enalapril and Disease-Models--Animal

In arterial hypertension, left ventricular (LV) hypertrophy (H) is a prognostically relevant target organ damage associated with systolic and diastolic LV dysfunction. The level of LV dysfunction seems to be related to the degree of myocardial fibrosis. Prognosis of hypertensive patients who have LVH regression appears to be improved. Therefore, LVH regression is an important antihypertensive treatment goal. The renin-angiotensin-aldosterone system is implicated in LVH development and myocardial fibrosis in essential arterial hypertension. Early studies in the 80s and 90s have led expectations that angiotensin converting enzyme (ACE) inhibitors could induce greater LVH regression than other antihypertensive drugs at similar blood pressure reduction. In the late 90s, the double-blind randomized controlled PRESERVE trial (Prospective Randomize Enalapril Study Evaluating Reversal of Ventricular Enlargement) has been designed to evaluate whether the ACE inhibitor enalapril was more effective than nifedipine GITS in regressing LVH and improving LV diastolic dysfunction. The PRESERVE study demonstrated a mildly higher antihypertensive effect of nifedipine GITS than enalapril, which required more frequently association with hydrochlorothiazide to control blood pressure. However, at similar level of blood pressure reduction achieved with enalapril and long-acting nifedipine in association with hydrochlorothiazide or atenolol, both antihypertensive treatments showed similar efficacy in LVH regression and LV diastolic filling improvement.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atenolol; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Diuretics; Drug Therapy, Combination; Enalapril; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Hypertrophy, Left Ventricular; Meta-Analysis as Topic; Nifedipine; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Rats; Rats, Inbred SHR; Renin-Angiotensin System; Sodium Chloride Symporter Inhibitors; Time Factors; Ventricular Dysfunction, Left

There is now abundant evidence that treatment with angiotensin-converting enzyme inhibitors (ACE-I) ameliorates the progression of chronic renal disease. Attention has therefore focused on the role of the renin angiotensin-aldosterone (RAA) system in mediating the development of progressive glomerulosclerosis and angiotensin II (Ang II) has been implicated in several processes thought to be important in the pathogenesis of this entity. Conversely, ACE is also known to catalyse the breakdown of bradykinin. Thus, ACE-I treatment results in elevated bradykinin levels which may cause selective efferent arteriolar dilatation, suggesting an alternative explanation for the beneficial effects of this class of drugs in chronic renal disease. The development of specific angiotensin type 1 receptor antagonists (AT1RA) has provided a means of testing the relative importance of these two mechanisms. In addition, AT1RAs differ from ACE-I in their effect on the RAA system in other aspects which may represent therapeutic advantages. This paper reviews studies which have compared ACE-I and AT1RAs in several rat models of chronic renal disease. Most have found similar beneficial effects including amelioration of proteinuria and glomerulosclerosis, which suggests that the effects of ACE-I are due to a reduction in Ang II activity and not due to increased levels of bradykinin. One long-term study has suggested greater renal protection with candesartan than with enalapril. However, conclusions as regards the relative efficacy of these two groups of agents in ameliorating the progression of chronic renal disease await the results of further long-term studies.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Bradykinin; Chronic Disease; Disease Models, Animal; Enalapril; Follow-Up Studies; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Peptidyl-Dipeptidase A; Rats; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Tetrazoles; Treatment Outcome

Locally increased synthesis of angiotensin II (ANG II) in the kidney has been linked to glomerular hypertrophy, glomerulosclerosis and tubulo-interstitial fibrosis observed in chronic renal failure after subtotal nephrectomy. This action of ANG II is thought to be mediated mainly by transforming growth factor-beta (TGF-beta), which stimulates the synthesis and decreases the degradation of extracellular matrix (ECM) components, including various collagen types and fibronectin. Some recent reports indicate that reduced ANG II activity diminishes TGF-beta overexpression, and in consequence renal injury. However, no studies in SNx models concerning the influence of ANG II on gene expression regulated by TGF-beta have so far been performed. Therefore, the present study has been initiated with the following aims: 1. To develop a RT-PCR assay for evaluating gene expression concerning renin (REN), angiotensinogen (ATG) and the following ECM components: transforming growth factor-beta 1 (TGF-beta 1), fibronectin (FN), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinases-2 (TIMP-2); 2. To assess the influence of renal mass reduction (RMR) caused by subtotal (5/6) or partial (2/6) nephrectomy on gene expression for TGF-beta 1, FN, MMP-2 and TIMP-2; 3. To evaluate the correlation between expression of these genes and activity of the circulatory or renal renin-angiotensin systems; 4. To assess the influence of treatment with enalapril (angiotensin-converting enzyme inhibitor) on renal expression of these genes, renal morphology and function in rats, relative to duration of treatment and RMR. The study consisted of two independent experiments performed in adult male Sprague-Dawley rats. Ten days prior to surgery, the animals were matched for body weight and systolic blood pressure (SBP) values and subsequently were distributed into untreated (control) and enalapril treated groups. Treatment with enalapril (EN) (50 mg/l in drinking water) was started 9 days prior to surgery. The first (short-term) experiment was performed in rats with chronic renal failure caused by subtotal nephrectomy. Remnant kidneys were taken for molecular studies at the day of SNx and 3, 7 and 21 days thereafter. Blood samples collected at the time of sacrifice served to determine plasma renin activity and plasma concentration of angiotensinogen and angiotensin II. The second (long-term) experiment was done in subtotally (5/6) and partially (2/6) nephrectomized rats. Remna

Topics: Angiotensins; Animals; Blood Pressure; Disease Models, Animal; Disease Progression; Enalapril; Fibronectins; Gene Expression; Kidney Failure, Chronic; Nephrectomy; Rats; Renin; RNA, Messenger

Classically, the renin-angiotensin system (RAS) in diabetes was thought to be suppressed, and relatively unimportant in the regulation of hemodynamics and the development of complications. However, recent developments have caused reconsideration of this notion. Studies of pharmacological interruption of the RAS with angiotensin converting enzyme (ACE) inhibition have implicated this hormonal system in the progression of diabetic nephropathy, both experimentally and clinically. Preliminary evidence also suggests a beneficial effect of angiotensin II (ANG II) receptor antagonists. The relative roles of the systemic versus intrarenal RAS in the pathogenesis of diabetic nephropathy have recently been evaluated. Although plasma renin level is generally low, it is not yet clear whether RAS component processing is normal in diabetes; there may be subtle changes in ANG II metabolism that sustain relatively higher plasma ANG II levels. Furthermore, the intrarenal RAS may not be suppressed. Renal renin levels tend to be disproportionately elevated, as compared with plasma renin values. Renal ANG II levels are normal, and renal mRNAs for RAS components have been variable. In general, lack of RAS suppression (despite plasma volume and increased exchangeable sodium) may indicate inappropriate activity of the RAS in diabetes. RAS-mediated injury may occur via stimulation of a number of sclerosing mediators, and there is evidence that hyperglycemia acts synergistically with ANG II to promote cellular injury. Finally, various RAS candidate genes for development of diabetic nephropathy have been examined and, although controversy remains, ACE gene polymorphisms may be involved. Together, these recent investigations lend further support to the notion that the RAS plays an important role in diabetic nephropathy, and are beginning to shed light on the mechanisms of progressive renal injury.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Enalapril; Hemodynamics; Plasma Volume; Rats; Renin-Angiotensin System

