angiotensin-converting enzyme enalapril or Ca2+-antagonist amlodipine to patients with ESRD. Thirty-nine ESRD patients with hypertension were randomly assigned to receive losartan (n=13), enalapril (n=13), or amlodipine (n=13). Ultrasonic integrated backscatter (IBS) and serological markers of collagen type I synthesis and degradation were used to assess the degree of myocardial fibrosis just before and after 6 months of treatment. There were no significant differences in antihypertensive effects among the three agents. In the enalapril- and amlodipine-treated groups, the mean calibrated IBS values increased significantly after 6 months of treatment (enalapril: -31.6 +/- 1.3 to -29.4 +/- 1.2 dB, p=0.011; amlodipine: -30.6 +/- 1.4 to -27.2 +/- 1.2 dB, p=0.012). However, the mean calibrated IBS values in the losartan-treated group did not increase after 6 months of treatment (-31.2 +/- 1.7 to -31.3 +/- 1.4 dB, p=0.88). The ratio of the serum concentration of procollagen type I carboxy-terminal peptide to the serum concentration of collagen type I pyridinoline cross-linked carboxy-terminal telopeptide was significantly reduced in the losartan-treated group (42.6 +/- 4.6 to 34.4 +/- 3.6, p=0.038). The present study indicates that losartan more effectively suppresses myocardial fibrosis in patients with ESRD than does enalapril or amlodipine despite a comparable antihypertensive effect among the three drugs.

Topics: Amlodipine; Angiotensin II Type 1 Receptor Blockers; Collagen; Double-Blind Method; Echocardiography; Enalapril; Female; Fibrosis; Humans; Kidney Failure, Chronic; Losartan; Male; Middle Aged; Myocardium; Peptide Fragments; Procollagen

Fibrosis of left ventricle commonly occurs in end stage renal disease(ESRD) patients and is an independent risk factor of cardiovascular events. Angiotensin II type 1 receptor antagonist may be able to reverse fibrosis of left ventricle in ESRD patients. Ultrasonography-integrated backscatter(IBS) of myocardial walls is directly related to the morphometrically evaluated collagen content in humans. In this study, 30 chronically hemodialyzed patients with hypertension were randomly allocated to receive antihypertensive therapy with either angiotensin II type 1 receptor(AT1-R) antagonist losartan(n = 10), angiotensin-converting enzyme(ACE) inhibitor enalapril(n = 10) or calcium antagonist amlodipine(n = 10). IBS of posterior wall of left ventricule were measured by IBS before and after 6 months treatment. Baseline demographic and clinical characteristics did not differ in three subgroups. Although losartan(34.2 +/- 1.8 to 30.2 +/- 2.4 dB: p = 0.0094) treatment demonstrated significant reduce of IBS values, enalapril(30.3 +/- 1.5 to 31.7 +/- 1.4 dB: p = 0.3268) and amlodipine (31.6 +/- 1.6 to 33.1 +/- 1.9 dB: p = 0.4632) did not changed it significantly before and after 6 months treatment. All three groups reduced left ventricular mass index(Losartan 154.5 +/- 9.9 to 114.6 +/- 5.8 g/m2: p = 0.0002) (enalapril 155.6 +/- 14.3 to 135.3 +/- 10.4 g/m2: p = 0.0275) (amlodipine 156.6 +/- 7.3 to 137.2 +/- 4.1 g/m2: p = 0.0589). Three groups manifested a similar significant decrease in the mean blood pressure. Plasma angiotensin II concentration was markedly increased by 5.0-fold relative to the control levels before treatment in Losartan treatment, in contrast unchanged in enalapril and only 2.0-fold increased in amlodipine treatment. This study indicates that losartan reduce of fibrosis of left ventricule and this effect may be via an anti-AT1-R effect.

Topics: Amlodipine; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Cardiomyopathies; Enalapril; Female; Fibrosis; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Losartan; Male; Middle Aged; Myocardium; Renal Dialysis

The ESS-1 study was designed to evaluate the long-term effects of enalapril (10 mg per day) on the cardiopulmonary system of patients with systemic sclerosis (SSc). The 3 months follow-up was completed by 41 patients (23 patients in enalapril group and 18 in placebo group). We analysed conventional time domain signal averaged ECG (SAECG). Late potentials were considered to be present in QRS duration (QRS) was > 114 ms or root mean square of last 40 ms (RMS40) was < 20 microV or terminal signal duration under 40 microV (LAS40) was > 38 ms at 40 Hz. At the beginning of study the prevalence of abnormal SAEG parameters was similar in both groups. We observed one abnormal parameter among 13% of patients in enalapril group and 16.7% of patients in placebo group. There were 2 abnormal parameters in 26.1% of patients in enalapril group and 16.7% of patients in placebo group. After three months of treatment we did not find any patient with 2 parameters of late potentials in enalapril group and only 8.7% of patients with one such parameter. In placebo group no substantial improvement was observed.. The 3 months enalapril treatment seems to decrease the incidence of late potentials in patients with systemic sclerosis.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Double-Blind Method; Electrocardiography; Enalapril; Female; Fibrosis; Follow-Up Studies; Humans; Male; Middle Aged; Scleroderma, Systemic

Diabetic cardiomyopathy (DC) is one of the severe secondary complications of diabetes mellitus in humans. Vinpocetine is an alkaloid having pleiotropic pharmacological effects. The present study is designed to investigate the effect of vinpocetine in DC in rats.. Rats were fed a high-fat diet for nine weeks along with single dose of streptozotocin after the second week to induce DC. The haemodynamic evaluation was performed to assess the functional status of rats using the Biopac system. Cardiac echocardiography, biochemical, oxidative stress parameters and inflammatory cytokine level were analysed in addition to haematoxylin-eosin and Masson's trichome staining to study histological changes, cardiomyocyte diameter and fibrosis, respectively. Phosphodiesterase-1 (PDE-1), transforming growth factor-β (TGF-β) and p-Smad 2/3 expression in cardiac tissues were quantified using western blot/RT-PCR.. Vinpocetine treatment and its combination with enalapril decreased the glucose levels compared to diabetic rats. Vinpocetine improved the echocardiographic parameters and cardiac functional status of rats. Vinpocetine decreased the cardiac biochemical parameters, oxidative stress, inflammatory cytokine levels, cardiomyocyte diameter and fibrosis in rats. Interestingly, expressions of PDE-1, TGF-β and p-Smad 2/3 were ameliorated by vinpocetine alone and in combination with enalapril.. Vinpocetine is a well-known inhibitor of PDE-1 and the protective effect of vinpocetine in DC is exerted by inhibition of PDE-1 and subsequent inhibition of the expression of TGF-β/Smad 2/3.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Enalapril; Fibrosis; Humans; Phosphoric Diester Hydrolases; Rats; Signal Transduction; Transforming Growth Factor beta

In this study we investigated the therapeutic potential of angiotensin II pathway inhibitors in attenuating post-surgical adhesion band formation in tendon injury.. We assigned 30 Wistar albino rats to 5 groups, including negative control, positive control, sham, Telmisartan- and Enalapril-treated groups (n=6). Telmisartan and Enalapril at a dose of 10 mg/kg were administered intraperitoneally for 21 days. Hematoxylin-Eosin, and Masson's trichrome staining were used to measure the inflammatory cell accumulation and collagen deposition in the Achilles tendon tissue sections. Oxidative stress markers were analyzed in tissue samples by spectrophotometric methods. Properties of Achilles tendon adhesions were compared based on Tang and Ishiyama scoring systems in the presence and absence of angiotensin II pathway inhibitors.. Telmisartan and Enalapril reduced severity, length, and density of surgical-induced tendon adhesion at site of injury (***p < 0.001). Our results showed that administration of angiotensin II pathway inhibitors decreased infiltration of inflammatory cells to the injured area (*p < 0.05) and suppressed inflammation by regulating oxidative stress markers including MDA (***p < 0.001), total thiol (***p < 0.001), CAT (***p < 0.001), and SOD (***p < 0.001), in post-operative Achilles tendon tissues. Significant lower collagen deposition and formation of fibrotic tissues was seen in Telmisartan- and Enalapril-treated groups as detected by Masson's trichrome staining which correlated with a decrease in quantity (**p < 0.01) and grading of fibrosis score (***p < 0.001), in adhesive tissues. Moreover, inhibition of angiotensin II pathway could also ameliorate mechanical properties including ultimate load (***p < 0.001), and ultimate stress (*p < 0.05) in injured Tendons.. Our results showed that ssuppression of inflammation and fibrosis are two mechanisms by which Telmisartan and Enalapril elicit potent protective responses post Achilles tendon injuries.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Drug Repositioning; Enalapril; Eosine Yellowish-(YS); Fibrosis; Hematoxylin; Inflammation; Pharmaceutical Preparations; Rats; Rats, Wistar; Sulfhydryl Compounds; Superoxide Dismutase; Telmisartan; Tissue Adhesions

To investigate the effect of Huangqi decoction on renal interstitial fibrosis and its association with the transforming growth factor-β1 (TGF-β1) / mitogen-activated protein kinase (MAPK) signaling pathway.. 120 C57/BL mice were randomly divided into six groups: sham group, Enalapril (20 mg/kg) group, 5/6 nephrectomy model group, and 5/6 nephrectomy model plus Huangqicoction (0.12, 0.36 and 1.08 g/kg respectively) groups. Detecting 24hours urinary protein, blood pressure, serum creatinine, urea nitrogen content changes. Periodic Acid-Schiff stain (PAS) and Masson's trichrome staining was used to observe the renal tissue pathological changes. Protein expression of TGF-β1, Phosphorylated P38 mitogen activated protein kinases (P-P38), Phosphorylated c-jun N-terminal kinase (P-JNK), Phosphorylated extracellular regulated proteinhnase (P-ERK), Fibroblast-specific protein-1 (FSP-1), Alpha smooth muscle actin (α-SMA), Type III collagen (Collagen III), Connective tissue growth factor (CTGF), Bcl-2 Assaciated X protein (Bax) and B cell lymphoma 2 (Bcl-2) were measured with western blot and immunohistochemical.. Both Huangqi decoction and Enalapril improved the kidney function, 24 h urinary protein and the fibrosis in 5/6 nephrectomy mice, Huangqi decoction downregulated the expressions of TGF-β1, FSP-1, α-SMA, Collagen III and CTGF in a dose-dependent manner, and it has a significant difference ( 0.01) compared with model group.Huangqi decoction downregulated the expressions of P-P38, P-JNK, P-ERK and Bcl-2 in a dose-dependent manner, while upregulated the expression of Bax.. The protective effect of Huangqi decoction for renal interstitial fibrosis in 5/6 nep-hrectomized mice the inhibition of Epithelial-Mesenchymal Transitions and downregulating the TGF-β1/ MAPK signaling pathway.

Topics: Animals; bcl-2-Associated X Protein; Drugs, Chinese Herbal; Enalapril; Fibrosis; Kidney; Kidney Diseases; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Nephrectomy; Signal Transduction; Transforming Growth Factor beta1; Ureteral Obstruction

Transient ACE (angiotensin-converting enzyme) inhibition in spontaneously hypertensive rats is known to protect against future injury-induced cardiac inflammation, fibrosis, and dysfunction; however, the mechanisms of protection have not been delineated. Here, we used single-cell RNA sequencing to test the hypothesis that transient ACE inhibitor treatment would induce a persistent shift in cardiac fibroblast subpopulations. Adult male spontaneously hypertensive rats (11 weeks old, hypertensive with cardiac hypertrophy) were treated for 2 weeks with an ACE inhibitor, enalapril (30 mg/kg per day, PO), or water (untreated spontaneously hypertensive rats) followed by a 2-week washout period (n=7/group). Cardiac fibroblasts were isolated from the left ventricle and subjected to single-cell RNA sequencing. Nine clusters of fibroblasts were identified, with 98% of cells in clusters 0 to 6. The transient treatment produced significant changes both within and across clusters. Cluster 1 depicted a highly fibrogenic gene profile, with cluster 6 serving as a gateway to cluster 1. Transient ACE inhibition depleted the gateway and expanded cluster 0, which was the least fibrogenic profile. Moreover, within cluster 1 fibroblasts, ACE inhibition reduced expression of individual fibrosis genes (eg,

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cells, Cultured; Cluster Analysis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type III; Enalapril; Fibroblasts; Fibronectins; Fibrosis; Gene Expression Profiling; Gene Expression Regulation; Heart; Hypertension; Male; Myocardium; Rats, Inbred SHR

Anti-cardiac fibrosis (CF) is one of the key therapeutic strategies for the treatment of various heart diseases. Therefore, development of drugs targeting CF is promising. However, there are very few studies that systemically explore effective drugs for CF. It has been known that many natural compounds display antifibrosis effects. In this work, we aim to build an integrated model for systematic pursuit of anti-CF agents from natural compounds. We first constructed a heart-specific CF marker-gene-centered functional gene module (HCFM) that represents a set of genes specifically involved in CF based on the CF marker genes and known gene coexpression knowledge. Then, we extracted transcriptional data induced by natural compounds from the Gene Expression Omnibus database. The anti-CF effects of compounds were evaluated by the correlation of HCFM in the compound-induced gene expression profiles by gene set enrichment analysis. Finally, the anti-CF effect of a top-predicted natural monomer, schisantherin A, was experimentally validated in the myocardial infarction animal model. This strategy integrating different types of technologies is expected to help create new opportunities for development of drugs targeting CF.

Topics: Animals; Biological Products; Cardiomyopathies; Fibrosis; Gene Regulatory Networks; Humans; Molecular Structure; Transcriptome

Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on

Topics: Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Disease Progression; Enalapril; Enzyme Inhibitors; Epoxide Hydrolases; Fibrosis; Glomerular Mesangium; Glomerulonephritis; Hypertension; Male; Mice; Phenylurea Compounds; Piperidines; Reperfusion Injury

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.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Apoptotic Protease-Activating Factor 1; Blood Urea Nitrogen; Collagen Type I; Creatinine; Disease Models, Animal; Enalapril; Epithelial Cells; Fas-Associated Death Domain Protein; Fibrosis; Kidney Diseases; Male; Pyridones; Random Allocation; Rats, Sprague-Dawley; Transcription Factor CHOP; Ureteral Obstruction

Brain renin-angiotensin system (RAS) hyperactivity has been implicated in sympathetic hyperactivity and progressive left ventricular (LV) dysfunction after myocardial infarction (MI). Angiotensin III, generated by aminopeptidase A (APA), is one of the main effector peptides of the brain RAS in the control of cardiac function. We hypothesized that orally administered firibastat (previously named RB150), an APA inhibitor prodrug, would attenuate heart failure (HF) development after MI in mice, by blocking brain RAS hyperactivity. Two days after MI, adult male CD1 mice were randomized to three groups, for four to eight weeks of oral treatment with vehicle (MI + vehicle), firibastat (150 mg/kg; MI + firibastat) or the angiotensin I converting enzyme inhibitor enalapril (1 mg/kg; MI + enalapril) as a positive control. From one to four weeks post-MI, brain APA hyperactivity occurred, contributing to brain RAS hyperactivity. Firibastat treatment normalized brain APA hyperactivity, with a return to the control values measured in sham group two weeks after MI. Four and six weeks after MI, MI + firibastat mice had a significant lower LV end-diastolic pressure, LV end-systolic diameter and volume, and a higher LV ejection fraction than MI + vehicle mice. Moreover, the mRNA levels of biomarkers of HF (Myh7, Bnp and Anf) were significantly lower following firibastat treatment. For a similar infarct size, the peri-infarct area of MI + firibastat mice displayed lower levels of mRNA for Ctgf and collagen types I and III (markers of fibrosis) than MI + vehicle mice. Thus, chronic oral firibastat administration after MI in mice prevents cardiac dysfunction by normalizing brain APA hyperactivity, and attenuates cardiac hypertrophy and fibrosis.

Topics: Administration, Oral; Animals; Biomarkers; Brain; Cardiomegaly; Disease Models, Animal; Enalapril; Enzyme Inhibitors; Fibrosis; Glutamyl Aminopeptidase; Heart; Heart Failure; Inflammation Mediators; Male; Mice; Myocardial Infarction; Renin-Angiotensin System; Stroke Volume

Renin-angiotensin system (RAS) blockade during nephrogenesis causes a broad range of renal mal-development. Here, we hypothesized that disruption of renal lymphangiogenesis may contribute to tubulointerstitial alterations after RAS blockade during kidney maturation.. Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle for 7 days after birth. Lymphangiogenesis was assessed via immunostaining and/or immunoblots for vascular endothelial growth factor (VEGF)-C, VEGF receptor (VEGFR)-3, Podoplanin, and Ki-67. The intrarenal expression of fibroblast growth factor (FGF)-1, FGF-2, FGF receptor (R)-1, α-smooth muscle actin (α-SMA), and fibroblast-specific protein (FSP)-1 was also determined. Sirius Red staining was performed to evaluate interstitial collagen deposition.. On postnatal day 8, renal lymphangiogenesis was disrupted by neonatal enalapril treatment. The expression of podoplanin and Ki-67 decreased in enalapril-treated kidneys. While the expression of VEGF-C was decreased, the levels of VEGFR-3 receptor increased following enalapril treatment. Enalapril treatment also reduced the renal expression of FGF-1, FGF-2, and FGFR-1. Enalapril-treated kidneys exhibited profibrogenic properties with increased expression of α-SMA and FSP-1 and enhanced deposition of interstitial collagen.. Enalapril treatment during postnatal renal maturation can disrupt renal lymphangiogenesis along with tubulointerstitial changes, which may result in a pro-fibrotic environment in the developing rat kidney.

Topics: Actins; Angiotensins; Animals; Animals, Newborn; Calcium-Binding Proteins; Collagen; Enalapril; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Fibrosis; Ki-67 Antigen; Kidney Diseases; Kidney Glomerulus; Kidney Tubules; Lymphangiogenesis; Muscle, Smooth; Rats; Rats, Sprague-Dawley; Receptor, Fibroblast Growth Factor, Type 1; Renin-Angiotensin System; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3

To observe the effect of enalapril on the apoptosis of renal tubular epithelial cells in renal interstitial fibrosis rats and to explore the mechanism of enalapril on renal interstitial fibrosis.
 Methods: Twenty-four SD male rats were randomly divided into a sham operation group, a model group and an enalapril group (n=8 in each group). The rats in the model group and the enalapril group underwent the operation of left urethral obstruction to establish the animal model of unilateral urethral obstruction (UUO). Fourteen days later after the operation, all rats were sacrificed and their obstructed kidneys were collected for HE and Masson staining to observe the pathological change of renal tissues. Terminal deoxynucleotidyl transferase-mediated (dUTP) nick end-labeling (TUNEL) staining was used to detect the apoptosis of renal tubular epithelial cells. Immunohistochemistry and Western blotting were used to detect the protein expression of Fas-associated death domain (FADD), apoptotic protease activating factor-1 (APAF-1) and C/EBP homologous protein (CHOP).
 Results: Compared with the sham operation group, the renal interstitial injury index and renal interstitial fibrosis index were significantly increased in the model group (P<0.05). Compared with the model group, the renal interstitial injury index and renal interstitial fibrosis index were both significantly decreased in the enalapril group (P<0.05). Compared with the sham group, the apoptosis rate of renal tubular epithelial cells was increased in the model group (P<0.05); compared with the model group, the apoptosis rate of renal tubular epithelial cells was significantly reduced in the enalapril group (P<0.05). The protein levels of FADD, APAF-1 and CHOP in the model group were significantly elevated than those in the sham group (all P<0.05), which were reversed in presence of enalapril (all P<0.05). 
 Conclusion: Enalapril can alleviate renal interstitial fibrosis through inhibiting apoptosis of renal tubular epithelial cells in UUO rats.. 目的：观察依那普利对肾间质纤维化大鼠肾小管上皮细胞凋亡的影响，探讨依那普利抗肾间质纤维化的作用机制。方法：将24只SD雄性大鼠随机分为假手术组(n=8)、模型组(n=8)和依那普利治疗组(n=8)。对模型组和依那普利治疗组大鼠行左侧输尿管结扎术，建立单侧输尿管梗阻(unilateral urethral obstruction，UUO)模型。术后14 d处死大鼠，留取梗阻侧肾组织分别进行HE和Masson染色，观察各组大鼠肾组织病理改变，用脱氧核糖核苷酸末端转移酶介导的缺口末端标记法[terminal deoxynucleotidyl transferase-mediated (dUTP) nick end-labeling，TUNEL]染色检查肾小管上皮细胞凋亡，免疫组织化学及蛋白质印迹法检测Fas相关死亡结构域(Fas-associated death domain，FADD)、凋亡蛋白酶活化因子-1(apoptotic protease activating factor-1，APAF-1)、C/EBP同源蛋白(C/EBP homologous protein，CHOP)的蛋白表达。结果：HE染色、Masson染色显示模型组肾间质损伤指数、肾间质纤维化指数均较假手术组明显增高(均P<0.05)，依那普利治疗组肾间质损伤指数、肾间质纤维化指数均较模型组明显降低(均P<0.05)。TUNEL染色显示模型组肾小管上皮细胞凋亡计数较假手术组明显增多(P<0.05)，依那普利治疗组肾小管上皮细胞凋亡数较模型组明显减少(P<0.05)。免疫组织化学及蛋白质印迹法显示模型组肾组织FADD，APAF-1和CHOP的蛋白表达均较假手术组明显增多(均P<0.05)，依那普利治疗组肾组织FADD，APAF-1和CHOP的蛋白表达均较模型组明显降低(均P<0.05)。结论：依那普利可通过抑制UUO大鼠的肾小管上皮细胞凋亡而起到抑制肾间质纤维化的作用。.

Topics: Animals; Apoptosis; Enalapril; Epithelial Cells; Fibrosis; Kidney Tubules; Male; Rats; Ureteral Obstruction

Transgenic mice constitutively overexpressing the cytokine transforming growth factor-β1 (TGF-β1) (TGF mice) display cerebrovascular alterations as seen in Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID), but no or only subtle cognitive deficits. TGF-β1 may exert part of its deleterious effects through interactions with angiotensin II (AngII) type 1 receptor (AT1R) signaling pathways. We test such interactions in the brain and cerebral vessels of TGF mice by measuring cerebrovascular reactivity, levels of protein markers of vascular fibrosis, nitric oxide synthase activity, astrogliosis, and mnemonic performance in mice treated (6 months) with the AT1R blocker losartan (10 mg/kg per day) or the angiotensin converting enzyme inhibitor enalapril (3 mg/kg per day). Both treatments restored the severely impaired cerebrovascular reactivity to acetylcholine, calcitonin gene-related peptide, endothelin-1, and the baseline availability of nitric oxide in aged TGF mice. Losartan, but not enalapril, significantly reduced astrogliosis and cerebrovascular levels of profibrotic protein connective tissue growth factor while raising levels of antifibrotic enzyme matrix metallopeptidase-9. Memory was unaffected by aging and treatments. The results suggest a pivotal role for AngII in TGF-β1-induced cerebrovascular dysfunction and neuroinflammation through AT1R-mediated mechanisms. Further, they suggest that AngII blockers could be appropriate against vasculopathies and astrogliosis associated with AD and VCID.

Topics: Animals; Brain; Enalapril; Female; Fibrosis; Gliosis; Losartan; Male; Mice; Mice, Transgenic; Receptor, Angiotensin, Type 1; Signal Transduction; Transforming Growth Factor beta1

Cardiovascular disease constitutes the leading cause of mortality in patients with chronic kidney disease (CKD) and end-stage renal disease. Despite increasing recognition of a close interplay between kidney dysfunction and cardiovascular disease, termed cardiorenal syndrome (CRS), the underlying mechanisms of CRS remain poorly understood. Here we report the development of pathological cardiac hypertrophy and fibrosis in early stage non-uremic CKD. Moderate kidney failure was induced three weeks after unilateral urinary obstruction (UUO) in mice. We observed pathological cardiac hypertrophy and increased fibrosis in UUO-induced CKD (UUO/CKD) animals. Further analysis indicated that this cardiac fibrosis was associated with increased expression of transforming growth factor β (TGF-β) along with significant upregulation of Smad 2/3 signaling in the heart. Moreover early treatment of UUO/CKD animals with an angiotensin-converting-enzyme inhibitor (ACE I), Enalapril, significantly attenuated cardiac fibrosis. Enalapril antagonized activation of the TGF-β signaling pathway in the UUO/CKD heart. In summary our study demonstrates the presence of pathological cardiac hypertrophy and fibrosis in mice early in UUO-induced CKD, in association with early activation of the TGF-β/Smad signaling pathway. We also demonstrate the beneficial effect of ACE I in alleviating this early fibrogenic process in the heart in UUO/CKD animals.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiomegaly; Enalapril; Fibrosis; Heart Ventricles; Hypertension; Male; Mice, Inbred C57BL; Organ Size; Renal Insufficiency, Chronic; Signal Transduction; Transforming Growth Factor beta; Up-Regulation; Ureteral Obstruction; Ventricular Remodeling

We investigated whether the treatment with enalapril maleate, combined with aerobic physical training, promotes positive effects on the autonomic balance, the morphology and the cardiac function in female rats submitted to early ovarian failure.. Thirty-five female Wistar rats, ovariectomized at 10weeks of age, were assigned into Ovariectomized rats (OVX) and Ovariectomized rats treated with enalapril maleate (OVX-EM, 10mg. The OVX-EM sedentary group showed a significant increase in cardiac fibrosis, relative heart weight, interventricular septum thickness and increased sympathetic participation and reduced participation of the vagal tone in the determination of the basal heart rate when compared to the OVX sedentary group. Physical training reduced cardiac fibrosis in both groups, however, with less intensity in the OVX-EM group. It also increased the absolute and relative heart weight and the end-systolic volume. Finally, the OVX-EM trained group showed higher values for left ventricular end-systolic volume and lower values for ejection fraction and shortening fraction than the sedentary OVX-EM group.. Enalapril maleate exacerbated cardiac fibrosis and increased sympathetic participation in the basal heart rate determination, without significantly affecting the cardiac function. Aerobic physical training did not change the cardiac autonomic control, but reduced cardiac fibrosis and had little effect on the cardiac function.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Echocardiography; Enalapril; Exercise Therapy; Female; Fibrosis; Heart; Heart Diseases; Hemodynamics; Myocardium; Organ Size; Ovarian Diseases; Ovariectomy; Physical Conditioning, Animal; Rats, Wistar; Swimming

Renal interstitial fibrosis (IF) is an important pathologic manifestation of disease progression in a variety of chronic kidney diseases (CKD). However, the quantitative and reproducible analysis of IF remains a challenge, especially in experimental animal models of progressive IF. In this study, we compare traditional polarized Sirius Red morphometry (SRM) to novel Second Harmonic Generation (SHG)-based morphometry of unstained tissues for quantitative analysis of IF in the rat 5 day unilateral ureteral obstruction (UUO) model. To validate the specificity of SHG for detecting fibrillar collagen components in IF, co-localization studies for collagens type I, III, and IV were performed using IHC. In addition, we examined the correlation, dynamic range, sensitivity, and ability of polarized SRM and SHG-based morphometry to detect an anti-fibrotic effect of three different treatment regimens. Comparisons were made across three separate studies in which animals were treated with three mechanistically distinct pharmacologic agents: enalapril (ENA, 15, 30, 60 mg/kg), mycophenolate mofetil (MMF, 2, 20 mg/kg) or the connective tissue growth factor (CTGF) neutralizing antibody, EX75606 (1, 3, 10 mg/kg). Our results demonstrate a strong co-localization of the SHG signal with fibrillar collagens I and III but not non-fibrillar collagen IV. Quantitative IF, calculated as percent cortical area of fibrosis, demonstrated similar response profile for both polarized SRM and SHG-based morphometry. The two methodologies exhibited a strong correlation across all three pharmacology studies (r2 = 0.89-0.96). However, compared with polarized SRM, SHG-based morphometry delivered a greater dynamic range and absolute magnitude of reduction of IF after treatment. In summary, we demonstrate that SHG-based morphometry in unstained kidney tissues is comparable to polarized SRM for quantitation of fibrillar collagens, but with an enhanced sensitivity to detect treatment-induced reductions in IF. Thus, performing SHG-based morphometry on unstained kidney tissue is a reliable alternative to traditional polarized SRM for quantitative analysis of IF.

Topics: Animals; Antibodies, Monoclonal; Azo Compounds; Collagen; Dose-Response Relationship, Drug; Enalapril; Fibrosis; Kidney Diseases; Male; Mycophenolic Acid; Non-Fibrillar Collagens; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Ureteral Obstruction

Chronic allograft fibrosis is the major cause of graft loss in kidney transplantation. Progression can only be reduced by inhibition of the renin-angiotensin system (RAS). We tested the hypothesis that the protection provided by angiotensin-converting enzyme (ACE) inhibition also decreases capillary rarefaction, lymphangiogenesis, and podocyte injury in allograft fibrosis. Fisher kidneys were transplanted into bilaterally nephrectomized Lewis rats treated with enalapril (60 mg/kg per day) (ACE inhibitor, ACEi) or vehicle. Proteinuria, blood urea nitrogen, and plasma creatinine were regularly assessed, and grafts were harvested for morphological and immunohistological analysis at various times up to 32 wk. In the vehicle group, many new lymphatic capillaries and severe and diffuse mononuclear infiltration of allografts were observed already 1 wk after transplantation. Lymphangiogenesis increased until week 4, by which time inflammatory infiltration became focal. Lymphatic capillaries were often located at sites of inflammation. Progressive interstitial fibrosis, glomerulosclerosis, capillary rarefaction, and proteinuria appeared later, at weeks 4-12 The number of lymphatic capillary cross sections strongly correlated with the interstitial fibrosis score. Podoplanin immunostaining, a marker of healthy podocytes, disappeared from inflamed or sclerotic glomerular areas. ACEi protected from lymphangiogenesis and associated inflammation, preserved glomerular podoplanin protein expression, and reduced glomerulosclerosis, proteinuria, tubulointerstitial fibrosis, and blood capillary rarefaction at 32 wk. In conclusion, ACEi considerably decreased and/or delayed both glomerulosclerosis and tubulointerstitial injury. Prevention of glomerular podoplanin loss and proteinuria could be attributed to the known intraglomerular pressure-lowering effects of ACEi. Reduction of lymphangiogenesis could contribute to amelioration of tubulointerstitial fibrosis and inflammatory infiltration after ACEi.

Topics: Allografts; Angiotensin-Converting Enzyme Inhibitors; Animals; Capillaries; Enalapril; Fibrosis; Kidney; Kidney Glomerulus; Kidney Transplantation; Lymphangiogenesis; Lymphatic Vessels; Male; Membrane Glycoproteins; Podocytes; Proteinuria; Rats; Rats, Inbred F344; Rats, Inbred Lew

Vitamin D receptor (VDR) agonists (VDRAs) are commonly used to manage hyperparathyroidism secondary to chronic kidney disease (CKD). Patients with CKD experience extremely high risks of cardiovascular morbidity and mortality. Clinical observations show that VDRA therapy may be associated with cardio-renal protective and survival benefits in patients with CKD. The 5/6 nephrectomized (NX) Sprague-Dawley rat with established uremia exhibits elevated serum parathyroid hormone (PTH), hypertension, and abnormal cardiac function. Treatment of 5/6 NX rats with VS-105, a novel VDRA (0.05 and 0.5 μg/kg po by gavage), once daily for 8 wk in the presence or absence of enalapril (30 mg/kg po via drinking water) effectively suppressed serum PTH without raising serum calcium. VS-105 alone reduced systolic blood pressure (from 174 ± 6 to 145 ± 9 mmHg, P < 0.05) as effectively as enalapril (from 174 ± 6 to 144 ± 7 mmHg, P < 0.05). VS-105 improved cardiac functional parameters such as E/A ratio, ejection fraction, and fractional shortening with or without enalapril. Enalapril or VS-105 alone significantly reduced left ventricular hypertrophy (LVH); VS-105 plus enalapril did not further reduce LVH. VS-105 significantly reduced both cardiac and renal fibrosis. The lack of hypercalcemic toxicity of VS-105 is due to its lack of effects on stimulating intestinal calcium transport and inducing the expression of intestinal calcium transporter genes such as Calb3 and TRPV6. These studies demonstrate that VS-105 is a novel VDRA that may provide cardiovascular benefits via VDR activation. Clinical studies are required to confirm the cardiovascular benefits of VS-105 in CKD.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Calcitriol; Cardiotonic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Fibrosis; Hyperparathyroidism; Hypertension; Hypertrophy, Left Ventricular; Kidney; Male; Myocardial Contraction; Myocardium; Nephrectomy; Parathyroid Hormone; Rats, Sprague-Dawley; Receptors, Calcitriol; Recovery of Function; Renal Insufficiency, Chronic; Stroke Volume; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left

The objective of this study is to determine the effect of two angiotensin-converting enzyme inhibitors (ACEi) (Enalapril and Captopril), an angiotensin-II receptor inhibitor (Losartan) and a renin inhibitor (Aliskiren) on renin, TGF-β1 and collagen expressions in human lung fibroblast cultures through real-time PCR and ELISA.. Normal commercial fibroblasts (CCD25) were exposed to 10(-6) M of enalapril, captopril, losartan, or aliskiren for 6 h. Subsequently, media were recovered and proteins were concentrated; RNA was extracted from the cells. Real time-PCR and ELISA were performed.. ACEi and losartan-stimulated fibroblasts showed an increase in the expression of TGF-β1, Collagen-Iα1 (Col-Iα1), and renin (except losartan) vs PolR2A (p < 0.05), and upregulation of TGF-β1 protein (p < 0.01), except with aliskiren.. Results show that ACEis and losartan could play a profibrosing role by inducing the overexpression of molecules such TGF-β1 and Collagen.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cells, Cultured; Collagen Type I; Collagen Type I, alpha 1 Chain; Enalapril; Fibroblasts; Fibrosis; Fumarates; Humans; Losartan; Lung; Protein Biosynthesis; Renin; Transcription, Genetic; Transforming Growth Factor beta1

What is the central question of this study? Although cardioprotective effects of dipeptidyl peptidase-4 (DPP-4) inhibitors have been demonstrated, their cardiac effects in chronic myocardial infarction (MI) are unclear. We determined the effects of a DPP-4 inhibitor on cardiac function and remodelling in rats with chronic MI. What is the main finding and its importance? We demonstrated, for the first time, that DPP-4 inhibitor, but not metformin, exerted similar efficacy in improving cardiac function and attenuating cardiac fibrosis compared with enalapril in rats with chronic MI. These findings reveal benefits additional to the glycaemic control by the DPP-4 inhibitor in chronic MI, and it might become the new drug of choice for MI in patients with diabetes mellitus. Adverse cardiac remodelling after myocardial infarction (MI) leads to progressive heart failure. Dipeptidyl peptidase-4 (DPP-4) inhibitors are new antidiabetic drugs that exert cardioprotection. However, their role in cardiac function and remodelling in chronic MI is unclear. We hypothesized that the DPP-4 inhibitor vildagliptin reduces adverse cardiac remodelling and improves cardiac function in rats with chronic MI. These effects were also compared with enalapril and metformin. Male Wistar rats (n = 36) with chronic MI induced by ligation of the left anterior descending coronary artery were divided into six groups to receive vehicle, vildagliptin (3 mg kg(-1)  day(-1) ), metformin (30 mg kg(-1)  day(-1) ), enalapril (10 mg kg(-1)  day(-1) ), combined metformin and enalapril or combined vildagliptin and enalapril for 8 weeks. At the end of the study, plasma malondialdehyde (MDA), heart rate variability (HRV), left ventricular (LV) function, pathological and biochemical studies of cardiac remodelling were investigated. Our study demonstrated that rats with chronic MI had increased oxidative stress levels, depressed HRV, adverse cardiac remodelling, indicated by cardiac fibrosis, and LV dysfunction. Treatment with vildagliptin or enalapril significantly decreased oxidative stress, attenuated cardiac fibrosis and improved HRV and LV function. We conclude that vildagliptin exerts similar cardioprotective effects to enalapril in attenuating oxidative stress and cardiac fibrosis and improving cardiac function in rats with chronic MI. Metformin does not provide these benefits in this model. Moreover, addition of either metformin or vildagliptin to enalapril does not provide additional benefit in a

Topics: Adamantane; Angiotensin-Converting Enzyme Inhibitors; Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Enalapril; Fibrosis; Heart Rate; Hypoglycemic Agents; Male; Metformin; Myocardial Infarction; Myocardium; Nitriles; Oxidative Stress; Pyrrolidines; Rats, Wistar; Recovery of Function; Signal Transduction; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling; Vildagliptin

The purpose of this study is to investigate the antifibrosis and antioxidation of ShenKang injection (SKI) in vivo and in vitro and to evaluate potential mechanisms involved in the treatment of chronic kidney disease (CKD).. In experimental animal studies, CKD was established by 5/6 nephrectomy (5/6Nx). Serum creatinine (Scr) and blood urea nitrogen (BUN) were determined. Histopathological tests were performed by H&E and Masson trichrome stained. The protein expressions of fibronectin (FN), collagen Ι, α-smooth muscle actin (α-SMA) and transforming growth factor-β (TGF-β) and phosphorylation of Smad3 were measured in 5/6Nx rats. In Human kidney proximal tubular cell line (HK-2) cells, the effects of TGF-β/Smad3 signalling pathway on renal fibrosis and oxidative injury were examined.. 5/6Nx induced severe renal damages. Treatment of rats with SKI markedly reduced levels of Scr and BUN, alleviated expression of fibrosis-associated signalling molecules and reduced expression of TGF-β and phosphorylated Smad3. Meanwhile, in HK-2 cells, after exposure to TGF-β and H2 O2 , the protein expression of renal fibrosis was significantly increased. The generation of oxidative stress was also elevated. The severity of fibrosis and oxidative damage appears to be reduced after treatment with SKI.. SKI inhibits renal fibrosis and oxidative stress through downregulation of TGF-β/Smad3 signalling pathway.