The management of sodium intake is clinically important in many disease states including heart failure, kidney disease, and hypertension. Tenapanor is an inhibitor of the sodium-proton (Na(+)/H(+)) exchanger NHE3, which plays a prominent role in sodium handling in the gastrointestinal tract and kidney. When administered orally to rats, tenapanor acted exclusively in the gastrointestinal tract to inhibit sodium uptake. We showed that the systemic availability of tenapanor was negligible through plasma pharmacokinetic studies, as well as autoradiography and mass balance studies performed with (14)C-tenapanor. In humans, tenapanor reduced urinary sodium excretion by 20 to 50 mmol/day and led to an increase of similar magnitude in stool sodium. In salt-fed nephrectomized rats exhibiting hypervolemia, cardiac hypertrophy, and arterial stiffening, tenapanor reduced extracellular fluid volume, left ventricular hypertrophy, albuminuria, and blood pressure in a dose-dependent fashion. We observed these effects whether tenapanor was administered prophylactically or after disease was established. In addition, the combination of tenapanor and the blood pressure medication enalapril improved cardiac diastolic dysfunction and arterial pulse wave velocity relative to enalapril monotherapy in this animal model. Tenapanor prevented increases in glomerular area and urinary KIM-1, a marker of renal injury. The results suggest that therapeutic alteration of sodium transport in the gastrointestinal tract instead of the kidney--the target of current drugs--could lead to improved sodium management in renal disease.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Electrolytes; Enalapril; Feces; Healthy Volunteers; Humans; Hypertrophy; Intestinal Mucosa; Intestines; Isoquinolines; Kidney; Male; Myocardium; Nephrectomy; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Sodium; Sodium Chloride, Dietary; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Sulfonamides

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antiviral Agents; Apolipoproteins E; Atherosclerosis; Disease Models, Animal; Enalapril; Female; Kidney Diseases; Male; Mice; Sex Characteristics

Acute renal failure (ARF) is a clinical critical syndrome with rapid and severe decline of renal function. Complications of ARF, especially its cardiac complications (cardiorenal syndrome type 3, CRS-3), are the main causes of death in patients with ARF. However, the shortage and limited efficacy of therapeutic drugs make it significant to establish new large-scale drug screening models. Based on the Nitroreductase/Metronidazole (NTR/MTZ) cell ablation system, we constructed a

Topics: Acute Kidney Injury; Animals; Animals, Genetically Modified; Cardio-Renal Syndrome; Cardiovascular Diseases; Digoxin; Disease Models, Animal; Drug Evaluation, Preclinical; Enalapril; Epithelial Cells; Humans; Kidney Tubules; Larva; Metronidazole; Regional Blood Flow; Thioctic Acid; Treatment Outcome; Zebrafish

The heart is a high energy demand organ and enhancing mitochondrial function is proposed as the next-generation therapeutics for heart failure. Our previous study found that anthelmintic drug niclosamide enhanced mitochondrial respiration and increased adenosine triphosphate (ATP) production in cardiomyocytes, therefore, this study aimed to determine the effect of niclosamide on heart failure in mice and the potential molecular mechanisms. The heart failure model was induced by transverse aortic constriction (TAC) in mice. Oral administration of niclosamide improved TAC-induced cardiac hypertrophy, cardiac fibrosis, and cardiac dysfunction in mice. Oral administration of niclosamide reduced TAC-induced increase of serum IL-6 in heart failure mice. In vitro, niclosamide within 0.1 μM increased mitochondrial respiration and ATP production in mice heart tissues. At the concentrations more than 0.1 μM, niclosamide reduced the increased interleukin- 6 (IL-6) mRNA expression in lipopolysaccharide (LPS)-stimulated RAW264.7 and THP-1 derived macrophages. In cultured primary cardiomyocytes and cardiac fibroblasts, niclosamide (more than 0.1 μM) suppressed IL-6- and phenylephrine-induced cardiomyocyte hypertrophy, and inhibited collagen secretion from cardiac fibroblasts. In conclusion, niclosamide attenuates heart failure in mice and the underlying mechanisms include enhancing mitochondrial respiration of cardiomyocytes, inhibiting collagen secretion from cardiac fibroblasts, and reducing the elevated serum inflammatory mediator IL-6. The present study suggests that niclosamide might be therapeutic for heart failure.

Topics: Adenosine Triphosphate; Animals; Anthelmintics; Cardiomegaly; Cell Line; Collagen; Disease Models, Animal; Enalapril; Fibroblasts; Heart Failure; Humans; Interleukin-6; Macrophages; Male; Mice; Mitochondria; Myocytes, Cardiac; Niclosamide; Phenylephrine; Proto-Oncogene Proteins c-bcl-2; Rats; STAT3 Transcription Factor; Survivin

The use of animal models to predict the response to new therapies in humans is a vexing issue in nephrology. Unlike patients with chronic kidney disease (CKD), few rodent models develop a progressive decline in glomerular filtration rate (GFR) so that experimental studies frequently report a reduction in proteinuria as the primary efficacy outcome. Moreover, while humans present with established kidney disease that continues to progress, many experimental studies investigate therapies in the prevention rather than in a therapeutic setting.. We used the remnant kidney (subtotal nephrectomy [SNX]) rat model that develops a decline in GFR in conjunction with heavy proteinuria and hypertension along with the histological hallmarks of CKD in humans, glomerulosclerosis and tubulointerstitial fibrosis. Using agents that had been shown to improve GFR as well as proteinuria in the prevention setting, angiotensin-converting enzyme (ACE) inhibition with enalapril and SIRT1 activation with SRT3025, treatment was initiated 6 weeks after SNX.. While enalapril reduced blood pressure, proteinuria and histological injury, it did not improve GFR, as measured by inulin clearance. SRT3025 improved neither GFR nor structural damage despite a reduction in proteinuria.. These findings demonstrate that neither a reduction in proteinuria nor a reversal of structural damage in the kidney will necessarily translate to a restoration of kidney function.

Topics: Angiotensin-Converting Enzyme Inhibitors; Anilides; Animals; Disease Models, Animal; Disease Progression; Enalapril; Glomerular Filtration Rate; Hypertension; Kidney; Nephrectomy; Postoperative Complications; Proteinuria; Rats; Renal Insufficiency, Chronic; Sirtuin 1; Thiazoles

Anticoagulant-related nephropathy (ARN), that was described in humans first as warfarin-related nephropathy, is characterized by acute kidney injury and red blood cell (RBC) tubular casts in the kidney. 5/6 nephrectomy (5/7NE) rats treated with warfarin or dabigatran show changes in kidney function and morphology that are similar to human disease. The role of glomerular filtration rate (GFR) in the pathogenesis of ARN is not clear. The aim of these studies was to elucidate the role of GFR in the pathogenesis of dabigatran-induced ARN in 5/6NE rats.. 5/6NE rats were treated per os with 150 mg/kg/day dabigatran alone or with drugs that lower (enalapril, 1.5 mg/kg/day) or increase (albuterol, 4.0 mg/kg/day) GFR for 7 days. Changes in coagulation and kidney function were recorded daily. Kidney morphology was evaluated on day 7 after the treatment.. Dabigatran resulted in activated partial thromboplastin time increase that was not affected by GFR-modifying drugs. Blood pressure was significantly lower in 5/6NE rats treated with enalapril and dabigatran as compared to dabigatran alone. The GFR was decreased by 35% in enalapril/dabigatran- and increased by 26% in albuterol/dabigatran-treated animals. There were no changes in serum creatinine, hematuria or urinary kidney injury molecule (KIM-1) levels when GFR-modifying drugs were added to dabigatran. All dabigatran-treated animals had RBC casts in the kidney regardless of the GFR modification.. GFR does not play a significant role in the dabigatran-induced acute kidney injury in 5/6 nephrectomy model in rats. Based in these data, modification of GFR in patients with ARN is not warranted.