Topics: Animals; Blood Urea Nitrogen; Cell Line; Creatinine; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Enalapril; Fibrosis; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Hydrogen Peroxide; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

You-gui Pill (YGP), a traditional Chinese medicinal prescription, was widely used to warm and recuperate "kidney-yang" clinically for hundreds of years in China. Recent studies found that YGP had a potential benefit for renoprotection.. The present study aimed to elucidate the in vivo and in vitro efficacy of YGP on renal tubulointerstitial fibrosis, and the molecular mechanism is also investigated.. Rat renal tubulointerstitial fibrosis model was elicited by unilateral ureteral obstruction (UUO). Sprague-Dawley rats underwent UUO and were studied after 14 days. Animals were randomly subjected to six groups: sham, UUO, UUO/YGP (0.14, 0.42, 1.26g/kg/d), and UUO/enalapril (10mg/kg/d). HE, Masson and ELISA were used for evaluate renal injury and function. Immunohistochemical analysis and western blot were used to detect the expressions of α-SMA, fibronectin, collagen matrix and Smads. In vitro studies were investigated in TGF-β1-stiumlated NRK-49F cell line.. Oral administration of YGP significantly decreased UUO-induced inflammatory cell infiltration, tubular atrophy and interstitial fibrosis, and there was no significant difference between YGP at 1.26g/kg and enalapril at 10mg/kg treatment (P>0.05). Meanwhile, serum creatinine and blood urea nitrogen levels were reduced dramatically (P<0.01). In coincide with the decreased of TGF-β1, α-SMA, fibronectin and collagen matrix expressions were also declined with YGP treatment in both UUO kidneys and TGF-β1-stimulated NRK-49F cell line. Additionally, nuclear translocation of p-Smad2/3 was markedly down-regulated by YGP (P<0.001), with a relative mild up-regulated expression of Smad7 (P<0.05).. Our findings demonstrate that YGP had a renoprotective effect in ameliorating renal tubulointerstitial fibrosis, and this activity possibly via suppression of the TGF-β and its downstream regulatory signaling pathway, including Smad2/3.

Topics: Actins; Animals; Cells, Cultured; Dose-Response Relationship, Drug; Down-Regulation; Drugs, Chinese Herbal; Enalapril; Fibrosis; Kidney Diseases; Male; Rats; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Up-Regulation

Transient angiotensin-converting enzyme (ACE) inhibition induces persistent changes that protect against future nitric oxide synthase (NOS) inhibitor-induced cardiac fibrosis and inflammation. Given the role of fibroblasts in mediating these effects, the present study investigates whether prior ACE inhibition produced persistent changes in cardiac fibroblast physiology. Adult male spontaneously hypertensive rats (SHRs) were treated with vehicle (C+L) or the ACE inhibitor, enalapril (E+L) for 2 wk followed by a 2-wk washout period and a subsequent 7-day challenge with the NOS inhibitor N(ω)-nitro-l-arginine methyl ester. A third set of untreated SHRs served as controls. At the end of the study period, cardiac fibroblasts were isolated from control, C+L, and E+L left ventricles to assess proliferation rate, collagen expression, and chemokine release in vitro. After 7 days of NOS inhibition, there were areas of myocardial injury but no significant change in collagen deposition in E+L and C+L hearts in vivo. In vitro, cardiac fibroblasts isolated from C+L but not E+L hearts were hyperproliferative, demonstrated increased collagen type I gene expression, and an elevated secretion of the macrophage-recruiting chemokines monocyte chemoattractant protein-1 and granulocyte macrophage-colony stimulating factor. These findings demonstrate that in vivo N(ω)-nitro-l-arginine methyl ester treatment produces phenotypic changes in fibroblasts that persist in vitro. Moreover, this is the first demonstration that transient ACE inhibition can produce a persistent modification of the cardiac fibroblast phenotype to one that is less inflammatory and fibrogenic. It may be that the cardioprotective effects of ACE inhibition are related in part to beneficial changes in cardiac fibroblast physiology.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomyopathies; Cell Proliferation; Cells, Cultured; Chemokine CCL2; Collagen Type I; Disease Models, Animal; Enalapril; Fibroblasts; Fibrosis; Granulocyte-Macrophage Colony-Stimulating Factor; Heart Ventricles; Hypertension; Inflammation Mediators; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Phenotype; Rats, Inbred SHR; Time Factors

Relaxin is a naturally occurring peptide hormone that mediates systemic hemodynamic and renal adaptive changes during pregnancy and abrogates aberrant scar tissue formation (fibrosis) in diverse pathogeneses. However, its efficacy relative to renin–angiotensin system blockade, the most effective antifibrotic strategy currently available, is not known. We compared the individual versus combined antifibrotic effects of serelaxin (a recombinant form of human gene-2 relaxin) and the angiotensin-converting enzyme inhibitor enalapril, in preventative (started before injury) and therapeutic (treatment of established fibrosis) strategies, in a mouse model of isoprenaline-induced cardiac injury (at 17 days). Changes in systolic blood pressure, organ hypertrophy, and tissue remodeling/fibrosis were assessed. Pretreatment with serelaxin (0.5 mg/kg per day via subcutaneous administration) alone reduced cardiac fibrosis to a greater extent than enalapril (200 mg/L via drinking water; equivalent to 48 mg/kg per day) alone (P<0.05 versus enalapril alone). Additionally, the combined effects of serelaxin and enalapril reduced cardiac fibrosis by at least 2-fold compared with enalapril alone, when administered preventatively or therapeutically; by suppressing transforming growth factor-β1 expression and phosphorylation of Smad2 (an intracellular regulator of transforming growth factor-β1 activity; both P<0.05 versus enalapril alone) to a greater extent. The effects of serelaxin were independent of blood pressure, while enalapril lowered systolic blood pressure in the model studied. These findings suggest that serelaxin alone and in combination with an angiotensin-converting enzyme inhibitor more effectively ameliorates fibrosis than angiotensin-converting enzyme inhibition alone in the diseased heart, in a clinically relevant experimental scenario.

Topics: Animals; Blood Pressure; Enalapril; Fibrosis; Heart; Heart Diseases; Male; Mice; Myocardium; Recombinant Proteins; Relaxin; Renin-Angiotensin System; Treatment Outcome

Chinese herbal compound prescription has a unique therapeutic action on chronic kidney disease (CKD) in China. In clinics, Uremic Clearance Granules (UCG), a compounded Chinese patent medicine, has been frequently used to treat chronic renal failure (CRF) patients for nearly 30 years, however, the deep therapeutic mechanisms involved in vivo remain a challenge. This study aims to demonstrate the effects and mechanisms of UCG on renal dysfunction and tubulointerstitial fibrosis by regulating extracellular matrix (ECM) degradation and transforming growth factor (TGF)-beta1/Smad signaling activity in vivo, compared with enalapril.. Twenty-six rats were randomly divided into 4 groups, a sham-operated group (Sham group), a vehicle-intervened group (Vehicle group), a UCG-treated group (UCG group) (5g/kg/day) and an enalapril-treated group (Enalapril group) (20mg/kg/day). The rats with renal failure were induced by adenine (150 mg/kg/day) and unilateral ureteral obstruction (UUO), and killed on day 35 after the administration. Proteinuria, urinary N-acetyl-beta-D-glucosaminidase (UNAG), blood biochemical parameters, renal morphological changes, collagen type IV (CIV), matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitors of metalloproteinase (TIMP)-1, as well as the key molecular protein expressions in TGF-beta1/Smad signaling pathway were observed, respectively.. Adenine administration and UUO induced severe renal damages, as indicated by renal dysfunction, proteinuria and the marked histopathological injuries in the tubules and interstitium, which were associated with MMP-2/TIMP-1 imbalance and TGF-beta1/Smad signaling activity, as shown by up-regulation of the protein expressions of TGF-beta1, TGF-beta receptor type I (RI), TGF-beta receptor type II (RII), Smad2/3, phosphorylated-Smad2/3 (p-Smad2/3) and Smad4, as well as down-regulation of the protein expression of Smad7 in the kidney. UCG treatment, however, significantly not only attenuated renal dysfunction and tubulointerstitial fibrosis, but also improved the protein expressions of MMP-2, TIMP-1, TGF-beta1, TGF-beta RI, p-Smad2/3, Smad4 and Smad7 in the kidney. Besides, the effects of UCG were stronger than those of enalapril partly.. UCG similar to enalapril, is renoprotective via ameliorating renal dysfunction and tubulointerstitial fibrosis in the renal failure model. The potential mechanisms by which UCG exerts its therapeutical effects in vivo are through promoting ECM degradation and regulating MMP-2/TIMP-1 balance or signaling molecular activity in TGF-beta1/Smad pathway in the kidney. These findings suggest that UCG treatment is undoubtedly useful in preventing the progression of CRF.

Topics: Acetylglucosaminidase; Animals; Disease Models, Animal; Drugs, Chinese Herbal; Enalapril; Extracellular Matrix; Fibrosis; Kidney; Male; Protective Agents; Rats, Sprague-Dawley; Renal Insufficiency; Smad Proteins; Transforming Growth Factor beta1

The renin-angiotensin system (RAS), through angiotensin II and the angiotensin-converting enzyme (ACE), is involved in the genesis and progression of fibrotic diseases characterized by the replacement of normal tissue by an accumulation of an extracellular matrix (ECM). Duchenne muscular dystrophy (DMD) presents fibrosis and a decrease in muscle strength produced by chronic damage. The mdx mouse is a murine model of DMD and develops the same characteristics as dystrophic patients when subjected to chronic exercise. The connective tissue growth factor (CTGF/CCN2) and transforming growth factor type beta (TGF-β), which are overexpressed in muscular dystrophies, play a major role in many progressive scarring conditions. We have tested the hypothesis that ACE inhibition decreases fibrosis in dystrophic skeletal muscle by treatment of mdx mice with the ACE inhibitor enalapril. Both sedentary and exercised mdx mice treated with enalapril showed improvement in gastrocnemius muscle strength explained by a reduction in both muscle damage and ECM accumulation. ACE inhibition decreased CTGF expression in sedentary or exercised mdx mice and diminished CTGF-induced pro-fibrotic activity in a model of CTGF overexpression by adenoviral infection. Enalapril did not have an effect on TGF-β1 expression or its signaling activity in sedentary or exercised dystrophic mice. Thus, ACE inhibition might improve muscle strength and decrease fibrosis by diminishing specifically CTGF expression and activity without affecting TGF-β1 signaling. Our data provide insights into the pathogenic events in dystrophic muscle. We propose ACE as a target for developing therapies for DMD and related diseases.

Topics: Adenoviridae; Adenoviridae Infections; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Connective Tissue Growth Factor; Enalapril; Fibrosis; Male; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Muscle Strength; Muscle, Skeletal; Muscular Dystrophy, Animal; Peptidyl-Dipeptidase A; Physical Conditioning, Animal; Renin-Angiotensin System; Signal Transduction; Transforming Growth Factor beta1

Cardiovascular disease is the primary cause of mortality in patients with chronic kidney disease (CKD). Heart remodeling in CKD comprises mainly interstitial fibrosis and capillary loss. Beyond correcting renal anemia, erythropoietin (Epo) has potentially beneficial pleiotropic effects on heart remodeling.. 12-week-old male Sprague-Dawley rats were randomized to 5/6 nephrectomy (NX) or sham operation (sham-op); subsequently, they received murine Epo (2.5 μg/kg/week), enalapril (12 mg/kg/day), Epo + enalapril, Epo + dihydralazine (25 mg/kg/day), or vehicle. Heart function and morphology was assessed after 16 weeks of treatment.. Compared with sham-op (81.2%), left ventricle fractional shortening was reduced in vehicle-treated NX (66.3%) and this was ameliorated by Epo (72.6%) and even prevented by enalapril (80.6%). Capillary length density was lower and the area of fibrosis more marked in vehicle-treated NX compared to sham-op. Capillary rarefaction and heart fibrosis were prevented in NX treated with Epo + enalapril and reduced in NX treated with enalapril and Epo + dihydralazine. Despite higher blood pressure, treatment with Epo reduced heart fibrosis but failed to prevent capillary loss. In parallel, expression of the p47phox NADPH oxidase was higher in untreated NX and was effectively reduced in NX treated with Epo + enalapril. Under basal conditions there was no difference between the groups regarding myocardial hypoxia as reflected by pimonidazole staining.. Epo in combination with enalapril caused additive reduction of cardiac fibrosis and microvessel disease in 5/6 nephrectomized rats presumably by decreasing myocardial oxidative stress.

Topics: Albumins; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Apoptosis; Blood Pressure; Drug Synergism; Echocardiography; Enalapril; Erythropoietin; Fibrosis; Heart; Heart Rate; Hemoglobins; Kidney; Kidney Failure, Chronic; Male; Microcirculation; Myocardium; Nephrectomy; Oxidative Stress; Rats; Rats, Sprague-Dawley; Time Factors

Diabetes mellitus is characterized by hyperglycemia, which induces oxidative stress and perturbs a number of pathways, leading to tissue injury. One of the pathological responses to tissue injury is the development of fibrosis and cell death. Enalapril is a non-thiol angiotensin-converting enzyme inhibitor that is commonly used in the treatment of diabetes-associated hypertension. The present study examines the possible beneficial effects of enalapril on the development of diabetes associated fibrosis and DNA damage in rats. Sprague-Dawley rats (250 ± 10 g) were used in the study. Enalapril (10 mg kg(-1) per oral) was administered for four consecutive weeks to the streptozotocin (STZ)-induced diabetic rats. After 4 weeks, all the animals were sacrificed and comet assay (normal and modified) was performed to detect the normal as well as oxidative DNA damage. Expression of profibrotic marker CCN2 and fibrosis was examined in the heart, kidney and liver of diabetic rats. Enalapril treatment significantly restored the malondialdehyde and glutathione content as well as the DNA damage in the heart, kidney and liver of diabetic rat. Significant decrease in the expression of CCN2 was observed in the heart, kidney and liver of diabetic rat receiving enalapril treatment as compared with the diabetic group. Further, the enalapril treatment led to significant decrease in the fibrosis and CCN2 expression in the diabetic group as compared with control. The results of the present study clearly demonstrate that enalapril ameliorates the DNA damage, cell death and expression of CCN2 in the heart, kidney and liver of the STZ-induced diabetic rat.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Comet Assay; Connective Tissue Growth Factor; Diabetes Mellitus, Experimental; DNA Damage; Enalapril; Fibrosis; Heart; Kidney; Liver; Male; Myocardium; Oxidative Stress; Rats; Rats, Sprague-Dawley; Streptozocin

Hydrogen sulfide (H2S) has been recently found to be an endogenous signaling gasotransmitter. Cardiac hypertrophy often develops in the course of heart failure. It is unknown whether or not endogenous H2S protects cardiac hypertrophy. This study was conducted to examine the effects of H2S on cardiac hypertrophy and fibrosis induced by abdominal aortic coarctation and to explore its mechanisms. Male Sprague-Dawley rats were randomly divided into five groups: normal, sham, abdominal aortic coarctation (AAC), AAC treated with enalapril and AAC treated with H2S. One week after surgery, enalapril and sodium hydrosulfide (NaHS)-treated rats were fed for 28 consecutive days and sacrificed. After that, the left ventricle mass index (LVMI), cardiomyocyte size and areas, collagen volume fraction (CVF) of the rats were measured. In the AAC rats, the LVMI, the cardiomyocyte size and areas, and the CVF were all markedly increased while in the H2S groups they were significantly reduced. H2S decreased the levels of Ang-II in the heart, but not in plasma. In addition, H2S also improved the expression of connexin 43 (Cx43). Our results suggest that H2S can significantly suppress cardiac hypertrophy and fibrosis induced by overloaded pressure, possibly by inhibiting the activity of intracardiac Ang-II and by modifying expression of Cx43.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Aortic Coarctation; Cardiomegaly; Connexin 43; Enalapril; Fibrosis; Hydrogen Sulfide; Male; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley

Our long-term goal is to use angiotensin converting enzyme (ACE) inhibitors to mitigate the increase in lung collagen synthesis that is induced by irradiation to the lung, which could result from accidental exposure or radiological terrorism. Rats (WAG/RijCmcr) were given a single dose of 13 Gy (dose rate of 1.43 Gy/min) of X-irradiation to the thorax. Three structurally-different ACE inhibitors, captopril, enalapril and fosinopril were provided in drinking water beginning 1 week after irradiation. Rats that survived acute pneumonitis (at 6-12 weeks) were evaluated monthly for synthesis of lung collagen. Other endpoints included breathing rate, wet to dry lung weight ratio, and analysis of lung structure. Treatment with captopril (145-207 mg/m(2)/day) or enalapril (19-28 mg/m(2)/day), but not fosinopril (19-28 mg/m(2)/day), decreased morbidity from acute pneumonitis. Lung collagen in the surviving irradiated rats was increased over that of controls by 7 months after irradiation. This increase in collagen synthesis was not observed in rats treated with any of the three ACE inhibitors. Analysis of the lung morphology at 7 months supports the efficacy of ACE inhibitors against radiation-induced fibrosis. The effectiveness of fosinopril against fibrosis, but not against acute pneumonitis, suggests that pulmonary fibrosis may not be a simple consequence of injury during acute pneumonitis. In summary, three structurally-different ACE inhibitors mitigate the increase in collagen synthesis 7 months following irradiation of the whole thorax and do so, even when therapy is started one week after irradiation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Collagen; Dose-Response Relationship, Radiation; Drug Evaluation, Preclinical; Enalapril; Female; Fibrosis; Fosinopril; Gene Expression Regulation; Lung; Pulmonary Fibrosis; Radiation Pneumonitis; Rats; Renin-Angiotensin System; Thorax

Angiotensin converting enzyme (ACE) inhibitors reduce left ventricular (LV) hypertrophy and cardiovascular-renal fibrosis. Experimentally, changes in the LV and kidney persist even after cessation of treatment. The present study investigates whether brief ACE inhibition in spontaneously hypertensive rats (SHR) provides long-term protection against the LV and kidney damage induced by the nitric oxide synthase inhibitor N-ω-nitro-L-arginine-methyl ester (L-NAME). SHR received the ACE inhibitor enalapril (n = 36) or tap water (n = 36). In all, 12 control and treated SHR were sacrificed after 2 weeks and remaining rats were taken off-treatment. After a 2-week washout, 12 controls or previously treated SHR were sacrificed and remaining rats were treated with L-NAME ((control (Con)+L, enalapril (Enal)+L) for 10 days. At sacrifice, blood pressure was recorded via carotid artery cannulation in anesthetized rats, and blood, the kidney and LV were isolated for analysis. LV mass and arterial pressure were significantly reduced by enalapril. LV mass showed a persistent reduction throughout the study. In LV, prior enalapril treatment provided significant (P<0.05) protection against L-NAME-induced increases in proliferating cells (Con+L: 11 ± 10.0 mm(2) vs. Enal+L: 4 ± 4.4 mm(2)), interstitial fibrosis (Con+L: 3 ± 2.5% vs. Enal+L: 1 ± 1.0%) and tissue macrophages (Con+L: 12 ± 9 mm(2) vs. Enal+L: 5 ± 3.6 mm(2)). In the kidney, prior enalapril treatment protected against L-NAME-induced interstitial fibrosis and vascular injury. There was no difference in glomerular size or glomerulosclerosis regardless of prior treatment. Plasma creatinine and urea were significantly increased in L-NAME treated rats. This study suggests that brief ACE inhibition confers protection against future heart and kidney injury, even in the absence of continued antihypertensive treatment.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cell Proliferation; Creatinine; Disease Models, Animal; Enalapril; Fibrosis; Hypertension; Hypertrophy, Left Ventricular; Kidney; Male; NG-Nitroarginine Methyl Ester; Rats; Rats, Inbred SHR; Urea

ACE inhibitors (ACEi) reduce renal tubulointerstitial fibrosis but are not completely effective. Combined extract of Astragalus membranaceus and Angelica sinensis (A&A) is a traditional antifibrotic agent in China. The present investigation aimed to determine whether an ACEi (Enalapril) and A&A together have a better antifibrotic effect in unilateral ureteral obstruction (UUO) than monotherapy with either agent. Male Sprague-Dawley rats (N = 4 per group) had either sham operation or UUO alone, with A&A (combined aqueous and ethanol extract equivalent to 2.1 g dried herbs), with Enalapril (in drinking water at 200 mg/mL) or with both treatments. Kidney and liver were collected for protein extraction or fixed for histologic stains, immunohistochemistry (IHC), microscopy. Enalapril or A&A individually were antifibrotic. Transforming growth factor-beta1, fibroblast activation, collagen deposition, macrophage accumulation and tubular cell apoptosis were all decreased. The combination of the two drugs was significantly more effective than Enalapril alone in reducing tumor necrosis factor-alpha, collagen accumulation, activation of fibroblasts, and tubular cell apoptosis. In conclusion, Enalapril with A&A significantly decreased tubulointerstitial fibrosis to a greater extent than treatment with Enalapril alone. Further studies focusing on the isolation of the active constituents of A&A and the clinical application of the combination of ACEi plus A&A are warranted to determine the value of this treatment in humans.

Topics: Angelica sinensis; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Astragalus propinquus; Collagen; Drugs, Chinese Herbal; Enalapril; Fibroblasts; Fibrosis; Kidney Tubules; Macrophages; Male; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Ureteral Obstruction

Renal fibrosis is the final common pathway of chronic kidney disease, and its progression predicts the degree of renal dysfunction. We investigated the renoprotective properties of pirfenidone in a remnant kidney model of chronic renal failure to determine its pharmacological potency compared to enalapril. Five-sixths nephrectomized rats were fed diet containing pirfenidone (approximately 700mg/kg/day) for 8weeks. Pirfenidone steadily inhibited the progression of proteinuria, but not to a significant degree. Pirfenidone prevented the elevation of plasma creatinine and blood urea nitrogen. At the end of the experiment, pirfenidone had reduced systolic blood pressure by means of its renoprotective effect. In a histological study, pirfenidone improved interstitial fibrosis in the renal cortex. These effects were supported by the suppression of the expression of TGF-beta and fibronectin in the mRNA of the kidney. In contrast, pirfenidone had little effect on the expression of alpha-smooth muscle actin, which is one of the proteins responsible for epithelial-mesenchymal transition. This property was confirmed by the TGF-beta-induced transdifferentiation observed in cultured normal rat kidney tubular epithelial NRK52E cells. These results suggest that pirfenidone improves the progression of chronic renal failure via its antifibrotic action, although pirfenidone has less effective TGF-beta-induced epithelial to mesenchymal transdifferentiation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Differentiation; Cell Line; Chronic Disease; Disease Progression; Enalapril; Epithelial Cells; Fibrosis; Kidney; Kidney Failure, Chronic; Male; Mesoderm; Nephrectomy; Proteinuria; Pyridones; Rats; Rats, Wistar; Transforming Growth Factor beta

To explore the mechanism of enalapril for renal interstitial fibrosis by observing the effect of enalapril on the expression of transforming growth factor-beta1(TGF-beta1), p-Smad2/3 and Smad7 in renal tissuess of unilateral urethral obstruction (UUO) rat model.. Thirty female Sprague-Dawley(SD) rats were randomly subdivided into a sham-operated group, a model group and an enalapril treated group. UUO model was induced by ligating the left ureter of rats. All rats were sacrificed 14 days after UUO. Pathological changes of the renal tissue were observed by HE and Masson staining, the protein expressions of Collagen I (ColI), TGF-beta1, p-Smad2/3 and Smad7 were detected by immunohistochemical staining,and the mRNA expressions of TGF-beta1 and Smad7 were detected by RT-PCR.. The renal interstitial damage index, the relative Collagen area and the expression of ColI in the model group significantly increased(P<0.01). Enalapril reduced these indexes. The protein and mRNA expressions of TGF-beta1 and the protein expressions of p-Smad2/3 were low in the sham-operated group, but were strongly positive in the model group, and enalapril could decrease the expressions of TGF-beta1 and p-Smad2/3(P<0.01). The protein and mRNA expressions of Smad7 in the model group were less than that in the sham-operated group(P<0.01),and enalapril could improve the expressions of Smad7(P<0.01).. Enalapril could inhibit the renal interstitial fibrosis by affecting TGF-beta1, p-Smad2/3 and Smad7 of TGF-beta/smads pathway in the renal tissues of UUO rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Enalapril; Female; Fibrosis; Kidney; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Smad2 Protein; Smad3 Protein; Smad7 Protein; Transforming Growth Factor beta1; Urethral Obstruction

Angiotensin-converting enzyme (ACE) 2 is a recently identified homologue of ACE. There is great interest in the therapeutic benefit for ACE2 overexpression in the heart. However, the role of ACE2 in the regulation of cardiac structure and function, as well as maintenance of systemic blood pressure, remains poorly understood. In cell culture, ACE2 overexpression led to markedly increased myocyte volume, assessed in primary rabbit myocytes. To assess ACE2 function in vivo, we used a recombinant adeno-associated virus 6 delivery system to provide 11-week overexpression of ACE2 in the myocardium of stroke-prone spontaneously hypertensive rats. ACE2, as well as the ACE inhibitor enalapril, significantly reduced systolic blood pressure. However, in the heart, ACE2 overexpression resulted in cardiac fibrosis, as assessed by histological analysis with concomitant deficits in ejection fraction and fractional shortening measured by echocardiography. Furthermore, global gene expression profiling demonstrated the activation of profibrotic pathways in the heart mediated by ACE2 gene delivery. This study demonstrates that sustained overexpression of ACE2 in the heart in vivo leads to the onset of severe fibrosis.

Topics: Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Enalapril; Fibrosis; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; Gene Transfer Techniques; Heart Diseases; Hypertension; Male; Myocytes, Cardiac; Peptidyl-Dipeptidase A; Polysaccharides; Rats; Rats, Inbred SHR; Severity of Illness Index; Transduction, Genetic; Ultrasonography

We examined whether impaired renal function causes thickening of the aortic valve leaflets in hyperlipidemic apoE-knockout (apoE-/-) mice, and whether the putative effect on the aortic valves could be prevented by inhibiting the angiotensin-converting enzyme (ACE) with enalapril.. Thickening of the aortic valve leaflets in apoE-/- mice was induced by producing mild or moderate chronic renal failure resulting from unilateral nephrectomy (1/2 NX, n = 18) or subtotal nephrectomy (5/6 NX, n = 22), respectively. Additionally, the 5/6 NX mice were randomized to no treatment (n = 8) or enalapril treatment (n = 13). The maximal thickness of each leaflet was measured from histological sections of the aortic roots.. Leaflet thickness was significantly greater in the 5/6 NX mice than in the 1/2 NX mice (P = 0.030) or the unoperated mice (P = 0.003). The 5/6 NX mice treated with enalapril had significantly thinner leaflets than did the untreated 5/6 NX mice (P = 0.014).. Moderate uremia causes thickening of the aortic valves in apoE-/- mice, which can be attenuated by ACE inhibition. The nephrectomized apoE-/- mouse constitutes a new model for investigating the mechanisms of uremia-induced aortic valve disease, and also provides an opportunity to study its pharmacologic prevention.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aortic Valve; Aortic Valve Stenosis; Apolipoproteins E; Creatinine; Disease Models, Animal; Enalapril; Fibrosis; Hyperlipidemias; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephrectomy; Renal Insufficiency; Renin-Angiotensin System; Urea; Uremia

To dynamically observe the effect of enalapril on the expression of transforming growth factor beta1 (TGF-beta1), connective tissue growth factor (CTGF), alpha-smooth muscle actin (alpha-SMA), and Smad7 in the obstructed kidney after unilateral ureteral obstruction (UUO) in rats, and to investigate the effect of enalapril on transdifferentiation of renal tubular epithelial cells.. The model rats were induced by ligating the left ureter. Male Sprague-Dawley (SD) rats were divided into a normal control (sham-surgery) group, a model group, and a treatment group (enalapril 10 mg/ (kg * d) by gastric gavage from 24 h before the obstruction day). Rats were sacrificed on day 3, 7, 14, 21 after UUO was initiated. Sections of the renal tissue were stained with hematoxylin and eosin stain, which were used for histological and morphometric studies of the pathological change of the obstructed kidney. Real-time PCR was performed to examine the expression of TGF-beta1 mRNA and CTGF mRNA, and Western blot was performed to examine the expression of Smad7, alpha-SMA, and CTGF in the obstructed kidney.. The score of renal interstitial lesion increased with the extension of obstruction. The expression of TGF-beta1 mRNA, CTGF mRNA, alpha-SMA and CTGF increased in the model group with the extension of obstruction; but Smad7 expression decreased. Compared with the UUO group,the degree of renal interstitial lesion and the expression of TGF-beta1 mRNA, CTGF mRNA, alpha-SMA and CTGF were decreased, but the expression of Smad7 increased in the treatment group. Enalapril could significantly decrease TGF-beta1 mRNA on day 3, 7, 14, 21 after UUO. Enalapril could significantly affect the expression of CTGF mRNA,alpha-SMA,CTGF and Smad7 on day 3, 7, 14 after UUO initiation.. Enalapril significantly alleviates renal interstitial fibrosis by suppressing the expression of TGF-beta1, CTGF and alpha-SMA, upregulating the expression of Smad7, and has better effect at early stage (within 14 days after the UUO).

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Connective Tissue Growth Factor; Enalapril; Fibrosis; Kidney Tubules; Male; Rats; Rats, Sprague-Dawley; Smad7 Protein; Transforming Growth Factor beta1; Ureteral Obstruction

The objective was to evaluate structural changes of glomeruli during aging and the role of chronic renin-angiotensin system inhibition (RASi) on these changes; starting RASi on Wistar rats at two different moments: the first group after weaning and the second at the midpoint of their lifespan (12 months).. Thirty rats were divided, after weaning, into three groups of 10: group 1: control (C); group 2 : 30 mg/kg/day losartan (L); group 3 : 10 mg/kg/day enalapril (E). At 18 months, rats were placed in metabolic cages to evaluate proteinuria, then killed. Another group of 24 rats, 12 months old, were divided into three groups of eight: group 1: C; group 2: L; group 3: E. At 18 months the same procedure described above was carried out. Finally, a third group of 20 rats was studied as healthy controls and killed: 10 rats at 7 months and ten at 12 months of age. Tissue samples were collected after sacrifice. To evaluate glomerular fibrotic changes, both focal and periglomerular sclerosis, and mesangial matrix expansion, a scoring scale was established. We also evaluated anti-alpha-SM-actin and anti-collagen-III immunolabeling. Glomerular area was measured using an image analyzer.. Proteinuria and serum creatinine increased with age but were reduced in treated animals. Main glomerular changes present in 18-month-old rats were reduced by half in treated animals. Glomerular area showed significant increase with normal aging and all treatment strategies protected against it.. RAS plays a central role in natural process of renal aging, probably by producing effects influencing the biology of aging, the effects of which can be attenuated by RASi.

Topics: Actins; Age Factors; Aging; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Collagen Type III; Creatinine; Enalapril; Fibrosis; Kidney Glomerulus; Losartan; Male; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; Weaning

Increased activation of poly(ADP-ribose) polymerase (PARP) enzyme has been implicated in the pathogenesis of acute and chronic myocardial dysfunction. We have demonstrated the protective effect of PARP inhibitors against postinfarction myocardial remodeling and heart failure. The primary aim of our recent work was to compare the effect and efficacy of a potent PARP-inhibitor (L-2286) to enalapril, a widely used angiotensin-converting enzyme (ACE) inhibitor. in experimental heart failure model. Both L-2286 and enalapril were tested in a rat model of chronic heart failure after isoproterenol-induced myocardial infarction. After a 12-week treatment period, echocardiography was performed, cardiac hypertrophy and interstitial collagen deposition were assessed, and the phosphorylation state of Akt-1/GSK-3beta pathway as well as the PKC and MAPK kinases were determined. Both PARP and ACE inhibition reduced the progression of postinfarction heart failure by attenuating cardiac hypertrophy and interstitial fibrosis. More importantly, PARP inhibition increased the activity of the prosurvival signal transduction factors (Akt-1/GSK-3beta pathway, PKCepsilon). Due to these effects, L-2286 improved the systolic left ventricular function. Enalapril treatment exerted a similar, but weaker protective effect against postinfarction myocardial remodeling and heart failure. In conclusion, we demonstrated in an experimental heart failure model that L-2286 decreased the postinfarction myocardial remodeling more effectively than enalapril treatment.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomegaly; Disease Models, Animal; Echocardiography; Enalapril; Enzyme Inhibitors; Fibrosis; Heart Failure; Male; Myocardial Infarction; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Quinazolines; Rats; Rats, Sprague-Dawley; Signal Transduction; Ventricular Remodeling

Kidney dysfunction is often associated with cardiac left ventricular hypertrophy and increased cardiovascular mortality.. The aim of this study was to find out whether this reflects direct effects of uraemia on the heart or is dependent on accompanying hypertension.. Apolipoprotein-E (apoE)-deficient C57BL/6 mice are resistant to development of hypertension after renal mass reduction. To evaluate the impact of uraemia without hypertension on the heart, apoE-deficient mice underwent 5/6 nephrectomy (NX) or sham operation (Sh) and were randomized to treatment with the angiotensin converting enzyme inhibitor enalapril (12 mg kg(-1) d(-1)) or no medication.. NX did not affect systolic blood pressure (BP), but reduced mean creatinine clearance, body weight and blood haemoglobin to 27% (p < 0.01), 82% (p < 0.0001) and 73% (p < 0.0001), respectively, of the values in Sh mice. Thirty-six weeks after NX, heart wet weight, echocardiographic estimates of left ventricular mass and left ventricular diastolic and systolic functions were similar in NX and Sh mice. NX did not increase cardiac fibrosis or cardiac mRNA expression of biglycan, whereas it decreased the mRNA expression of procollagen (p < 0.01). Enalapril reduced BP (p < 0.001), heart wet weight and estimated left ventricular mass in both NX (p < 0.01) and Sh mice (p < 0.05), but did not affect cardiac diastolic or systolic function. Conclusions. The results suggest that uraemia does not impair cardiac structure or function in apoE-deficient mice. Since NX has no effect on BP in apoE-deficient mice, the results may indicate that hypertension is important for development of left ventricular disease in uraemia.