Topics: Acute Kidney Injury; Albuterol; Animals; Antihypertensive Agents; Antithrombins; Bronchodilator Agents; Dabigatran; Disease Models, Animal; Enalapril; Glomerular Filtration Rate; Male; Nephrectomy; Rats; Rats, Sprague-Dawley

Fibromyalgia is a potentially disabling chronic disease, characterized by widespread pain and a range of comorbidities such as hypertension. Among the mechanisms involved in fibromyalgia-like pain symptoms are kinins and their B

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Behavior, Animal; Captopril; Disease Models, Animal; Enalapril; Fibromyalgia; Male; Mice; Nervous System; Nociceptive Pain; Pain Threshold; Peptidyl-Dipeptidase A; Receptors, Bradykinin; Reserpine; Signal Transduction

This study aimed to determine if açai seed extract (ASE) could reverse pre-existing cardiovascular and renal injury in an experimental model of renovascular hypertension (2 kidney, 1 clip, 2K1C). Young male rats (Wistar) were used to obtain 2K1C and sham groups. Animals received the vehicle, ASE (200 mg/kg/d), or enalapril (30 mg/kg/d) in drinking water from the third to sixth week after surgery. We evaluated systolic blood pressure by tail plethysmography, vascular reactivity in the rat isolated mesenteric arterial bed (MAB), serum and urinary parameters, plasma inflammatory cytokines by ELISA, MAB expression of endothelial nitric oxide synthase and its active form peNOS by Western blot, plasma and MAB oxidative damage and antioxidant activity by spectrophotometry, and vascular and cardiac structural changes by histological analysis. ASE and enalapril reduced the systolic blood pressure, restored the endothelial and renal functions, and decreased the inflammatory cytokines and the oxidative stress in 2K1C rats. Furthermore, both treatments reduced vascular and cardiac remodeling. ASE substantially reduced cardiovascular remodeling and recovered endothelial dysfunction in 2K1C rats probably through its antihypertensive, antioxidant, and anti-inflammatory actions, supplying a natural resource for the treatment of renovascular hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Antioxidants; Biomarkers; Blood Pressure; Disease Models, Animal; Enalapril; Euterpe; Hypertension, Renovascular; Inflammation Mediators; Oxidative Stress; Plant Extracts; Rats, Wistar; Vascular Remodeling; Ventricular Remodeling

In the brain, aminopeptidase A (APA) generates angiotensin III, one of the effector peptides of the brain renin-angiotensin system (RAS), exerting tonic stimulatory control over blood pressure (BP) in hypertensive rats. Oral administration of firibastat, an APA inhibitor prodrug, in hypertensive rats, inhibits brain APA activity, blocks brain angiotensin III formation and decreases BP. In this study, we evaluated the efficacy of firibastat in combination with enalapril, an angiotensin I-converting enzyme inhibitor, and hydrochlorothiazide (HCTZ), in conscious hypertensive deoxycorticosterone acetate (DOCA)-salt rats, which display high plasma arginine-vasopressin levels, low circulating renin levels and resistance to treatment by systemic RAS blockers. We determined mean arterial BP, heart rate, plasma arginine-vasopressin levels and renin activity in DOCA-salt rats orally treated with firibastat, enalapril or HCTZ administered alone or in combination. Acute oral firibastat administration (30 mg/kg) induced a significant decrease in BP, whereas enalapril (10 mg/kg) or HCTZ (10 mg/kg) administered alone induced no significant change in BP in conscious DOCA-salt rats. The BP decrease induced by acute and nine-day chronic tritherapy [Firibastat+Enalapril+HCTZ] was significantly greater than that observed after bitherapy [Enalapril+HCTZ]. Interestingly, the chronic administration of a combination of firibastat with [Enalapril+HCTZ] reduced plasma arginine-vasopressin levels by 62% relative to those measured in DOCA-salt rats receiving bitherapy. Our data show that tritherapy with firibastat, enalapril and HCTZ improves BP control and arginine-vasopressin release in an experimental salt-dependent model of hypertension, paving the way for the development of new treatments for patients with currently difficult-to-treat or resistant hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Desoxycorticosterone Acetate; Disease Models, Animal; Disulfides; Enalapril; Glutamyl Aminopeptidase; Hydrochlorothiazide; Hypertension; Male; Rats; Rats, Inbred WKY; Renin-Angiotensin System; Sulfonic Acids; Vasopressins

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

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

The study objective was to evaluate the effect of bilateral sympathectomy on ventricular remodeling and function in a rat model of dilated cardiomyopathy induced by doxorubicin.. Dilated cardiomyopathy was induced in male Wistar rats by weekly intraperitoneal injection of doxorubicin (2 mg/kg) for 9 weeks. Animals were divided into 4 groups: dilated cardiomyopathy; bilateral sympathectomy, submitted on day 15 of the protocol to bilateral sympathectomy; angiotensin-converting enzyme inhibitor, treated with enalapril through day 15 until the end of the experimental protocol; and sham, nonsubmitted through doxorubicin protocol, with weekly intraperitoneal injections of saline solution (0.9%). The left ventricular function was assessed, and the heart was collected for posterior analyses.. Bilateral sympathectomy was effective in preventing remodeling and left ventricular dysfunction in a rat model of dilated cardiomyopathy induced by doxorubicin.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomyopathy, Dilated; Disease Models, Animal; Doxorubicin; Enalapril; Humans; Male; Rats; Rats, Wistar; Sympathectomy; Ventricular Dysfunction, Left; Ventricular Remodeling

Background The fractions of Corchorus olitorius leaf (COLF) were evaluated against oxidative stress, inflammation and apoptosis in isoproterenol (ISO)-induced myocardial injury (MI) Wistar rats. Methods The n-hexane, dichloromethane, ethylacetate and ethanol fractions were obtained from COLF extract. Male Wistar strains were randomly grouped into 11 groups (n = 6 in each group), which comprises normal control group, MI control group, 4 fraction groups with two doses (50 and 100 mg/kg) and enalapril (10 mg/kg). The sera were obtained for biochemical studies like AOPP (advance oxidized protein product), CRP (C-reactive protein), LDH (lactate dehydrogenase), CKMB (creatine kinase-MB) and myocardial tissue obtained for GSH, p65NFkB, bax, bcl2, p53 and p65NFkB assays. Results The subcutaneous administration of ISO increased the serum level of CRP, LDH and CKMB significantly (p < 0.05) and decreased serum AOPP, tissue GSH and p65NFkB (p < 0.05) in the infarction control rats. Pretreatment with COLF and enalapril increased the tissue GSH and p65NFkB levels (p < 0.05) and significantly reduced serum CRP, AOPP, LDH and CKMB. The dichloromethane fraction (CODCM) being the most active was chosen to evaluate the anti-apoptotic effect. CODCM (50 and 100 mg/kg) and enalapril showed a significant (p < 0.05) effect through severe expression of p65NFkB, which correlates with increased bcl2 protein expression, decreased bax protein and p53 expression. Gas chromatography mass spectrometry revealed the presence of 26 compounds in CODCM. Conclusions From the present study, COLF protected the myocardial tissue against ischemic injury in rats probably via the p65NFkB-dependent anti-apoptotic pathway and attenuation of pro-inflammatory marker level.