Topics: Animals; Apolipoproteins E; Disease Models, Animal; Enalapril; Fibrosis; Heart; Hypertension; Kidney; Male; Mice; Myocardium; Nephrectomy; Peptidyl-Dipeptidase A; Uremia

In unilateral ureteral obstruction (UUO), the kidney is characterized by increased fibrosis and apoptosis. Both transforming growth factor-beta (TGF-beta) and ANG II have been implicated, and ANG II may mediate its effects through TGF-beta. Previous studies demonstrated amelioration of renal damage when either TGF-beta or ANG II has been individually targeted. In this study, we sought to determine whether combining 1D11 (monoclonal antibody to TGF-beta) and an ACE inhibitor, enalapril, would be more effective in UUO than either individual treatment, as has been shown in diabetic and glomerulonephritic models. Rats underwent UUO and were given either control monoclonal antibody, 1D11 or enalapril, or 1D11/enalapril combination, for 14 days. Kidneys were harvested and examined for fibrosis [trichrome; collagen (real-time PCR, Sircol assay) and fibroblast-specific protein expression (immunohistochemistry), apoptosis (TUNEL), macrophage infiltration (immunohistochemistry), and TGF-beta expression (real-time PCR and tubular localization with immunohistochemistry)]. UUO was found to induce fibrosis, apoptosis, macrophage infiltration, and TGF-beta expression in the obstructed kidney. Administration of either 1D11 or enalapril individually significantly decreased all these changes; when 1D11 and enalapril were combined, there was little additive effect, and the combination did not provide full protection against damage. The results demonstrate that, for the most part, combination therapy is not additive in UUO. This could be due to the continued presence of a physical obstruction or to biochemical differences between UUO and other renal disease models. Furthermore, it suggests that other targets may be amenable to pharmacological manipulation in UUO.

Topics: Animals; Antibodies, Monoclonal; Apoptosis; Collagen; Drug Therapy, Combination; Enalapril; Fibrosis; Immunohistochemistry; In Situ Nick-End Labeling; Kidney; Macrophage Activation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta; Ureteral Obstruction

Late capsular contraction around breast implants is one of the most difficult complications to prevent or resolve. The authors studied the mechanisms that control the fibrotic process in an animal model. Using angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonist, the authors previously described a significant reduction in fibrosis in different experimental models.. Four groups of six rats each had a mini breast implant, 12 with a smooth surface and 12 with a textured surface. In two groups, the angiotensin-converting enzyme inhibitor enalapril was administered in drinking water, ad libitum, to determine its effect on both implant types. Two control groups were given plain drinking water. Three months postoperatively, all of the rats were killed and the capsule sections were cut and stained with hematoxylin and eosin and Masson's trichrome. Immunolabeling of collagen III and transforming growth factor (TGF)-beta1 was performed using monoclonal antibodies.. Significant differences were found between smooth and textured implants, with a uniformly low inflammatory response found on textured implants. For both surfaces, the enalapril-treated group had a significant reduction of the inflammatory process that was especially marked in the textured implants. Immunostaining for collagen III and TGF-beta1 showed a consistent reduction in both fibrous tissue and cytokine mediator.. Enalapril lowers the expression of fibrotic mediators, TGF-beta1, inflammatory markers, anti-ED1, anti-collagen III monoclonals, and the periprosthetic fibrosis process. The reduction of TGF-beta1 indicates that the probable main cytokine mediator of the fibrotic cascade is attenuated. This hypothesis may provide the basis for a safe and cheap therapeutic strategy with which to modify the capsular contracture that sometimes affects women with mammary implants.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Breast Implants; Collagen Type III; Down-Regulation; Drug Evaluation, Preclinical; Enalapril; Equipment Design; Female; Fibrosis; Granuloma, Foreign-Body; Implants, Experimental; Mammary Glands, Animal; Postoperative Complications; Random Allocation; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Cardiomegaly; Enalapril; Fibrosis; Heart Ventricles; Humans; Hypertension; Male; Renal Artery Obstruction; Renin-Angiotensin System; Treatment Outcome

The relative roles of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) inhibition on cardiac and renal fibrosis in deoxycorticosterone acetate (DOCA)-salt hypertensive rats were studied.. The ACE/NEP inhibitor omapatrilat (40 mg/kg per day), the ACE inhibitor enalapril (10 mg/kg per day) and the NEP inhibitor CGS 25462(100 mg/kg per day) were administrated for 3 weeks to DOCA rats. Collagen was stained with Sirius red, and mediators of inflammation were identified by immunolabeling (vascular cell adhesion molecule, nuclear factor-kappaB, infiltrating ED-1-positive macrophages and monocyte chemotactic protein-1) or by western blot (platelet-endothelial cell adhesion molecule-1).. Elevated systolic blood pressure of DOCA rats was significantly reduced (P < 0.05) by omapatrilat and CGS 25462. Omapatrilat and CGS 25462 significantly (P < 0.05) decreased interstitial collagen density in the left ventricle of DOCA rats compared with untreated DOCA rats. Enalapril only decreased the subepicardial collagen of DOCA rats. Omapatrilat significantly (P < 0.05) decreased renal mesangial collagen deposition in DOCA rats. Cardiac and renal expression of surface adhesion molecules, nuclear factor-kappaB, monocyte chemotactic protein and ED-1-positive cells were decreased in omapatrilat-treated DOCA rats compared with untreated DOCA rats. Enalapril and CGS 25462 did not alter mesangial collagen of DOCA rats.. Dual ACE/NEP inhibition was more effective than ACE or NEP inhibition in decreasing inflammatory mediators, and improving cardiac and renal fibrosis. This suggests a role for NEP inhibition added to blockade of the renin-angiotensin system that may explain the greater efficacy of omapatrilat.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Cell Adhesion Molecules; Collagen; Desoxycorticosterone; Drug Therapy, Combination; Enalapril; Fibrosis; Heart Diseases; Hypertension; Inflammation; Kidney Diseases; Metalloendopeptidases; Neprilysin; NF-kappa B; Organophosphonates; Pyridines; Rats; Rats, Sprague-Dawley; Thiazepines

Tubulointerstitial inflammation and fibrosis are hallmarks of chronic progressive renal diseases. To characterize the functional interaction between cell infiltration and matrix expansion, this study compared the immunosuppressant mycophenolate mofetil (MMF), intended as primarily anti-inflammatory intervention, the angiotensin-converting enzyme inhibitor enalapril, intended as primarily an anti-fibrotic drug, and a combination of both as anticipated anti-inflammatory/anti-fibrotic intervention. The model used was anti-thy1-induced chronic-progressive glomerulosclerosis (cGS) in the rat, where a brief anti-thy1-induced glomerular injury progresses spontaneously toward tubulointerstitial fibrosis and renal insufficiency. cGS was induced by injection of anti-thy1 antibody into uninephrectomized Wistar rats. One week after disease induction, animals were randomly assigned to the following groups: cGS, cGS plus MMF (20 mg.kg body wt(-1).day(-1)), cGS plus high-dose enalapril (12 mg.kg body wt(-1).day(-1)), and cGS plus both. At week 16 after disease induction, MMF or enalapril alone reduced signs of chronic renal disease significantly and similarly compared with the untreated cGS group. Variables measured included proteinuria, blood pressure, tubulointerstitial and glomerular matrix accumulation, expression of transforming growth factor-beta(1), fibronectin, and plasminogen activator inhibitor-1, infiltration of lymphocytes and macrophages, plasma creatinine and urea levels, and glomerular filtration rate. Combined MMF and enalapril treatment was not superior to single therapy. In conclusion, MMF slows the progression of chronic renal fibrosis and renal insufficiency as effectively as high-dose enalapril in the anti-thy1-induced chronic-progressive glomerulosclerosis model. The dual anti-inflammatory/anti-fibrotic intervention does not yield additive renoprotective effects, indicating that MMF and enalapril interfere with similar or very closely related pathways involved in progression of renal disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Cell Count; Blood Pressure; Body Weight; Disease Progression; Drug Interactions; Eating; Enalapril; Fibronectins; Fibrosis; Glomerulosclerosis, Focal Segmental; Immunohistochemistry; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Male; Mycophenolic Acid; Nephrectomy; Plasminogen Activator Inhibitor 1; Proteinuria; Rats; Rats, Wistar; Thy-1 Antigens; Transforming Growth Factor beta; Transforming Growth Factor beta1

In this study we examined diabetes- and hypertension-induced changes in cardiac structure and function in an animal model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We hypothesized that treatment with omapatrilat, a vasopeptidase inhibitor, which causes simultaneous inhibition of angiotensin converting enzyme and neutral endopeptidase, provides additional cardioprotective effects, during normal- as well as high sodium intake, compared to treatment with enalapril, a selective inhibitor of angiotensin converting enzyme. Fifty-two GK rats were randomized into 6 groups to receive either normal-sodium (NaCl 0.8%) or high-sodium (NaCl 6%) diet and enalapril, omapatrilat or vehicle for 12 weeks. The GK rats developed hypertension, cardiac hypertrophy and overexpression of cardiac natriuretic peptides and profibrotic connective tissue growth factor compared to nondiabetic Wistar rats. The high dietary sodium further increased the systolic blood pressure, and changed the mitral inflow pattern measured by echocardiography towards diastolic dysfunction. Enalapril and omapatrilat equally decreased the systolic blood pressure compared to the control group during normal- as well as high-sodium diet. Both drugs had beneficial cardioprotective effects, which were blunted by the high dietary sodium. Compared to enalapril, omapatrilat reduced the echocardiographically measured left ventricular mass during normal-sodium diet and improved the diastolic function during high-sodium diet in GK rats. Furthermore, omapatrilat reduced relative cardiac weight more effectively than enalapril during high sodium intake. Our results suggest that both the renin-angiotensin and the neutral endopeptidase system are involved in the pathogenesis of diabetic cardiomyopathy since vasopeptidase inhibition was shown to provide additional benefits in comparison with selective angiotensin converting enzyme inhibition alone.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Body Weight; Cardiomegaly; Collagen; Diabetes Mellitus, Type 2; Echocardiography; Enalapril; Fibrosis; Heart; Insulin; Male; Metalloendopeptidases; Myocardium; Natriuretic Peptide, Brain; Organ Size; Protease Inhibitors; Pyridines; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Sodium Chloride, Dietary; Thiazepines

Nephrotic syndrome has long been treated in China with two herbs, Astragalus mongholicus and Angelica sinensis, which may have antifibrotic effects.. Rats with chronic puromycin-induced nephrosis were treated with Astragalus and Angelica 3 mL/d (n = 7) or enalapril 10 mg/kg/d (n = 7). Normal control rats (n = 7) received saline rather than puromycin, and an untreated control group (n = 7) received puromycin but no treatment. After 12 weeks, stained sections of the glomerulus and tubulointerstitium were evaluated for injury. Immunohistochemistry staining measured extracellular matrix components, transforming growth factor-beta1 (TGFbeta1), osteopontin, ED-1-positive cells, and alpha-actin. TGFbeta1 mRNA was assessed by in situ hybridization. Renin, ACE activity, angiotensin, and aldosterone were measured by radioimmunoassay or colorimetry. In the untreated rats, chronic renal injury progressed to marked fibrosis at 12 weeks. Astragalus and Angelica significantly reduced deterioration of renal function and histologic damage. Expressions of type III and IV collagen, fibronectin, and laminin also decreased significantly. This anti-fibrotic effect was similar to that of enalapril. The herbs had no effect on the renin-angiotensin system but did reduce the number of ED-1-positive, and alpha-actin positive cells and expression of osteopontin compared to untreated controls. The combination of Astragalus and Angelica retarded the progression of renal fibrosis and deterioration of renal function with comparable effects of enalapril. These effects were not caused by blocking the intrarenal renin-angiotensin system, but associated with suppression of the overexpression of TGFbeta1 and osteopontin, reduction of infiltrating macrophages, and less activation of renal intrinsic cells [corrected].

Topics: Angelica sinensis; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Astragalus Plant; China; Drugs, Chinese Herbal; Enalapril; Fibrosis; Humans; Kidney; Male; Medicine, Chinese Traditional; Nephrosis; Phytotherapy; Plant Preparations; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; Regression Analysis; Transforming Growth Factor beta; Transforming Growth Factor beta1

We have shown previously that the concentration of Vasoactive Intestinal Peptide (VIP) in the heart is inversely correlated with the degree of fibrosis in a number of experimental models of early myocardial fibrosis. Vasopeptidase inhibition and angiotensin converting enzyme inhibition both decrease myocardial fibrosis. In this study, we sought to determine whether this myocardial protective effect might reflect increased VIP concentrations in the heart. We compared the effects of 4 weeks treatment of the vasopeptidase inhibitor omapatrilat and the angiotensin converting enzyme inhibitor enalapril on the degree of fibrosis and the concentration of VIP in the heart in salt sensitive hypertension induced by treatment with L-nitro-omega-methylarginine (L-NAME). Systolic blood pressure decreased in both treatment groups compared with control (omapatrilat P<0.005; enalapril P<0.001). Myocardial fibrosis was less for omapatrilat than control (P<0.0005) and enalapril (P<0.0005) groups. Myocardial VIP was greater in omapatrilat than in controls (P<0.005) and enalapril-treated rats (P<0.05). We conclude that vasopeptidase inhibition exerts a greater myocardial protective effect than angiotensin converting enzyme inhibition. Further, this myocardial protective effect is associated with increased VIP in the heart suggesting a pathogenetic role for VIP depletion in the development of fibrosis in the heart.

Topics: Animals; Enalapril; Fibrosis; Hypertension; Male; Myocardium; Peptide Hydrolases; Protease Inhibitors; Pyridines; Rats; Rats, Inbred WKY; Thiazepines; Vasoactive Intestinal Peptide

The cardioprotective properties of angiotensin-converting enzyme (ACE) inhibitors, quinapril and enalapril were studied in a rat model of heart failure. Seventy-five rats were divided into five groups and administered quinapril or enalapril at 2 and 20 mg/kg/day (groups Q2, Q20, E2 and E20) or vehicle alone (group V, all groups n = 15). Although both ACE inhibitors improved survival rate and ventricular function in a dose-dependent manner, the left ventricular end-diastolic pressure and expression level of transforming growth factor-beta1 mRNA were the lowest in group Q20. These results suggest that quinapril may confer greater protection than enalapril against injury from the renin-angiotensin system in heart failure.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiomyopathy, Dilated; Collagen Type III; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Fibrosis; Male; Myocardium; Quinapril; Rats; Rats, Inbred Lew; RNA, Messenger; Survival Rate; Tetrahydroisoquinolines; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Function, Left; Ventricular Pressure

Effects of enalapril on a canine model of atrial pacing-induced atrial fibrillation (AF) with rapid ventricular responses were determined.. Four weeks of atrial rapid pacing was performed on twenty-four beagles pretreated with placebo (Group I, n = 14) or enalapril 1 mg/kg (Group II, n = 10). Atrial effective refractory period (ERP), P-wave width, duration of AF, and left ventricular ejection fraction (LVEF) were evaluated every week. AF cycle length was determined by spectral analyses of fibrillation waves. Quantitative analysis of histology was added.. After 4 weeks of pacing, P-wave width was longer in Group I than in Group II, and the duration of induced AF was significantly longer in Group I (59.6 +/- 66.3 seconds) than in Group II (3.6 +/- 3.4 seconds, P < 0.05). AF cycle length was longer in Group I than in Group II despite similar shortening of atrial ERP. Mean ventricular rate during rapid atrial pacing was not different between the two groups. LVEF similarly decreased in both groups. Interstitial fibrosis and expression of connexin43 was greater in Group I than in Group II (interstitial fibrosis, 9.2 +/- 8.4 versus 1.9 +/- 2.1%, P < 0.05; connexin43, 5.3 +/- 2.2 versus 1.1 +/- 1.1%, P < 0.05).. Enalapril suppressed atrial pacing-induced AF with tachycardia-mediated cardiomyopathy by suppressing interstitial fibrosis, connexin43 over-expression and conduction delay.

Topics: Animals; Atrial Fibrillation; Cardiac Pacing, Artificial; Connexin 43; Disease Models, Animal; Dogs; Enalapril; Female; Fibrosis; Male; Ventricular Dysfunction, Left

Peritoneal fibrosis (PF) is one of the most serious causes of technique failure in long-term peritoneal dialysis (PD). Although the mechanisms responsible for the genesis of PF are not well understood, angiotensin II is known to promote fibrosis and inflammation in various tissues and angiotensin converting enzyme inhibitors (ACEIs) have been shown to attenuate those effects. We previously showed that ACEIs have beneficial effects on peritoneal alterations induced by hypertonic (3.86% glucose) PD solutions. In the present study, we investigated the local effects of intraperitoneal (IP) enalapril on peritoneal alterations induced by 3.86% glucose PD solution in rats on chronic PD. One week after peritoneal catheter insertion, 23 non uremic male rats were randomly divided into two groups: group A (n = 11) received 20 mL 3.86% PD solution twice daily, and group B (n = 12) received 20 mL 3.86% PD solution containing 1 mg/L enalapril twice daily. After 4 weeks of such infusions, we measured net ultrafiltration (UF) volume and obtained samples of visceral peritoneum from the liver for thickness measurement. Net UF was significantly higher (6.6 +/- 0.2 mL vs. 5.6 +/- 0.2 mL) and peritoneal thickness was significantly lower (30 +/- 5 microm vs. 52 +/- 0.8 microm) in group B. We conclude that intraperitoneal enalapril (an ACEI) protects the peritoneal membrane from the effects of hypertonic glucose. This protection might be mediated by enalapril's interference with angiotensin though inhibition of cytokine overexpression.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Enalapril; Fibrosis; Glucose Solution, Hypertonic; Hemodialysis Solutions; Infusions, Parenteral; Male; Peritoneal Dialysis; Peritoneum; Protective Agents; Rats; Rats, Wistar; Tissue Adhesions

Although angiotensin II (Ang II) blockade is rapidly becoming standard antifibrotic therapy in renal diseases, current data suggest that Ang II blockade alone cannot stop fibrotic disease. New therapies, such as antibodies to transforming growth factor-beta (TGF-beta), or drug combinations will be required to further slow or halt disease progression. Here, using the anti-Thy1 model of glomerulonephritis, the maximally therapeutic dose of the TGF-beta neutralizing mouse monoclonal antibody (1D11) was determined and compared with the maximally effective dose of enalapril. Then, the effect of combining both treatments at maximal doses was determined.. After disease induction with the anti-Thy1 antibody, OX-7, increasing doses of 1D11 were given intraperitoneally (IP) on days 1, 3, and 5. Enalapril was administered in drinking water from day 1. The fibrotic response was assessed at day 6.. 1D11 dose-dependently reduced fibrosis, with the 0.5 and 5 mg/kg doses showing maximal therapeutic effects, reducing period-acid Schiff (PAS) staining by 56% and 45%, respectively. Fibronectin and collagen I staining was reduced by 32% to 36%, respectively. Glomerular mRNA and production of fibronectin, plasminogen activator inhibitor-1 (PAI-1), TGF-beta1, and p-Smad2 protein were also reduced. The maximal therapeutic effects of 1D11 and enalapril alone were very similar. However, combination therapy led to further reduction in disease. Notably, matrix deposition was reduced by 80%.. While 1D11 or enalapril at maximal doses reduce fibrosis equally, simultaneous blockade of Ang II and TGF-beta reduces fibrotic disease considerably more, offering hope that such drug combinations may confer a therapeutic advantage over angiotensin blockade alone.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibodies, Monoclonal; Dose-Response Relationship, Drug; Drug Synergism; Enalapril; Fibrosis; Glomerulonephritis; Kidney; Male; Mice; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