Topics: Animals; Apoptosis; Cardiotonic Agents; Corchorus; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Gas Chromatography-Mass Spectrometry; Isoproterenol; Male; Myocardial Infarction; Oxidative Stress; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Transcription Factor RelA

The incidence of depression doubles in diabetic patients and is associated with poor outcomes. Studies indicate that renin-angiotensin-aldosterone system inhibitors (RAASi) might relieve depression, however the mechanism of action is not well understood. We recently showed that angiotensin receptor blockers have antidepressant effects in experimental diabetes comorbid depression. Here we investigated whether all types of RAASi exhibit antidepressant and neuroprotective properties. Diabetes was induced by streptozotocin in adult male Wistar rats. After 5 weeks of diabetes, rats were treated per os with non-pressor doses of enalapril, ramipril, spironolactone or eplerenone for 2 weeks. Behavior was evaluated using forced swim test and open field test. Inflammatory response and brain-derived neurotrophic factor (BDNF) signaling were investigated in the hippocampus. Both ACEi and MR antagonists reversed diabetes-induced behavioral despair confirming their antidepressant-like effect. This may occur via alterations in hippocampal cytokine-mediated inflammatory response. Repressed BDNF production was restored by RAASi. Both ACEi and MR antagonists facilitated the BDNF-tropomyosin receptor kinase B-cAMP response element-binding protein signaling pathway as part of their neuroprotective effect. These data highlight the important benefits of ACEi and MR antagonists in the treatment of diabetes-associated depressive symptoms. Our novel findings support the link between diabetes comorbid depression, inflammation and repressed BDNF signaling. RAASi could provide new therapeutic options to improve the outcomes of both disorders.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antidepressive Agents; Antihypertensive Agents; Behavior, Animal; Blood Pressure; Depression; Diabetes Mellitus, Experimental; Disease Models, Animal; Down-Regulation; Enalapril; Eplerenone; Male; Mineralocorticoid Receptor Antagonists; Ramipril; Rats; Rats, Wistar; Renin-Angiotensin System; Spironolactone

Aseptic loosening, the most frequent complication after total joint replacement, is probably caused by an inflammatory response to the shedding of wear debris from the implant. The only effective treatment is surgical revision. Using a mouse model, we investigated whether enalapril inhibits wear debris-induced inflammatory osteolysis.. Titanium (Ti) alloy particles were introduced, and calvarial bone from syngeneic mice was implanted into air pouches established in BALB/c mice. Histological and molecular analyses were performed with inflammatory tissue samples obtained from mice treated with and without enalapril.. Enalapril inhibited tissue inflammation and inflammatory osteolysis induced by Ti particles, reducing pouch membrane thickness and decreasing inflammatory cell infiltration. In addition, enalapril inhibited the expression of the inflammatory cytokines vascular endothelial growth factor and tumor necrosis factor-α.. Our study provides evidence that enalapril inhibits Ti particle-induced inflammatory osteolysis, and it may be a potentially useful treatment for aseptic loosening.

Topics: Animals; China; Disease Models, Animal; Enalapril; Female; Inflammation; Mice; Mice, Inbred BALB C; Osteoclasts; Osteolysis; Prostheses and Implants; Prosthesis Failure; Titanium; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

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

Praliciguat, a clinical-stage soluble guanylate cyclase (sGC) stimulator, increases cGMP via the nitric oxide-sGC pathway. Praliciguat has been shown to be renoprotective in rodent models of hypertensive nephropathy and renal fibrosis. In the present study, praliciguat alone and in combination with enalapril attenuated proteinuria in the obese ZSF1 rat model of diabetic nephropathy. Praliciguat monotherapy did not affect hemodynamics. In contrast, enalapril monotherapy lowered blood pressure but did not attenuate proteinuria. Renal expression of genes in pathways involved in inflammation, fibrosis, oxidative stress, and kidney injury was lower in praliciguat-treated obese ZSF1 rats than in obese control rats; fasting glucose and cholesterol were also lower with praliciguat treatment. To gain insight into how tubular mechanisms might contribute to its pharmacological effects on the kidneys, we studied the effects of praliciguat on pathological processes and signaling pathways in cultured human primary renal proximal tubular epithelial cells (RPTCs). Praliciguat inhibited the expression of proinflammatory cytokines and secretion of monocyte chemoattractant protein-1 in tumor necrosis factor-α-challenged RPTCs. Praliciguat treatment also attenuated transforming growth factor-β-mediated apoptosis, changes to a mesenchyme-like cellular phenotype, and phosphorylation of SMAD3 in RPTCs. In conclusion, praliciguat improved proteinuria in the ZSF1 rat model of diabetic nephropathy, and its actions in human RPTCs suggest that tubular effects may contribute to its renal benefits, building upon strong evidence for the role of cGMP signaling in renal health.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Cell Line; Cytokines; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Enalapril; Guanylyl Cyclase C Agonists; Humans; Inflammation Mediators; Kidney Tubules, Proximal; Male; Nephritis; Phosphorylation; Pyrazoles; Pyrimidines; Rats, Zucker; Signal Transduction; Smad3 Protein

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

Chronic kidney disease (CKD) is a significant global health concern with limited treatment options. Oxidative stress and inflammatory responses have been implicated in the pathology of CKD. Patients with CKD are frequently affected with neurological complications that affect both the central and peripheral nervous system. Identification of effective treatment strategies are of much clinical value in the therapy of CKD. Tangeretin, a plant-derived flavonoid has been described to retain extensive pharmacological properties. In the present study, we explored whether tangeretin exerted protective effects in 5/6 nephrectomized rats. CKD was induced in Sprague-Dawley rats by 5/6 nephrectomy (Nx). Separate groups of 5/6 Nx rats were treated with tangeretin (50, 100 or 200 mg/kg b.wt.) or enalapril for 30 days (starting 5 days after surgery for 35 days). Control animals were not subjected to Nx nor were treated with tangeretin or enalapril. Renal dysfunction, as evinced by raised serum urea, serum creatinine, proteinuria, and histological alterations were significantly reduced by tangeretin and enalapril treatment. 5/6 Nx animals exhibited raised levels of malondialdehyde (MDA) and reactive oxygen species. Elevated TNF-α, nitric oxide (NO) and cytokines-IL-6 and IL-1β with upregulated NF-κB/TNF-α/iNOS signalling pathways were effectively down-regulated by tangeretin. Cognitive disturbances and memory impairments observed in Nx rats were substantially improved by tangeretin. Collectively, the experimental data indicate that the anti-oxidant and anti-inflammatory effects of tangeretin effectively improved renal function and reduced the cognitive and memory impairments in CKD-induced animals.

Topics: Animals; Cognition; Cognition Disorders; Cytokines; Disease Models, Animal; Down-Regulation; Enalapril; Flavones; Inflammation; Kidney; Male; Memory; Nephrectomy; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Rats, Sprague-Dawley; Renal Insufficiency; Renal Insufficiency, Chronic; Signal Transduction; Tumor Necrosis Factor-alpha; Up-Regulation

Clinical studies suggest beneficial effects of renin-angiotensin system blockade for prevention of left ventricular (LV) dysfunction after chemotherapy. However, the efficacy of this strategy as primary prevention has been poorly studied. This study aimed at identifying the pathophysiological mechanisms by which mineralocorticoid receptor antagonism (MRA) or angiotensin converting enzyme inhibition (ACEi) provide protection against doxorubicin-induced cardiotoxicity (DIC) in mouse models of acute and chronic toxicity.. Acute DIC was induced by a single injection of Dox at 15 mg/kg and chronic DIC applied 5 injections of Dox at 4 mg/kg/week. MRA was achieved using eplerenone or cardiomyocyte-specific ablation of the MR gene in transgenic mice and ACEi using enalapril. Drugs were provided with the first dose of Dox and applied until the end of the study. In both model of DIC, Dox induced cardiac atrophy with decreased LV volume, reduced cardiomyocyte cell size, and cardiac dysfunction. In the acute model, neither MRA nor ACEi protected against these manifestations of DIC. In the chronic model, concomitant treatment with eplerenone did not protect against DIC and drastically increased plasma aldosterone levels and cardiac levels of angiotensin II type 1 receptor and of connective tissue growth factor (CTGF), as observed in acute DIC. Enalapril treatment in the chronic model, however, protected against cardiac dysfunction and cardiomyocyte atrophy and was associated with increased activation of the PI3K/AKT/mTOR pathway along with normal levels of CTGF.. Enalapril and eplerenone disparately impact on cellular signalling in DIC. Eplerenone, on top of Dox treatment was not protective and associated with increased levels of plasma aldosterone and of cardiac CTGF. In contrast, we show that primary prevention with enalapril preserves LV morphology and function in a clinically relevant model of chronic DIC, with increased stimulation of the PI3K/AKT/mTOR axis and normal CTGF levels suggesting potential therapeutic implications.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiotoxicity; Connective Tissue Growth Factor; Disease Models, Animal; Doxorubicin; Enalapril; Eplerenone; Male; Mice, Inbred C57BL; Mice, Knockout; Mineralocorticoid Receptor Antagonists; Myocytes, Cardiac; Phosphatidylinositol 3-Kinase; Primary Prevention; Proto-Oncogene Proteins c-akt; Receptor, Angiotensin, Type 1; Receptors, Mineralocorticoid; Renin-Angiotensin System; Signal Transduction; TOR Serine-Threonine Kinases; Ventricular Dysfunction, Left; Ventricular Function, Left

The purpose of this study was to compare the effects of oral enalapril, an angiotensin-converting enzyme inhibitor (ACE-I), oral candesartan, an angiotensin receptor blocker (ARB), and intralesional corticosteroid treatments in reducing scar formation.. Twenty male rabbits were divided into five study groups: A (sham), B (control), C (ACE-I), D (ARB) and E (intralesional corticosteroid). The rabbit ear hypertrophic scar model was used. The hypertrophic scars were photographed and analyzed with the program ImageJ quantitatively to determine the degree of collagen fibers. The scar elevation index (SEI) was calculated at the end of the 40th day. Tissue samples were stained with hematoxylin and eosin and Masson's trichrome and examined under light microscopy for the determination of fibroblast number, epithelization, vascularization, inflammation and fibrosis.. The SEI was the highest in the control group with the highest number of fibroblasts under the epithelium. In the steroid group, the SEI was significantly lower than both the ACE-I (p: 0.02) and ARB (p: 0.001) groups. The density of type 1 collagen fibers was the lowest in the control group, whereas type 3 collagen fibers were highest in that group. The ACE-I and ARB groups were similar regarding densities of type 1 and type 3 collagen fibers. The density of type 1 collagen fibers was the highest in the steroid group, whereas the density of type 3 collagen fibers was the lowest in that group.. Enalapril, candesartan and intralesional steroid therapies were all effective in reducing scar tissue development; however, enalapril and steroid groups revealed better results.. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Topics: Administration, Oral; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biopsy, Needle; Biphenyl Compounds; Chi-Square Distribution; Cicatrix, Hypertrophic; Disease Models, Animal; Enalapril; Follow-Up Studies; Immunohistochemistry; Injections, Intralesional; Male; Rabbits; Random Allocation; Risk Assessment; Tetrazoles; Treatment Outcome; Triamcinolone

Renal vasoconstriction, oxidative stress, endothelial dysfunction, and apoptosis are the major causes of contrast-induced nephropathy (CIN). The aim of this study was to evaluate the protective effects of enalapril maleate and folic acid tablets on CIN in diabetic rats.. Thirty-two Sprague-Dawley rats were divided into four groups: CIN (C), CIN + enalapril maleate (CE), CIN + folic acid (CF), and CIN + enalapril maleate and folic acid tablets (CEF). CE, CF, and CEF rats were treated orally with enalapril maleate, folic acid, or enalapril maleate and folic acid tablets, respectively, for 5 days. CIN was induced in all groups followed by analyzed biochemical parameters, oxidative stress markers, endothelial dysfunction parameters, renal histopathology, and TUNEL staining.. Serum creatinine, blood urea nitrogen, and malondialdehyde levels were lower in the CEF group than in the C group. Homocysteine, superoxide dismutase, glutathione peroxidase, and nitric oxide levels were higher in the CEF group than in the C group. Histopathology scores and percentage of apoptotic kidney cells in the CEF group were significantly decreased compared with those in the C group.. These results suggest that enalapril maleate and folic acid tablets have a protective effect against CIN in diabetic rats.

Topics: Animals; Apoptosis; Blood Urea Nitrogen; Contrast Media; Creatinine; Diabetes Mellitus, Experimental; Disease Models, Animal; Drug Combinations; Enalapril; Endothelial Cells; Folic Acid; Humans; Kidney; Kidney Diseases; Nitric Oxide; Oxidative Stress; Rats

The metabolic syndrome is a cluster of risk correlates that can progress to type 2 diabetes. The present study aims to evaluate a novel molecule with a dual action against the metabolic syndrome and type 2 diabetes.. We developed and tested a novel dual modulator, RB394, which acts as a soluble epoxide hydrolase (sEH) inhibitor and a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist in rat models of the metabolic syndrome-the obese spontaneously hypertensive (SHROB) rat and the obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat. In SHROB rats we studied the ability of RB394 to prevent metabolic syndrome phenotypes, while in ZSF1 obese diabetic rats we compared RB394 with the ACE inhibitor enalapril in the treatment of type 2 diabetes and associated comorbid conditions. RB394 (10 mg/kg daily) and enalapril (10 mg/kg daily) were administered orally for 8 weeks.. RB394 blunted the development of hypertension, insulin resistance, hyperlipidaemia and kidney injury in SHROB rats and reduced fasting blood glucose and HbA. These findings demonstrate that a novel sHE inhibitor/PPAR-γ agonist molecule targets multiple risk factors of the metabolic syndrome and is a glucose-lowering agent with a strong ability to treat diabetic complications.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Enalapril; Enzyme Inhibitors; Epoxide Hydrolases; Fatty Liver; Glucose Tolerance Test; Hypertension; Insulin Resistance; Kidney Glomerulus; Liver Cirrhosis; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; PPAR gamma; Rats; Rats, Zucker