Experimental aristolochic acid nephropathy (AAN), characterized by interstitial fibrosis, tubular atrophy, and chronic renal failure, was reported after 35-day injections of aristolochic acids (AA) to salt-depleted male Wistar rats. The link between renal fibrosis and the renin-angiotensin system (RAS) in this model remains unknown.. We investigated the impact of sodium diets (low and normal), of RAS inhibition with enalapril (ENA) alone, or combined with candesartan (CSN) for 35 days, and ENA + CSN for 65 days on AAN development. At the end of each observation period, blood pressure and renal angiotensin-converting enzyme activity were measured, as well as renal functional impairment (plasma creatinine increase, proteinuria) and histologic lesions (interstitial fibrosis, monocytes/macrophages infiltration, myofibroblasts collagens type I and IV, proliferating cells).. Sodium intake did not modify renal functional and morphologic impairment induced by AA. The RAS blockade by ENA or ENA + CSN in rats receiving AA did not result in any statistical difference in terms of renal failure, proteinuria, and interstitial fibrosis on day 35 or 65. On day 35, the monocytes/macrophages infiltration was significantly decreased by two-fold when ENA (P < 0.01) or ENA + CSN (P < 0.01) was given from day 0.. Our data demonstrate that RAS modulation by salt depletion and pharmacologic blockade do not influence renal failure and interstitial fibrosis in the rat model of AAN. We suggest that pathways of interstitial renal fibrosis may be independent of RAS at least in some conditions.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aristolochic Acids; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Diet, Sodium-Restricted; Drug Synergism; Enalapril; Fibrosis; Kidney; Kidney Diseases; Male; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Renin-Angiotensin System; Tetrazoles

Angiotensin receptor blocker (ARB) and angiotensin-converting enzyme (ACE) inhibitor (ACEI) each act in a different manner to prevent myocardial fibrosis and left ventricular (LV) stiffness in animals with pathways in the heart for generating ANG II as well as ACE. A model of pacing-induced congestive heart failure (CHF) was used to test the central hypothesis that ARB + ACEI prevents myocardial fibrosis and decreases LV stiffness to a greater extent than ARB or ACEI alone. Thirty-five dogs were assigned to the following treatment protocols on the 8th day of a 4-wk pacing schedule: 1) rapid ventricular pacing, 2) ARB (candesartan cilexetil, 1.5 mg.kg(-1).day(-1)) with pacing, 3) ACEI (enalapril, 1.9 mg.kg(-1).day(-1)) with pacing, 4) ARB (candesartan cilexetil, 0.75 mg.kg(-1).day(-1)) + ACEI (enalapril, 0.95 mg.kg(-1).day(-1)) with pacing, and 5) sham operation. The LV stiffness coefficient was significantly increased after rapid pacing but was significantly lower with ARB + ACEI than with ARB or ACEI alone. The collagen volume fraction and mRNA levels of collagen I and III, which were increased by rapid pacing, were significantly lower with ARB + ACEI than with ARB or ACEI alone. Thus ARB + ACEI prevents myocardial fibrosis and decreases LV stiffness during the progression of CHF compared with ARB or ACEI alone.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Cardiac Volume; Collagen Type I; Collagen Type III; Dogs; Drug Therapy, Combination; Enalapril; Fibrosis; Gene Expression; Heart Failure; Male; Myocardium; Norepinephrine; Tetrazoles; Ventricular Function, Left; Ventricular Pressure

In congestive heart failure, angiotensin-converting enzyme inhibitors (ACEIs) may prevent cardiac fibrosis via interaction with both angiotensin II and endothelin-1, which enhance myocardial collagen synthesis. However, whether endogenous bradykinin with an ACEI modifies the cardiac collagen architecture, affecting the endothelin system, has not yet been fully elucidated. We evaluated the changes in circulating hormonal factors, myocardial fibrosis and cardiac gene expression closely linked with heart failure, using an orally active specific bradykinin type 2 receptor antagonist, FR173657 (0.3 mg/kg/day, n = 6), with an ACEI, enalapril (1 mg/kg/day), in dogs with tachycardia-induced congestive heart failure (270 p.p.m., 22 days) and compared the effects with enalapril alone (n = 6). Although there were no differences observed in blood pressure, plasma renin activity, aldosterone and endothelin-1 levels, combined FR173657 significantly increased the cardiac expression of preproendothelin- 1 mRNA (P < 0.05) and collagen type I and type III mRNA (P < 0.05), and cardiac collagen deposits (P < 0.05), and decreased eNOS gene expression (P < 0.05) in the left ventricle compared with the ACEI-treated group. Furthermore, there was a significant negative correlation between the expression of preproendothelin- 1 and eNOS mRNA levels (r = -0.708, P < 0.001). In conclusion, bradykinin may prevent cardiac fibrosis in part via suppression of the local endothelin system in the failing heart through the enhancement of nitric oxide production under chronic angiotensin-converting enzyme inhibition.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Collagen; Disease Models, Animal; Dogs; Enalapril; Endothelin-1; Fibrosis; Heart Failure; Hemodynamics; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Quinolines; Receptor, Bradykinin B2; Renin; RNA, Messenger

Unilateral ureteral obstruction (UUO) is a well-established model for the study of interstitial fibrosis in the kidney. It has been shown that the renin-angiotensin system plays a central role in the progression of interstitial fibrosis. Recent studies indicate that endothelin, a powerful vasoconstrictive peptide, may play an important role in some types of renal disease. To investigate the effects of angiotensin II on endothelin and its receptors in the kidney, mice were subjected to UUO and treated with or without enalapril, an orally active angiotensin-converting enzyme inhibitor, in their drinking water (100 mg/l). The animals were killed 5 days later. Using RT coupled with PCR, we measured the levels of endothelin-1, endothelin A, and endothelin B (ET(B)) along with transforming growth factor-beta, TNF-alpha, and collagen type IV mRNA expression in the kidney with UUO and the contralateral kidney along with interstitial expansion in the kidney cortex by a standard point counting method. We found that enalapril administration ameliorated the increased expression of ET-1 mRNA in the obstructed kidney by 44% (P < 0.02). Although the level of endothelin A mRNA expression was significantly increased in the obstructed kidney, it was not affected by enalapril. We found that enalapril treatment increased ET(B) mRNA expression by 115% (P < 0.05) and protein expression (measured by Western blot) in the kidney with an obstructed ureter. Enalapril treatment alone inhibited the expansion of interstitial volume due to UUO by 52%. Cotreatment with enalapril and the ET(B) receptor antagonist BQ-788 inhibited the expression of interstitial volume by only 19%. This study confirms that enalapril inhibits the interstitial fibrosis in UUO kidneys. It also suggests a beneficial and unforeseen effect of enalapril on the obstructed kidney by potentially stimulating the production of nitric oxide through an increased expression of the ET(B) receptor.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Enalapril; Female; Fibrosis; Gene Expression; Kidney; Mice; Mice, Inbred C57BL; Nitric Oxide; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Ureteral Obstruction

Recent experimental studies in chronic kidney disease have suggested that sympathicolytic drugs, similar to angiotensin II antagonism, limit renal fibrosis independent of blood pressure control. Using the model of acute and normotensive anti-thy1 glomerulonephritis, we analysed the action of beta-adrenergic blockade (as compared with angiotensin-converting enzyme inhibition) on renal overexpression of the profibrotic cytokine transforming growth factor (TGF)-beta.. One day after induction of anti-thy1 glomerulonephritis, rats were given increasing doses of the beta-blockers metoprolol or nebivolol (0.1-fold, one-fold, 10-fold and 20-fold of the known blood pressure dose) until day 6 and the 20-fold dose until day 12. Additional animals were treated with a high dose of the angiotensin-converting enzyme inhibitor enalapril. At the end of each experiment, blood pressure and heart rate were recorded, glomerular matrix expansion was scored histologically, and protein expression of TGF-beta(1), fibronectin and plasminogen activator inhibitor-1 was determined in the supernatant of cultured glomeruli.. Metoprolol and nebivolol reduced heart rate in a dose-dependent manner. Blood pressure was normal in untreated animals and not significantly affected by either treatment. Compared with untreated nephritic rats, TGF-beta(1) overexpression was not significantly changed by metoprolol or nebivolol in any dose or treatment period. In contrast, TGF-beta(1) levels were significantly reduced by enalapril both 6 and 12 days after disease induction (-52 and -63%, respectively). The changes in glomerular matrix score, fibronectin and plasminogen activator inhibitor-1 production closely followed expression of TGF-beta(1).. In a model of acute and normotensive glomerular fibrosis, beta-adrenergic antagonism does not reduce TGF-beta overexpression, suggesting that its pressure-independent antifibrotic action may be limited to chronic renal diseases. The beneficial effect of angiotensin II inhibition even on acute matrix expansion may be a relevant mechanism as to the explanation of its superiority in treating fibrotic renal diseases.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzopyrans; Biomarkers; Blood Pressure; Body Weight; Dose-Response Relationship, Drug; Drinking; Eating; Enalapril; Ethanolamines; Fibrosis; Glomerulonephritis; Heart Rate; Isoantibodies; Male; Metoprolol; Nebivolol; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Transforming Growth Factor beta; Transforming Growth Factor beta1

Vasectomy induces testicular interstitial fibrosis in time dependent fashion and inhibits spermatogenesis. We investigated the contribution of angiotensin II (Ang II) to the development of interstitial fibrosis after vasectomy.. Bilateral vasectomy was performed in 8-week-old Wistar rats and the testes were harvested 1 to 24 weeks after vasectomy. Interstitial fibrosis was evaluated by Masson's trichrome staining. Western blotting and immunohistochemistry were done to examine the expressions of heat shock protein 47 (HSP47), HNE (4-hydroxy-2,3-nonenal) and transforming growth factor-beta1 (TGF-beta1). The antioxidative agent N-acetylcysteine (NAC), the Ang II type 1 receptor antagonist losartan or the Ang converting enzyme inhibitor enalapril was given orally for 24 weeks to vasectomized rats. Spermatogenesis was evaluated by testicular weight and the percent of haploid cells was analyzed by flow cytometry.. Vasectomy significantly increased interstitial fibrosis (more than 8 weeks) and induced the expression of HSP47, HNE modified protein and TGF-beta1. TGF-beta1 and HSP47 immunoreactivity was localized to Leydig cells and fibroblasts. NAC or losartan but not enalapril inhibited the expression of these molecules induced by vasectomy. Increased interstitial fibrosis and impaired spermatogenesis were partially abrogated by NAC or losartan administration.. There is Ang II type 1 receptor dependent fibrosis after vasectomy. Oxidative condition is considered to trigger and promote these fibrogenic processes. Ang II contributes to the regulation of intratesticular autocrine or paracrine functions after vasectomy.

Topics: Acetylcysteine; Aldehydes; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Enalapril; Fibrosis; Heat-Shock Proteins; HSP47 Heat-Shock Proteins; Leydig Cells; Losartan; Male; Rats; Rats, Wistar; Spermatogenesis; Testis; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vasectomy

The efficacy of ACE inhibitors (ACEIs) in the treatment of chronic heart failures is well documented. However, ACEIs may provide incomplete blockade of the renin-angiotensin system (RAS) because of the alternative pathways for angiotensin II (All) production. We hypothesized that more complete blockade of RAS by adding an AT1 receptor blocker (ARB) may have greater potential to decrease mortality associated with heart failure and improve cardiac function than monotherapy with ACEIs. The objective of this study was to evaluate the effect of combined therapy on cardiac functions and survival in cardiomyopathic hamsters. Male cardiomyopathic hamsters (BIO TO2) were administered either placebo (group C), enalapril (30 mg/kg/day) (group E), or enalapril (30 mg/kg/day) + valsartan (500 mg/ kg/day) (group EV), starting at the age of 6 weeks. Kaplan-Meier analysis was performed to assess the differences in survival. Cardiac functions were evaluated by echocardiogram and cardiac catheterization. Group EV showed significant increases in fractional shortening, LV dP/dTmax, and deceleration time, and showed significant decreases in left ventricular diastolic dimension, LV dP/dTmin, and early diastolic mitral velocity/atrial systolic velocity. Treatment with enalapril resulted in longer survival compared with placebo. Moreover, life expectancy (median probability of survival: 433 days) increased significantly in group EV compared with group E (P<0.05) as well as group C (P<0.001). It is concluded that combined therapy improved cardiac function and survival compared to placebo or enalapril monotherapy.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomyopathy, Dilated; Cell Count; Chronic Disease; Cricetinae; Drug Therapy, Combination; Echocardiography, Doppler; Enalapril; Fibrosis; Hemodynamics; Male; Myocytes, Cardiac; Random Allocation; Receptors, Angiotensin; Renin-Angiotensin System

Angiotensin II upregulates tumor necrosis factor-alpha (TNF-alpha) in the rat kidney with unilateral ureteral obstruction (UUO). In a mouse model of UUO, we found that tubulointerstitial fibrosis is blunted when the TNF-alpha receptor, TNFR1, is functionally knocked out. In this study, we used mutant mice with UUO in which the angiotensin II receptor AT(1a) or the TNF-alpha receptors TNFR1 and TNFR2 were knocked out to elucidate interactions between the two systems. The contribution of both systems to renal fibrosis was assessed by treating TNFR1/TNFR2-double knockout (KO) mice with an angiotensin-converting enzyme inhibitor, enalapril. The increased interstitial volume (Vv(int)) in the C57BI/6 wild-type mouse was decreased in the AT(1a) KO from 32.8 +/- 4.0 to 21.0 +/- 3.7% (P < 0.005) or in the TNFR1/TNFR2 KO to 22.3 +/- 2.1% (P < 0.005). The Vv(int) of the TNFR1/TNFR2 KO was further decreased to 15.2 +/- 3.7% (P < 0.01) by enalapril compared with no treatment. The induction of TNF-alpha mRNA and transforming growth factor-beta1 (TGF-beta1) mRNA in the kidney with UUO was significantly blunted in the AT(1a) or TNFR1/TNFR2 KO mice compared with the wild-type mice. Treatment of the TNFR1/TNFR2 KO mouse with enalapril reduced both TNF-alpha and TGF-beta1 mRNA and their proteins to near normal levels. Also, alpha-smooth muscle actin expression and myofibroblast proliferation were significantly inhibited in the AT(1a) or TNFR1/TNFR2 KO mice, and they were further inhibited in enalapril-treated TNFR1/TNFR2 KO mice. Incapacitating the angiotensin II or the TNF-alpha systems individually leads to partial blunting of fibrosis. Incapacitating both systems, by using a combination of genetic and pharmacological means, further inhibited interstitial fibrosis and tubule atrophy in obstructive nephropathy.

Topics: Actins; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antigens, CD; Collagen; Enalapril; Enzyme-Linked Immunosorbent Assay; Fibrosis; Kidney; Lymphotoxin-alpha; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron; Muscle, Smooth; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; RNA, Messenger; Tumor Necrosis Factor-alpha; Ureteral Obstruction

The purpose of this study was to evaluate whether plasma aldosterone (ALD) is extracted or produced through the heart in patients with acute myocardial infarction (AMI) and to determine the relationship between transcardiac extraction of plasma ALD and left ventricular (LV) remodeling.. Although we demonstrated that circulating ALD was extracted through the failing heart and that transcardiac extraction of ALD correlated with LV end-diastolic volume index (LVEDVI) in patients with congestive heart failure, the existence and increase of ALD synthase in the hearts of infarct rats were reported, suggesting cardiac production of ALD in patients with AMI.. We measured plasma ALD in the aortic root (Ao) and coronary sinus (CS) in 57 consecutive patients who received successful revascularization and enalapril, with first AMI at acute phase and after one month. We also measured plasma procollagen type III aminoterminal peptide (PIIINP) in the CS.. Plasma ALD was significantly lower in the CS than it was in the Ao at the acute phase (84.7 +/- 6.3 pg/ml vs. 105.5 +/- 8.0 pg/ml, p < 0.0001). Significant positive correlations exist between the transcardiac gradient of ALD at the acute phase and the LVEDVI at one month. Moreover, the transcardiac gradient of plasma ALD at the acute phase has a significant correlation with plasma PIIINP, a biochemical marker of fibrosis, after one month. Stepwise multivariate analysis showed that transcardiac extraction of plasma ALD at the acute phase had an independent and significant positive relationship with a large LVEDVI after one month.. These results indicate that plasma ALD is extracted through the heart in patients with AMI at the acute phase and that the extracted ALD plays an important role in modulating post-infarct LV remodeling.