Chronic kidney disease (CKD) is a global health concern, but the current treatments only slow down the progression. Thus an improved understanding of the pathogenesis and novel treatments of CKD are needed. The nephrotoxic nephritis (NTN) model has the potential to study the pathogenesis of CKD as it resembles human CKD. The classical treatments with angiotensin II receptor blocker (ARB) or the angiotensin-converting enzyme inhibitor (ACE I) have shown a clinical effect in CKD.. We characterized the disease development in the NTN model over 11 weeks by investigating functional and histopathological changes. We tested doses of 15 and 30 mg/kg/day enalapril and losartan in the NTN model in order to investigate the effect of inhibiting the renin-angiotensin-system (RAS).. The NTN model displayed albuminuria peaking on days 6-7, mesangial expansion (ME), renal fibrosis, inflammation and iron accumulation peaking on day 42. However, albuminuria, ME, renal fibrosis and inflammation were still significantly present on day 77, suggesting that the NTN model is useful for studying both the acute and chronic disease phases. Enalapril and losartan significantly enhanced the glomerular filtration rate (GFR) and decreased albuminuria, ME, renal fibrosis and inflammation of NTN-induced kidney disease in mice.. This is the first study showing a comprehensive pathological description of the chronic features of the murine NTN model and that inhibiting the RAS pathway show a significant effect on functional and morphological parameters.

Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Glomerular Filtration Rate; Kidney; Losartan; Mice; Nephritis; Renin-Angiotensin System

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

The safety of testosterone supplements in men remains unclear. In the present study, we tested the hypothesis that in young and old male spontaneously hypertensive rats (SHR), long-term testosterone supplements increase blood pressure and that the mechanism is mediated in part by activation of the renin-angiotensin system.. In untreated males, serum testosterone exhibited a sustained decrease after 5 months of age, reaching a nadir by 18 to 22 months of age. The reductions in serum testosterone were accompanied by an increase in body weight until very old age (18 months). Testosterone supplements were given for 6 weeks to young (12 weeks-YMSHR) and old (21-22 months-OMSHR) male SHR that increased serum testosterone by 2-fold in young males and by 4-fold in old males. Testosterone supplements decreased body weight, fat mass, lean mass, and plasma leptin, and increased plasma estradiol in YMSHR but had no effect in OMSHR. Mean arterial pressure (MAP) was significantly higher in OMSHR than in YMSHR and testosterone supplements decreased MAP in OMSHR, but significantly increased MAP in YMSHR. Enalapril, the angiotensin-converting enzyme inhibitor, reduced MAP in both control and testosterone-supplemented YMSHR, but had a greater effect on MAP in testosterone-treated rats, suggesting the mechanism responsible for the increase in MAP in YMSHR is mediated at least in part by activation of the renin-angiotensin system.. Taken together with previous studies, these data suggest that testosterone supplements may have differential effects on men depending on age, cardiovascular and metabolic status, and dose and whether given long-term or short-term.

Topics: Adiposity; Age Factors; Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arterial Pressure; Disease Models, Animal; Enalapril; Estradiol; Hormone Replacement Therapy; Hypertension; Leptin; Male; Rats, Inbred SHR; Renin-Angiotensin System; Risk Factors; Testosterone; Weight Gain

Mitochondrial activity is essential for cardiac and skeletal muscle. The relationship between mitochondrial dysfunction and different cardiovascular conditions has been well described. Pharmacological treatment for heart failure involves different drugs as: angiotensin-converting enzyme inhibitors, B-adrenergic blockers, digitalis glycosides and diuretics. The clinical benefit from medication is clear, however, the role of this drugs in mitochondrial metabolisms is not well understood.. The objective of our study was to analyze structural and functional characteristics of cardiac and skeletal muscle mitochondria in mice treated with drugs normally used for heart failure and compare it to a control group. Methods: Twenty-five Albino Mice divided in five groups were treated with heart failure medication during 30 days (group I to IV). 30 days after treatment they were sacrificed, heart and skeletal muscle were analyzed and compared with a control group (V). Results: Enzymatic activity was slightly increased in groups treated with heart failure medication compared to control group (p>0.05). Mitochondrial morphology was significantly altered in groups treated compared to control group, in addition, mitochondrial area was significantly increased in the treated groups, in both cardiac and skeletal muscle. Conclusions: We concluded that heart failure medication could produce modifications in mitochondrial function; we believe that mitochondria maintains the enzymatic activity by increasing size and modifying morphology.. Twenty-five Albino Mice divided in five groups were treated with heart failure medication during 30 days (group I to IV). 30 days after treatment they were sacrificed, heart and skeletal muscle were analyzed and compared with a control group (V). Results: Enzymatic activity was slightly increased in groups treated with heart failure medication compared to control group (p>0.05). Mitochondrial morphology was significantly altered in groups treated compared to control group, in addition, mitochondrial area was significantly increased in the treated groups, in both cardiac and skeletal muscle. Conclusions: We concluded that heart failure medication could produce modifications in mitochondrial function; we believe that mitochondria maintains the enzymatic activity by increasing size and modifying morphology.. Enzymatic activity was slightly increased in groups treated with heart failure medication compared to control group (p>0.05). Mitochondrial morphology was significantly altered in groups treated compared to control group, in addition, mitochondrial area was significantly increased in the treated groups, in both cardiac and skeletal muscle. Conclusions: We concluded that heart failure medication could produce modifications in mitochondrial function; we believe that mitochondria maintains the enzymatic activity by increasing size and modifying morphology.. We concluded that heart failure medication could produce modifications in mitochondrial function; we believe that mitochondria maintains the enzymatic activity by increasing size and modifying morphology.. la actividad mitocondrial es esencial para el músculo cardíaco y esquelético. La relación entre la disfunción mitocondrial y diferentes condiciones cardiovasculares ha sido bien descrita. El tratamiento farmacológico de la insuficiencia cardíaca implica diferentes medicamentos como: inhibidores de la enzima convertidora de la angiotensina, bloqueadores B-adrenérgicos, glucósidos digitálicos y diuréticos. Los beneficios clínicos del tratamiento son claros, sin embargo, el papel de estos fármacos en el metabolismo mitocondrial no esta bien establecido.Objetivo del estudio: El objetivo de nuestro estudio fue analizar las características estructurales y funcionales de las mitocondrias del músculo cardíaco y esquelético en ratones tratados con fármacos habitualmente utilizados para la insuficiencia cardíaca y compararlo con un grupo control.Métodos: Veinticinco ratones albinos divididos en cinco grupos fueron tratados con la medicación para insuficiencia cardíaca durante 30 días (grupo I a IV). 30 días después del tratamiento se sacrificaron, el corazón y el músculo esquelético se analizaron y se compararon con un grupo control (V).Resultados: La actividad enzimática se incrementó ligeramente en los grupos tratados con medicamentos insuficiencia cardiaca en comparación con el grupo control (p> 0,05). morfología mitocondrial se modificó significativamente en los grupos tratados en comparación con el grupo control, además, el área mitocondrial fue significativamente mayor en los grupos tratados, tanto en el músculo cardíaco y estriado.Conclusiones: Concluimos que la medicación insuficiencia cardíaca podría producir modificaciones en la función mitocondrial; creemos que las mitocondrias pueden mantener la actividad enzimática mediante el aumento de tamaño y modificación de la morfología.. El objetivo de nuestro estudio fue analizar las características estructurales y funcionales de las mitocondrias del músculo cardíaco y esquelético en ratones tratados con fármacos habitualmente utilizados para la insuficiencia cardíaca y compararlo con un grupo control.. Veinticinco ratones albinos divididos en cinco grupos fueron tratados con la medicación para insuficiencia cardíaca durante 30 días (grupo I a IV). 30 días después del tratamiento se sacrificaron, el corazón y el músculo esquelético se analizaron y se compararon con un grupo control (V).Resultados: La actividad enzimática se incrementó ligeramente en los grupos tratados con medicamentos insuficiencia cardiaca en comparación con el grupo control (p> 0,05). morfología mitocondrial se modificó significativamente en los grupos tratados en comparación con el grupo control, además, el área mitocondrial fue significativamente mayor en los grupos tratados, tanto en el músculo cardíaco y estriado.Conclusiones: Concluimos que la medicación insuficiencia cardíaca podría producir modificaciones en la función mitocondrial; creemos que las mitocondrias pueden mantener la actividad enzimática mediante el aumento de tamaño y modificación de la morfología.. La actividad enzimática se incrementó ligeramente en los grupos tratados con medicamentos insuficiencia cardiaca en comparación con el grupo control (p> 0,05). morfología mitocondrial se modificó significativamente en los grupos tratados en comparación con el grupo control, además, el área mitocondrial fue significativamente mayor en los grupos tratados, tanto en el músculo cardíaco y estriado.Conclusiones: Concluimos que la medicación insuficiencia cardíaca podría producir modificaciones en la función mitocondrial; creemos que las mitocondrias pueden mantener la actividad enzimática mediante el aumento de tamaño y modificación de la morfología.. Concluimos que la medicación insuficiencia cardíaca podría producir modificaciones en la función mitocondrial; creemos que las mitocondrias pueden mantener la actividad enzimática mediante el aumento de tamaño y modificación de la morfología.

Topics: Animals; Antihypertensive Agents; Atenolol; Cardiotonic Agents; Digoxin; Disease Models, Animal; Diuretics; Electrocardiography; Enalapril; Female; Furosemide; Heart Failure; Isosorbide Dinitrate; Male; Mice; Mitochondria, Heart; Spironolactone

We investigated the cardiovascular autonomic effects of physical training associated with Enalapril or Losartan pharmacological treatments in spontaneously hypertensive rats (SHR).. SHRs, 18weeks of age (N=48) was assigned to either sedentary (N=24) and trained (N=24; aerobic training by swimming for 10wk). Each group was subdivided in 3 subgroups (N=8) vehicle (control); Enalapril (10mg·kg. The groups treated with Enalapril, sedentary and trained, showed more significant decrease in blood pressure when compared to the other groups. Autonomic evaluation showed that the sedentary group treated with Enalapril or Losartan had similar results, characterized by decreased effect of sympathetic tone and/or increased effect of cardiac vagal tone associated with improved BRS. Isolated physical training attenuated only the effect of sympathetic tone. The association of physical training with Enalapril showed the best results, characterized by the predominance of vagal tone in cardiac autonomic balance, increased HRV, reduced SAPV and increased BRS.. Enalapril and Losartan promoted similar beneficial cardiovascular autonomic effects in sedentary animals, while only the association of physical training with Enalapril potentiated these effects.

Topics: Animals; Antihypertensive Agents; Atropine; Autonomic Nervous System; Baroreflex; Blood Pressure; Combined Modality Therapy; Disease Models, Animal; Enalapril; Exercise Therapy; Heart Rate; Hypertension; Losartan; Male; Parasympatholytics; Propranolol; Rats, Inbred SHR; Sedentary Behavior; Swimming

Drug-induced liver injury (DILI) is a major concern in drug development and clinical drug therapy. Since the underlying mechanisms of DILI have not been fully understood in most cases, elucidation of the hepatotoxic mechanisms of drugs is expected. Although enalapril (ELP), an angiotensin-converting enzyme inhibitor, has been reported to cause liver injuries with a low incidence in humans, the precise mechanisms by which ELP causes liver injury remains unknown. In this study, we established a mouse model of ELP-induced liver injury and analyzed the mechanisms of its hepatotoxicity. Mice that were administered ELP alone did not develop liver injury, and mice that were pretreated with a synthetic glucocorticoid dexamethasone (DEX) and a glutathione synthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO) exhibited liver steatosis without significant increase in plasma alanine aminotransferase (ALT). In mice pretreated with DEX and BSO, ALT levels were significantly increased after ELP administration, suggesting that hepatic steatosis sensitized the liver to ELP hepatotoxicity. An immunohistochemical analysis showed that the numbers of myeloperoxidase-positive cells that infiltrated the liver were significantly increased in the mice administered DEX/BSO/ELP. The levels of oxidative stress-related factors, including hepatic heme oxygenase-1, serum hydrogen peroxide and hepatic malondialdehyde, were elevated in the mice administered DEX/BSO/ELP. The involvement of oxidative stress in ELP-induced liver injury was further supported by the observation that tempol, an antioxidant agent, ameliorated ELP-induced liver injury. In conclusion, we successfully established a model of ELP-induced liver injury in DEX-treated steatotic mice and demonstrated that oxidative stress and neutrophil infiltration are involved in the pathogenesis of ELP-induced liver injury.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Enalapril; Glutathione; Glutathione Disulfide; Liver; Male; Mice; Mice, Inbred BALB C; Neutrophils; Oxidative Stress

The relationship between hypertension and sleep-related movement disorders has been hypothesized for humans, but the causes and mechanisms have not been elucidated. We investigated whether an alteration in blood pressure (BP) induced by physical exercise and/or an angiotensin-converting enzyme inhibitor (enalapril) could affect locomotor activity in spontaneously hypertensive rats, with emphasis on the dopaminergic system. We used SHR and normotensive Wistar rats distributed into 4 groups for each strain: control, physical exercise, enalapril and physical exercise+enalapril. Physical exercise was performed on a treadmill, and enalapril was administered by gavage, both for 8weeks. During this period, locomotor activity was evaluated in an open field test, and BP was evaluated by tail plethysmography. Dopaminergic receptors, dopamine transporter and tyrosine hydroxylase levels at the striatum were evaluated by Western blotting. The control group of spontaneously hypertensive rats showed higher BP, increased activity in the open field test and lower levels of D2 receptors and tyrosine hydroxylase compared with all other groups throughout the experimental period. In general, physical exercise and enalapril attenuated these alterations. This study suggested the existence of comorbidity between hypertension and sleep-related movement disorders in spontaneously hypertensive rats. Physical exercise and enalapril conferred protection for both hypertension and the observed behavioral changes. In addition, these treatments led to changes in dopaminergic signaling in the striatal region (i.e., D2 receptor, TH and DAT).

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Enalapril; Exercise Therapy; Male; Motor Activity; Movement Disorders; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Dopamine; Sleep Wake Disorders; Time Factors; Tyrosine 3-Monooxygenase

The co-administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARB) that bind angiotensin type 1 receptors (AT1R) may protect from Alzheimer's disease (AD) better than each treatment taken alone. We tested the curative potential of the non brain-penetrant ACEi enalapril (3 mg/kg/day) administered for 3 months either alone or in combination with the brain penetrant ARB losartan (10 mg/kg/day) in aged (∼15 months) transgenic mice overexpressing a mutated form of the human amyloid-β protein precursor (AβPP, thereafter APP mice). We studied cerebrovascular function, protein levels of oxidative stress markers (superoxide dismutases SOD1, SOD2 and the NADPH oxidase subunit p67phox), amyloid-β (Aβ) pathology, astrogliosis, cholinergic innervation, AT1R and angiotensin IV receptor (AT4R) levels, together with cognitive performance. Both treatments normalized cerebrovascular reactivity and p67phox protein levels, but they did not reduce the cerebrovascular levels of SOD1. Combined treatment normalized cerebrovascular SOD2 levels, significantly attenuated astrogliosis, but did not reduce the increased levels of cerebrovascular AT1R. Yet, combined therapy enhanced thioflavin-S labeled Aβ plaque burden, a tendency not significant when Aβ1 - 42 plaque load was considered. None of the treatments rescued cognitive deficits, cortical AT4R or cholinergic innervation. We conclude that both treatments normalized cerebrovascular function by inhibiting the AngII-induced oxidative stress cascade, and that the positive effects of the combined therapy on astrogliosis were likely due to the ability of losartan to enter brain parenchyma. However, enalapril did not potentiate, and may even dampen, the reported cognitive benefits of losartan, raising caution when selecting the most appropriate antihypertensive therapy in AD patients.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidosis; Analysis of Variance; Animals; Antihypertensive Agents; Cerebrovascular Disorders; Cholinesterases; Disease Models, Animal; Drug Combinations; Enalapril; Female; Glial Fibrillary Acidic Protein; Humans; Losartan; Male; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Mutation

Aberrant glomerular polyanionic charge of glycosaminoglycans (GAGs) and sialic acid expression has been observed in proteinuric human and experimental glomerular diseases. Angiotensin-converting enzyme inhibitors (ACEI) lower proteinuria and amend renal function deterioration via hemodynamic mechanisms. We tested the hypothesis that ACEI modulate proteinuria additionally by modifying glomerular GAGs.. In this study, we explored the effects of the ACEI enalapril on proteinuria and GAG synthesis in puromycin aminonucleoside (PAN)-treated rats. We employed cationic colloidal gold (CCG) localization in glomerular basement membranes (GBM) to identify GAGs by electron microscopy and determined sialic acid residues by immunohistochemical staining with lectins. To clarify ACEI effects on GAG production in vitro, we studied de novo GAG synthesis into newly synthesized proteoglycans in podocytes and mesangial cells using. PAN rats developed severe proteinuria that was significantly improved by enalapril treatment. In non-treated PAN rats GBM GAGs were reduced, whereas in the enalapril-treated group GBM GAGs were significantly increased to control levels. Enalapril did not affect glomerular sialic acid. Furthermore, in cultured podocytes and mesangial cells PAN decreased de novo GAG synthesis, an effect which was significantly ameliorated by enalaprilat treatment.. Treatment with ACEI improves permselectivity properties of the glomerular capillary wall by maintaining its GAG content. This finding provides an additional new mechanism, whereby ACEI exert anti-proteinuric effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Glycosaminoglycans; Immunohistochemistry; Kidney Glomerulus; Male; Microscopy, Electron, Transmission; Nephrosis; Podocytes; Protein Synthesis Inhibitors; Puromycin Aminonucleoside; Rats; Rats, Wistar

There is strong evidence to suggest that angiotensin-converting enzyme inhibitors (ACEIs) protect against local myocardial ischemia/reperfusion (I/R) injury. This study was designed to explore whether ACEIs exert cardioprotective effects in a swine model of cardiac arrest (CA) and resuscitation. Male pigs were randomly assigned to three groups: sham‑operated group, saline treatment group and enalapril treatment group. Thirty minutes after drug infusion, the animals in the saline and enalapril groups were subjected to ventricular fibrillation (8 min) followed by cardiopulmonary resuscitation (up to 30 min). Cardiac function was monitored, and myocardial tissue and blood were collected for analysis. Enalapril pre‑treatment did not improve cardiac function or the 6-h survival rate after CA and resuscitation; however, this intervention ameliorated myocardial ultrastructural damage, reduced the level of plasma cardiac troponin I and decreased myocardial apoptosis. Plasma angiotensin (Ang) II and Ang‑(1‑7) levels were enhanced in the model of CA and resuscitation. Enalapril reduced the plasma Ang II level at 4 and 6 h after the return of spontaneous circulation whereas enalapril did not affect the plasma Ang‑(1‑7) level. Enalapril pre-treatment decreased the myocardial mRNA and protein expression of angiotensin-converting enzyme (ACE). Enalapril treatment also reduced the myocardial ACE/ACE2 ratio, both at the mRNA and the protein level. Enalapril pre‑treatment did not affect the upregulation of ACE2, Ang II type 1 receptor (AT1R) and MAS after CA and resuscitation. Taken together, these findings suggest that enalapril protects against ischemic injury through the attenuation of the ACE/Ang II/AT1R axis after CA and resuscitation in pigs. These results suggest the potential therapeutic value of ACEIs in patients with CA.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Western; Cardiopulmonary Resuscitation; Cardiotonic Agents; Disease Models, Animal; Enalapril; Gene Expression; Heart; Heart Arrest; Humans; Immunohistochemistry; Male; Microscopy, Electron, Transmission; Myocardial Reperfusion Injury; Myocardium; Peptidyl-Dipeptidase A; Random Allocation; Receptor, Angiotensin, Type 1; Reverse Transcriptase Polymerase Chain Reaction; Swine; Time Factors; Ventricular Fibrillation

Renal fibrovascular injury often persists in chronic kidney disease patients treated with renin-angiotensin system blockers. Intriguingly, early outgrowth cell-derived factor infusion also inhibits chronic renal injury. We sought to determine whether early outgrowth cell-derived factor administration provides further renoprotection when added to renin-angiotensin system blockade.. Conditioned medium was generated by incubating rat early outgrowth cells with serum-free endothelial basal medium-2 to collect their secreted factors. Subtotal nephrectomy rats received enalapril 0.5 mg/L in drinking water or placebo, beginning 8 weeks post-surgery. Four weeks later, enalapril-treated rats received intravenous injections of either conditioned medium or control endothelial basal medium-2 for 2 weeks. Glomerular filtration rate, urinary protein excretion and renal structure were assessed 4 weeks later at 16 weeks post-surgery.. Enalapril-treated subtotal nephrectomy rats receiving control endothelial basal medium-2 injections experienced only partial renoprotection when compared to vehicle-treated subtotal nephrectomy rats. In contrast, conditioned medium infusion, when administered in addition to enalapril, attenuated the progression of