Topics: Acute Disease; Aged; Aldosterone; Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Aorta; Biomarkers; Coronary Vessels; Cytochrome P-450 CYP11B2; Disease Progression; Enalapril; Female; Fibrosis; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Multivariate Analysis; Myocardial Infarction; Peptide Fragments; Procollagen; Prospective Studies; Severity of Illness Index; Stroke Volume; Time Factors; Veins; Ventricular Remodeling

Oxidative stress is involved in both the pathogenesis and complications of diabetes. ACE inhibitors can slow the progression of cardiac and renal impairments related to diabetes. The effect of enalapril treatment on oxidative stress and tissue injury was studied in hearts, kidneys, and livers from streptozotocin-induced diabetic rats. Twenty-four rats were divided into the following groups: streptozotocin (65 mg/kg, single intraperitoneal dose), streptozotocin+enalapril (20 mg enalapril/L drinking water), and control (intraperitoneal saline). Seven months after streptozotocin injection, organs were studied by light microscopy and collagen III immunolabeling. Tissue lesions and collagen labeling were graded by a semiquantitative score (0 to 4). Total glutathione content, glutathione redox status (reduced/oxidized glutathione), antioxidant enzyme activities, protein-associated sulfhydryls, thiobarbituric acid-reactive substances, and fluorescent chromolipids were determined in tissue homogenates. Glycemia was higher in both the streptozotocin and streptozotocin+enalapril groups relative to the control group. In the streptozotocin group, creatinine clearance and body weight were lower, and systolic blood pressure and urinary albumin excretion were higher than in the streptozotocin+enalapril and control groups. Heart, kidney, and liver lesion/labeling scores were significantly higher in the streptozotocin group compared with the streptozotocin+enalapril and control groups. Kidney and liver total glutathione was lower in the streptozotocin group relative to the control group (P<0.05). Enalapril treatment significantly attenuated the reduction of total glutathione. In the heart, kidney, and liver, both glutathione and proteins were relatively more oxidized in the streptozotocin group relative to the control group (P<0.05). Protein and glutathione oxidation were attenuated in the streptozotocin+enalapril group in the 3 tissues studied (P<0.05). Enalapril treatment attenuated the oxidation of lipids in the heart and kidney (P<0.05). Tissue fibrosis scores were inversely correlated with (1) both total glutathione and reduced/oxidized glutathione in heart, kidney, and liver and (2) glutathione reductase activity in the kidney. These results suggest that in streptozotocin-induced diabetic rats, the protective action of enalapril might be mediated, at least in part, by its effect on tissue oxidant/antioxidant status.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Fibrosis; Glutathione; Glutathione Disulfide; Kidney; Lipid Metabolism; Liver; Liver Cirrhosis; Male; Myocardium; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Nephropathy, interstitial pneumopathy, and renal and lung fibrosis are major complications of bone marrow transplantation (BMT). This study evaluated the antifibrotic property of an angiotensin II (A2) type-1 receptor blocker (L-159,809) and compared it with those of Captopril and Enalapril, two angiotensin-converting enzyme (ACE) inhibitors, in a rat model of BMT. Male WAG/Rij/MCW rats received a preparative regimen of 60 mg/kg body wt of cytoxan (i.p., Days 9 and 8) and 18.5 Gy of total body irradiation (TBI) in six twice daily fractions (Days 2, 1, and 0) followed immediately (Day 0) by BMT. Modifiers were given in drinking water from Day 10 until autopsy, 8 weeks after BMT. Rats treated with TBI plus cytoxan alone developed severe nephropathy. Trichrome staining showed marked collagen deposition in glomeruli, renal interstitium, and renal arteries and arterioles (especially in their adventitia). Collagen deposition and renal damage were markedly reduced by the three modifiers. Of the three, L-158,809-treated rats had slightly thinner vessels and slightly less collagen than nonirradiated normal controls. The study shows the effectiveness of these drugs in the protection of the renal parenchyma from the development of radiation-induced fibrosis. It also indicates a role for angiotensin II in the modulation of collagen synthesis.

Topics: Aldosterone; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Bone Marrow Transplantation; Captopril; Disease Models, Animal; Enalapril; Enzyme Inhibitors; Fibrosis; Imidazoles; Kidney Diseases; Male; Radiotherapy; Rats; Tetrazoles; Time Factors

To assess the effect of an ACE inhibitor and an Ang II type 1 (AT1) receptor antagonist on preventing hepatic fibrosis induced by CCl4 in rats and to investigate whether there is the expression of AT1 receptors on hepatic stellate cells.. Studies were conducted in male Sprague-Dawley rats. Except for model group and control group, in three treated groups, either enalapril (5 mg/kg), or losartan (10 mg/kg), or enalapril + losartan were given to the fibrotic rats (daily gavage). Saline vehicle was given to the control group. After 6 weeks, liver fibrosis was assessed directly by hepatic morphometric analysis. The expression of AT1 receptors and alpha-smooth muscle actin (alpha-SMA) in liver tissue and isolated hepatic stellate cells (HSC) were detected by immunohistochemical techniques.. Compared with the fibrosis in rats of the model group, rats treated with either enalapril or losartan, or a combination of two drugs, showed a limited expansion of the interstitium (P < 0.05), but no significant difference was observed among the three treated groups (P > 0.05). The expression of AT1 receptors was found in abundance in the fibrotic interstitium of the fibrotic rats, whereas in the normal control rats they were limited to the vascular wall. AT1 receptors were also expressed on activated HSC in culture plates.. Angiotensin-converting enzyme inhibitors and AT1 blockers might slow the progression of hepatic fibrosis. Activated HSCs expressed AT1 receptors. Activation of RAS might be related to hepatic fibrogenesis induced by CCl4.

Topics: Alanine Transaminase; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Cells, Cultured; Enalapril; Fibrosis; Immunohistochemistry; Liver; Losartan; Male; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System

Unilateral ureteral obstruction (UUO) is a model of renal injury characterized by progressive tubulointerstitial fibrosis and renal damage, while relatively sparing the glomerulus and not producing hypertension or abnormalities in lipid metabolism. Tubulointerstitial fibrosis is a major component of several kidney diseases associated with the progression to end-stage renal failure. Here we report that when a critical renal developmental morphogen, osteogenic protein-1 (OP-1; 100 or 300 microg/kg body wt), is administered at the time of UUO and every other day thereafter, interstitial inflammation and fibrogenesis are prevented, leading to preservation of renal function during the first 5 days after obstruction. Compared with angiotensin-converting enzyme inhibition with enalapril treatment, OP-1 was more effective in preventing tubulointerstitial fibrosis and in preserving renal function. The mechanism of OP-1- induced renal protection was associated with prevention of tubular atrophy, an effect not shared with enalapril, and was related to preservation of tubular epithelial integrity. OP-1 blocked the stimulation of epithelial cell apoptosis produced by UUO, which promoted maintenance of tubular epithelial integrity. OP-1 preserved renal blood flow (RBF) during UUO, but enalapril also stimulated RBF. Thus OP-1 treatment inhibited tubular epithelial disruption stimulated by the renal injury of UUO, preventing tubular atrophy and diminishing the activation of tubulointerstitial inflammation and fibrosis and preserving renal function.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Atrophy; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Cell Size; Collagen; Enalapril; Epithelial Cells; Fibrosis; Immunohistochemistry; Inflammation; Kidney; Macrophages; Rats; Rats, Sprague-Dawley; Renal Circulation; Transforming Growth Factor beta; Ureteral Obstruction

The present study compared renoprotective effects of angiotensin II type I receptor antagonist (AT1RA) with angiotensin converting enzyme inhibitor (ACEI), and their influence on the renin-angiotensin-system (RAS). Experimental nephrotic syndrome was induced in SD rats by repeated peritoneal injections of puromycin. Twenty-eight rats were randomly divided into four groups: normal control, nephrotic control, ACEI-treated, and AT1RA-treated groups. Serum, urine, and renal tissue were collected for study at the end of 12 weeks. Compared with those of the nephrotic control group, urinary protein was less and renal function was better in both treated groups. The glomerular and interstitial damage indexes of both ACEI- and AT1RA-treated rats were lower than those of nephrotic control rats, with no significant difference observed between the two treated groups. Local renal ACE activity and angiotensin II concentration were elevated in nephrotic rats (p< 0.01). However, there is no significant difference in circulating RAS, renal tissue renin, and aldosterone between the normal control and nephrotic control rats. As expected, enalapril inhibited the local renal ACE activity and significantly decreased angiotensin II (p< 0.01). Intrarenal ACE activity and angiotensin concentration returned to normal levels after treatment with irbesartan (p< 0.01). In conclusion, AT1RA and ACEI have comparable renal protective effects, and these protective effects were associated with the inhibition of intrarenal ANG II.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Enalapril; Fibrosis; Irbesartan; Kidney; Male; Nephrotic Syndrome; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Tetrazoles

Previous studies have demonstrated in normal rats that chronic treatment, from weaning to 30 days, with either enalapril or losartan, induced significant changes in cardiovascular structure and function. The present study was performed to assess the effect of either enalapril or losartan on the structure and function of the heart and arteries given to normal rats from weaning until 6 months of age. Animals (n = 48) were divided into three groups: control, enalapril treated, and losartan treated; treated rats received 10 mg/kg/day of drug. Blood pressure, body weight, and water intake were recorded for that time period. DNA, cGMP, collagen, degree of fibrosis, and nitric oxide synthase-NADPH-diaphorase-dependent activity in the heart and arteries were determined. Only significant differences (P < .05) are reported. Blood pressure increased only in control rats (13 +/- 1 mm Hg), enalapril treatment enhanced water intake and reduced the rate of body growth (control, 672.9 +/- 15.4 g; losartan, 692.4 +/- 21.8 g; enalapril, 541.8 +/- 13.8 g). In the heart, DNA (control, 120 +/- 5; losartan, 99 +/- 4; enalapril, 93 +/- 6 microg/100 mg), collagen (control, 2.5 +/- 0.2; enalapril, 1.85 +/- 0.08 microg/100 mg), and fibrosis (control, 3.5 +/- 0.4%; losartan, 2.2 +/- 0.3%; enalapril, 2.1 +/- 0.4%) were reduced by treatment. In the aorta, cGMP (control, 0.15 +/- 0.01; losartan, 0.24 +/- 0.02 pmol/mg), and NADPH-diaphorase (control, 0.114 +/- 0.003; losartan, 0.148 +/- 0.006; enalapril, 0.169 +/- 0.003 as optical density) were enhanced. The enzyme was also higher in the aortic endothelium of treated animals (control, 0.193 +/- 0.010; losartan, 0.228 +/- 0.009; enalapril, 0.278 +/- 0.005). The lower rate of body weight increase, the enhanced water intake, and the reduced cardiac and left ventricular weight attributable to enalapril treatment do not seem to be related to inhibition of the renin-angiotensin system. On the other hand, renin-angiotensin system inhibition induces a protective effect on the heart and aorta through structural and functional changes. Most of this action seems to be exerted through angiotensin II type 1 receptors.

Topics: Angiotensin II; Animals; Aorta; Blood Pressure; Body Weight; Cardiovascular System; Collagen; Cyclic GMP; DNA; Drinking; Enalapril; Fibrosis; Losartan; Male; Myocardium; NADPH Dehydrogenase; Rats; Rats, Wistar; Reference Values; Systole; Time Factors

Hypertension and renal injury in experimental polycystic kidney disease.. Hypertension accelerates renal failure in autosomal dominant polycystic kidney disease (ADPKD), and evidence suggests a role for the renin-angiotensin system (RAS) in the functional and structural changes. To explore the hypothesis that RAS adaptations contribute to disease progression, we examined RAS activity and the long-term consequences of antihypertensive drugs, which suppress (enalapril) or stimulate (hydralazine) the RAS, in experimental polycystic kidney disease.. Studies were conducted in male heterozygous cystic Han:SPRD rats (Cy/+) and in unaffected littermates (controls). In protocol 1, either angiotensin II (Ang II), enalaprilat, or saline vehicle was acutely infused into cystic and control rats, which were aged 10 to 12 weeks. The mean arterial pressure (MAP), glomerular filtration rate (GFR), and renal plasma flow (RPF) were measured at baseline and after an infusion of test substances. In protocol 2, cystic rats received chronic therapy with either enalapril, hydralazine, or no therapy for 10 to 12 weeks of age and then underwent renal function and RAS studies. In protocol 3, similar cohorts were followed for 40 weeks to assess the effects of therapy on blood pressure, proteinuria, serum creatinine, RAS parameters, and renal morphology.. In protocol 1, cystic rats had massive kidneys, slightly elevated blood pressure, and profound renal vasoconstriction and reduced GFR. Ang II induced similar changes in MAP and renal function in control and cystic rats. Enalaprilat induced little effect on MAP but more striking increases in GFR and RPF in cystic rats. In protocol 2, at 10 weeks of age, enalapril was superior in preserving renal function, but neither drug limited the expansion of the tubulointerstitium. In protocol 3, at 40 weeks of age, both drugs ameliorated the increase in serum creatinine, although only enalapril reduced proteinuria and kidney size.. In polycystic rats, acute RAS suppression markedly ameliorates renal dysfunction. However, although chronic enalapril and hydralazine protect against the loss of renal function, only enalapril limits renal growth and proteinuria, and neither significantly limits tubulointerstitial fibrosis. The long-term studies give clear support to the importance of blood pressure control, per se, but only partial support to the importance of the particular agent used. As in clinical studies, angiotensin-converting enzyme inhibition may be less beneficial in ADPKD than in renal diseases characterized by predominant glomerular injury.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Enalapril; Fibrosis; Hydralazine; Hypertension, Renal; Kidney Glomerulus; Male; Polycystic Kidney, Autosomal Dominant; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Vasoconstrictor Agents

Rats injected with a single, 50-mg dose of bromoethylamine (BEA) developed papillary necrosis accompanied by sever interstitial fibrosis. At 1 mo, the creatinine clearance decreased (control 0.66 versus BEA 0.33 ml/min per 100 g body wt, P = 0.02), and the urine albumin-to-creatinine ratio increased markedly (control 0.19 versus BEA 0.51, P = 0.02). In a group of animals given the angiotensin-converting enzyme inhibitor enalapril (Enal; 100 mg/L) in their drinking water for 4 wk, beginning 1 wk before BEA injection, creatinine clearance improved significantly (BEA 0.33 versus Enal + BEA 0.52 ml/min per 100 g body wt, P = 0.01) and albumin excretion fell to zero. Histologic examination revealed an 88% decrease in the area of papillary necrosis and a decrease in the degree of interstitial fibrosis in the corticomedullary junction. To determine whether this was due to changes in urine flow rate induced by enalapril, a group of animals was injected with BEA, and enalapril at the above dose was begun 1 wk later. After 1 mo, the enalapril-treated animals showed the same improvement in creatinine clearance (BEA 0.33 versus BEA + Enal 0.50 ml/min per 100 g body wt, P = 0.03) and suppression of albumin excretion. The area of papillary necrosis was reduced by 67%. In the BEA animals treated with enalapril, ED-1-positive cells, alpha-smooth muscle actin, and transforming growth factor-beta1 were decreased compared with BEA alone. It is concluded that in this model of papillary necrosis, enalapril protects renal function and decreases interstitial fibrosis mediated at least in part through an angiotensin II/bradykinin-dependent mechanism.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Creatinine; Enalapril; Ethylamines; Fibrosis; Glomerular Filtration Rate; Kidney; Kidney Diseases; Kidney Papillary Necrosis; Male; Rats; Rats, Sprague-Dawley

The prehypertrophic state of hypertensive heart disease is characterized by morphologic changes (interstitial fibrosis, increase in intramyocardial arteriolar wall thickness) as well as by functional alterations (diastolic dysfunction, decrease in coronary reserve). These changes most probably represent the earliest cardiac end-organ lesions that can clinically be detected. In cardiac hypertrophy, long-term (9-12 months) pharmacotherapy with beta-blockers, calcium channel blockers, or ACE inhibitors reverses left ventricular hypertrophy by 8% to 14%, whereas marked improvement in coronary reserve and diastolic dysfunction is achieved by calcium blocker and preferably by ACE inhibitors.

Topics: Antihypertensive Agents; Arterioles; Bisoprolol; Blood Pressure; Coronary Circulation; Diastole; Diltiazem; Disease Progression; Enalapril; Fibrosis; Heart Ventricles; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Isradipine; Treatment Outcome; Ventricular Dysfunction, Left

Overproduction of transforming growth factor-beta (TGF-beta) is a key mediator of extracellular matrix accumulation in fibrotic diseases. We hypothesized that the degree of reduction of pathological TGF-beta expression can be used as a novel index of the antifibrotic potential of angiotensin II (Ang II) blockade in renal disease.. One day after induction of Thy 1.1 glomerulonephritis, rats were treated with increasing doses of the Ang I converting enzyme (ACE) inhibitor enalapril and/or the Ang II receptor blocker losartan in the drinking water. Six days after disease induction the therapeutic effect on glomerular TGF-beta overexpression was evaluated.. Both enalapril and losartan reduced TGF-beta overproduction in a dose-dependent manner, showing a moderate reduction at doses known to control blood pressure in renal forms of hypertension. A maximal reduction in TGF-beta expression of approximately 45% was seen for both drugs starting at 100 mg/liter enalapril and 500 mg/liter losartan, with no further reduction at doses of enalapril up to 1000 mg/liter or losartan up to 2500 mg/liter. Co-treatment with both drugs was not superior to single therapy. Consistent with our hypothesis that reduction in TGF-beta expression is a valid target, other disease measures, including glomerular matrix accumulation, glomerular production and mRNA expression of the matrix protein fibronectin and the protease inhibitor plasminogen-activator-inhibitor type 1 (PAI-1) closely followed TGF-beta expression.. The data suggest that these therapies act through very similar pathways and that, in order to more effectively treat renal fibrosis, these drugs must be combined with other drugs that act by different mechanisms.

Topics: Angiotensin II; Animals; Blood Pressure; Body Weight; Eating; Enalapril; Fibronectins; Fibrosis; Glomerulonephritis, Membranoproliferative; Kidney; Losartan; Male; Plasminogen Activator Inhibitor 1; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

We examined the potential of in vivo linkage of plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) in the setting of endothelial injury and sclerosis following radiation injury in the rat. PAI-1 is a major physiological inhibitor of the plasminogen activator (PA)/plasmin system, a key regulator of fibrinolysis and extracellular matrix (ECM) turnover. PAI-1 mRNA expression in the kidney was markedly increased (9-fold) at 12 weeks after irradiation (P < 1.001 vs. normal control). In situ hybridization revealed significant association of PAI-1 expression with sites of glomerular injury (signal intensity in injured vs. intact glomeruli, P < 0.001). Angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril) or angiotensin II receptor antagonist (AIIRA, L158,809) markedly reduced glomerular lesions (thrombosis, mesangiolysis, and sclerosis; sclerosis index, 0 to 4+ scale, 0.49 +/- 0.20 in untreated vs. 0.05 +/- 0.02, 0.02 +/- 0.01, 0.04 +/- 0.02 in captopril, enalapril and AIIRA, respectively, all P < 0.01 vs untreated). Further, ACEI and AIIRA markedly attenuated increased PAI-1 mRNA expression in the irradiated kidney (36, 19 and 20% expression, respectively, for captopril, enalapril and AIIRA, compared to untreated irradiated kidney, P < 0.05, < 0.01, < 0.01). This effect was selective in that neither tissue-type nor urokinase-type PA mRNA expression was affected by these interventions. Thus, we speculate that inhibition of the renin-angiotensin system may ameliorate injury following radiation by accelerating fibrinolysis and ECM degradation, at least in part, via suppression of PAI-1 expression. In summary, inhibition of Ang II, in addition to its known effects on vascular sclerosis, may also by its novel effect to inhibit PAI-1, lessen fibrosis following endothelial/thrombotic injury.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Captopril; Cytokines; Enalapril; Fibrin; Fibrinolysin; Fibrosis; Gene Expression Regulation, Enzymologic; Growth Substances; Imidazoles; In Situ Hybridization; Kidney; Male; Plasminogen Activator Inhibitor 1; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Circulation; Renin; RNA, Messenger; Tetrazoles; Thrombosis; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; Vasoconstrictor Agents

The renal protective properties of candesartan cilexetil (TCV-116), an angiotensin II type 1 receptor antagonist (AT1A), and enalapril, an angiotensin I converting enzyme inhibitor (ACEI), were investigated in 5/6 nephrectomized (NX) rats. Candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) were administered orally to 5/6 NX rats for four weeks (during the early phase of disease development) or 16 weeks (through the late phase). In vehicle-treated rats, proteinuria, glomerulosclerosis, interstitial mononuclear cell (MNC) infiltration and interstitial fibrosis developed. Moreover, immunohistological studies showed enhanced expression of transforming growth factor-beta 1 (TGF-beta 1) in the injured glomeruli. Both drugs inhibited these adverse changes in the early phase. In the late phase, the progressive proteinuria, interstitial MNC infiltration were attenuated by both drugs. However, candesartan cilexetil significantly inhibited the progression of glomerulosclerosis, the expression of TGF-beta 1 and the interstitial fibrosis, while enalapril did not. Candesartan cilexetil and enalapril showed comparable hypotensive effects after the 16-week administration. These results indicate that candesartan cilexetil shows a more potent protective effect than enalapril against the progression of renal injury in the late phase. Thus, an AT1A might be more useful than an ACEI for the treatment of patients with chronic renal failure.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Disease Progression; Enalapril; Fibrosis; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; Tetrazoles; Transforming Growth Factor beta

Tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) is driven by increased levels of angiotensin II (Ang II). In this study, we examined the time course of the fibrotic process in rats with UUO and explored the effect of delayed administration of an angiotensin converting enzyme (ACE) inhibitor, enalapril, on the tubulo-interstitial fibrosis of obstructive uropathy. Rats were sacrificed at 3, 5, 8, or 10 days after UUO was initiated. Some rats did not receive treatment, whereas others were treated with enalapril from day 4 to day 8 or from day 6 to day 10 after the onset of UUO. The levels of mRNA for transforming growth factor beta 1 (TGF-beta 1), collagen type IV (collagen IV), and tissue inhibitor of metalloproteinase (TIMP-1) were measured at each time point by reverse transcription-polymerase chain reaction (RT-PCR). The relative volume of the tubulointerstitium (Vv) was measured by a point-counting method. Monocyte/macrophage infiltration and collagen IV protein deposition were examined histologically using specific antibodies. There were significant increases in TGF-beta 1, TIMP-1, and collagen IV mRNAs in the obstructed kidney. Treatment with enalapril on day 4 through day 8 or on day 6 through day 10 significantly reduced the elevated mRNA levels of these compounds in the obstructed kidney. Histological studies showed augmented Vv, monocyte/macrophage infiltration, interstitial alpha-smooth muscle actin expression, and collagen IV protein deposition on days 3, 5, 8, or 10 of UUO; enalapril treatment from day 4 to 8 or from day 6 to 10 halted and to an extent reversed these increases. These data suggest that enalapril administration after several days of UUO is an effective means of preventing the progression of tubulointerstitial fibrosis of obstructive uropathy.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Base Sequence; Collagen; Enalapril; Female; Fibroblasts; Fibrosis; Glycoproteins; Immunohistochemistry; Macrophages; Molecular Sequence Data; Muscle, Smooth; Nephritis, Interstitial; Polymerase Chain Reaction; Protease Inhibitors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta; Ureteral Obstruction

Recent studies have shown that beside elevated arterial blood pressure, humoral factors such as angiotensin II, aldosterone, endothelin or bradykinin might play a role in the cardiac hypertrophy and fibrosis secondary to hypertension. In addition, it seems that perivascular fibrosis and interstitial fibrosis are controlled by independent mechanisms. Therefore, the goal of our study was to evaluate the respective role of the increased arterial pressure and of humoral factors on cardiac remodeling in an experimental hypertension model.. Uninephrectomized rats received DOCA, a high salt diet, and when hypertension was installed, they were treated for 6 weeks with either a long-acting calcium antagonist, mibefradil (30 mg/kg day-1), an ACE inhibitor, enalapril (3 mg/kg day-1), or a mixed ETA-ETB endothelin receptor antagonist, bosentan (100 mg/kg day-1). A group of hypertensive rats was left untreated and a sham-operated group of normotensive rats was used for control. At the end of treatment, maximal coronary blood flow was measured in isolated perfused hearts. Cardiac hypertrophy and interstitial as well as perivascular fibrosis were evaluated by quantitative morphometry.. DOCA-salt hypertensive rats exhibited a marked cardiac hypertrophy associated with a decrease of maximal coronary blood flow and interstitial and perivascular fibrosis. The calcium antagonist nearly normalized arterial pressure and suppressed all these changes. Enalapril had no effect on arterial pressure and perivascular fibrosis but decreased subendocardial fibrosis. Bosentan had a very small effect on arterial pressure but decreased cardiac hypertrophy and both perivascular and subendocardial fibrosis.. We conclude that in DOCA salt hypertension, humoral factors such as endothelin may play a role beside high blood pressure in cardiac remodeling. In addition, the different components of this remodeling (decrease of vascular reserve, cardiac hypertrophy and cardiac fibrosis) are controlled independently.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Bosentan; Calcium Channel Blockers; Cardiomegaly; Collagen; Coronary Circulation; Desoxycorticosterone; Enalapril; Endothelin Receptor Antagonists; Fibrosis; Hypertension; Male; Mibefradil; Myocardium; Perfusion; Rats; Rats, Wistar; Sulfonamides; Tetrahydronaphthalenes

The effects of nifedipine and enalapril on age-associated renal interstitial fibrosis were investigated in 60 CF1 female mice. Mice received 20 mg enalapril (ENAL) per L (N = 20), or 40 mg nifedipine (NIF) per L (N = 20) in their drinking water. Control (CONT) mice received tap water ad libitum. The percentages of both interstitial peritubular sclerosis (IPS) in cortex and interstitial medullary sclerosis (IMS) were determined. Kidney tissue was studied using immunological techniques and optical (OM) and electron microscopy (EM) to analyze the expression of renin. alpha-SM-actin and vimentine expression were also evaluated. The results showed that blood pressure levels in ENAL or NIF animals were not different from those of CONT. Renin expression was observed in arcuate vessels (AV) in ENAL animals, whereas no renin staining in AV was found in either NIF or CONT animals. Renin immunoreactivity in the juxtaglomerular apparatus was more intense in ENAL mice, as compared with NIF or CONT animals. Laboratory testing showed the following values: proteinuria (mg/mL): CONT 6.1 +/- 0.6, NIF 11.2 +/- 2.3, and ENAL 1.0 +/- 0.6 (P < 0.05); creatinine: CONT 1.37 +/- 0.24, NIF 0.87 +/- 0.16, and ENAL 0.63 +/- 0.1 (P < 0.01). The percentages of interstitial sclerosis were: %IPS: CONT 18.12 +/- 1.1, NIF 17.40 +/- 0.9, and ENAL 3.42 +/- 1.3 (P < 0.01); %IMS: CONT 23.41 +/- 1.5, NIF 21.80 +/- 1.9, and ENAL 6.12 +/- 1.2 (P < 0.01). Percentages of alpha-SM-actin expression were: CONT 13.10 +/- 1.9, NIF 13.80 +/- 0.2, and ENAL 1.00 +/- 0.1 (P < 0.01). Vimentine staining showed no differences among the groups. It was concluded that enalapril reduces the peritubular and medullar interstitial fibrosis, whereas nifedipine has no effect.

Topics: Actins; Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Calcium Channel Blockers; Enalapril; Extracellular Matrix; Female; Fibrosis; Kidney; Mice; Nifedipine; Renin-Angiotensin System; Sclerosis; Vimentin

High blood pressure results in cardiac hypertrophy and fibrosis, increased thickness and stiffness of large artery walls, and decreased renal function. The objective of our study was to assess the role of endothelin, angiotensin II, and high blood pressure in the end-organ damage observed in spontaneously hypertensive rats (SHR). For this purpose, SHR were treated for 10 weeks with either a mixed endothelin-A and endothelin-B receptor antagonist, bosentan (100 mg/kg per day), an angiotensin-converting enzyme inhibitor, enalapril (10 mg/kg per day), or a long-acting calcium antagonist, mibefradil (20 mg/kg per day). A group of SHR was left untreated, and a group of normotensive Wistar rats was used as control. At the end of treatment, maximal coronary blood flow was measured in isolated perfused hearts. Cardiac hypertrophy and fibrosis, aortic medial thickness, and extracellular matrix content were evaluated by quantitative morphometry. Proteinuria and urea and creatinine clearances were measured, and renal histopathology was assessed. SHR exhibited cardiac hypertrophy, perivascular fibrosis, and decreased maximal coronary blood flow. Aortic medial thickness was increased, whereas elastin density was decreased. Finally, SHR showed decreased urinary excretion and decreased urea and creatinine clearances. No renal histological lesions were observed. Although bosentan did not affect blood pressure, it normalized renal function and slightly decreased left ventricular hypertrophy and fibrosis. Enalapril and mibefradil were both effective in significantly decreasing blood pressure, left ventricular hypertrophy, and aortic medial thickness and improving coronary blood flow, but in contrast to bosentan, they did not improve creatinine clearance. We conclude that in SHR, high blood pressure plays a major role in end-organ damage and that endothelin may partly mediate renal dysfunction and cardiac remodeling independently of a direct hemodynamic effect.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Benzimidazoles; Body Weight; Bosentan; Calcium Channel Blockers; Cardiomegaly; Coronary Circulation; Enalapril; Endothelins; Fibrosis; Heart Ventricles; Hemodynamics; Hormones; Hypertension; Kidney; Mibefradil; Myocardium; Rats; Rats, Inbred SHR; Sulfonamides; Tetrahydronaphthalenes

Angiotensin-converting enzyme (ACE) inhibitors have been shown to minimize fibrosis of the kidney tubulointerstitium in several diseases. In addition to lowering angiotensin II levels, ACE inhibitors can increase kinin levels and subsequently increase nitric oxide formation. To determine whether nitric oxide generation is a component of the beneficial effect of ACE inhibitors on renal fibrosis, enalapril, enalapril plus NG-nitro-L-arginine methyl ester (L-NAME) or L-arginine was administered to rats that had undergone unilateral ureteral obstruction (UUO). Ureteral obstruction caused significant increases in interstitial volume, monocyte macrophage infiltration, interstitial collagen IV and alpha-smooth muscle actin expression, transforming growth factor-beta 1 mRNA, collagen IV mRNA, and tissue inhibitor of metalloproteinase-1 mRNA. Enalapril treatment significantly blunted the increase in all parameters during UUO. Cotreatment of the animals with enalapril and L-NAME reversed the beneficial effect of enalapril in the obstructed kidney for all parameters. Treatment of animals with UUO with L-arginine significantly blunted the increase in all parameters except for transforming growth factor-beta 1 mRNA expression. In the enalapril- plus-L-NAME-treated animals, there were modest but significant increases in monocyte/macrophage infiltration of the interstitium and glomerulus, and collagen IV and alpha-smooth muscle actin expression in the interstitium of the contralateral unobstructed kidney. The urine nitrite concentration was significantly increased by either enalapril or L-arginine treatment, whereas L-NAME significantly reduced urine nitrite concentration. These results suggest that treatment modalities that increase nitric oxide formation have a beneficial effect on the progression of cellular and molecular parameters of tubulointerstitial fibrosis caused by obstruction of the ureter.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Collagen; Enalapril; Enzyme Inhibitors; Female; Fibrosis; Kidney; Kidney Diseases; Kidney Tubules; Muscle, Smooth; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Sprague-Dawley; Ureteral Obstruction

Chronic unilateral ureteral obstruction (UUO) results in interstitial fibrosis of the affected kidney. In this study we determined that enalapril ameliorates the increased production of extracellular matrix (ECM) protein in the tubulointerstitium during UUO. The relative volume (Vv) of the tubulointerstitium measured by a point-counting method increased significantly at three or five days of UUO as compared to the contralateral kidney. Enalapril significantly blunted this increase at either three or five days. Immunofluorescence studies revealed that collagen type IV increased remarkably in both the tubular basement membrane (TBM) and the interstitial space at three or five days of UUO. Glomeruli did not show any change. Collagen types I and III were faintly stained in the control kidneys while they were obviously increased in the interstitial space of the obstructed kidney. We examined the expression of collagen type IV (COL IV) because this basement membrane matrix protein appeared to be a major ECM protein deposited in the tubulointerstitium of the obstructed kidney. Semiquantitative analysis of COL IV by immunofluorescence microscopy revealed that enalapril reduced slightly (21%) but significantly (P < 0.01) the deposition of COL IV in the obstructed kidney. Measurement of cyanogen bromide peptides from the obstructed kidney by Western blotting showed an increase of COL IV. This increase was reduced slightly (20%) by enalapril. The level of COL IV mRNA measured by reverse transcription-PCR was very low or undetectable in the control and contralateral kidneys, while it was significantly increased in the obstructed kidney at three or five days of UUO. COL IV mRNA was abundant in glomeruli while it was almost undetectable in renal tubules in the control and contralateral kidneys. However, COL IV mRNA was increased in renal tubules but not in the glomeruli of the obstructed kidney. Enalapril treatment resulted in a 42% decrease (P < 0.01) in COL IV mRNA in the cortex and a remarkable decrease in the renal tubules of the obstructed kidney at five days. Enalapril treatment resulted in an 89% decrease in the number of infiltrating ED-1 positive monocytes/macrophages. These results indicate that enalapril treatment ameliorates the tubulointerstitial fibrosis of the affected kidney in UUO. This effect of enalapril on fibrosis may be due to the severe reduction in monocytes/macrophages capable of secreting the profibrotic factor TGF-beta 1.

Topics: Animals; Base Sequence; Collagen; DNA Primers; Enalapril; Female; Fibrosis; Fluorescent Antibody Technique; Kidney Cortex; Kidney Tubules; Molecular Sequence Data; Rats; Rats, Sprague-Dawley; RNA, Messenger; Ureteral Obstruction

To test whether angiotensin-converting enzyme (ACE) inhibition may prevent myocardial damage and may affect coronary microvasculature in spontaneously hypertensive rats (SHR), young 5-week-old SHR were treated for 3 months with spirapril and changes in blood pressure (BP) were monitored. Untreated SHR were used as controls. The rats were killed; left ventricular (LV) shape, weight, and wall thickness were examined and the ventricular myocardium was analyzed morphometrically to determine the effect of the drug on the relative amount, number per unit area of myocardium, and average dimension of foci of myocardial scarring. Moreover, volume fraction, surface, numerical density, and diffusion distance for oxygen of the coronary capillaries were analyzed. BP remained 20-30% lower in treated SHR with respect to controls, and LV weight and thickness decreased 20 and 21%, respectively. The number and dimension of the foci of fibrosis were reduced, resulting in an overall 68% decrement in the amount of myocardial damage. Finally, a 28% increment in numerical density of capillary profiles associated with a 13% reduction in their cross-sectional area decreased the diffusion distance for oxygen from the capillary wall to the myocytes by 14% in treated SHR. Spirapril decreases BP and LV weight and thickness in the SHR model of hypertension and substantially improves coronary capillary microvasculature, decreasing hypertensive myocardial damage. These results may be attributed to inhibition of the systemic effects of angiotensin II (AII) as well as to a local protective action of the drug against possible intramyocardial AII production.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Capillaries; Coronary Vessels; Enalapril; Fibrosis; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; Male; Myocardium; Rats; Rats, Inbred SHR

Topics: Aging; Animals; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Enalapril; Fibrosis; Hypertension; In Vitro Techniques; Incidence; Myocardial Reperfusion; Myocardium; Oxygen; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Reference Values

Left ventricular hypertrophy (LVH) in rats with genetic hypertension is accompanied by abnormal myocardial diastolic stiffness and impaired coronary reserve. Whether these functional defects are related to a structural remodeling of the myocardium that includes an interstitial and perivascular fibrosis, myocyte hypertrophy, and medial thickening of intramyocardial coronary arteries is uncertain. To address these issues, 14-week-old male spontaneously hypertensive rats with established hypertension and LVH were treated with low-dose (SLO group: 2.5 mg/kg/day, n = 11) or high-dose (SHI group: 20 mg/kg/day, n = 9) oral lisinopril for 12 weeks to sustain hypertension and LVH or to normalize arterial pressure and myocardial mass, respectively. When SHI and SLO groups were compared with age- and sex-matched 26-week-old untreated spontaneously hypertensive rats (n = 11) and normotensive Wistar-Kyoto rats (n = 9), we found 1) normalization of blood pressure (p less than 0.005) and complete regression of LVH (p less than 0.005) in the SHI group and no significant blood pressure or LVH reduction in the SLO group, 2) complete regression of morphometrically determined myocardial interstitial and perivascular fibrosis in SHI and SLO groups (p less than 0.025) associated with normalization of diastolic stiffness, measured in the isolated heart (p less than 0.025), and 3) regression of medial wall thickening of intramyocardial coronary arteries only in the SHI group (P less than 0.005), accompanied by a normalization of coronary vasodilator reserve to adenosine (p less than 0.005). Thus, interstitial fibrosis and not LVH is responsible for abnormal myocardial diastolic stiffness, whereas medical wall thickening of intramyocardial resistance vessels, influenced by arterial pressure, is associated with impaired coronary reserve.

Topics: Animals; Antihypertensive Agents; Cardiomegaly; Coronary Circulation; Coronary Vessels; Diastole; Dose-Response Relationship, Drug; Elasticity; Enalapril; Fibrosis; Heart; Hemodynamics; Hypertension; Lisinopril; Male; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY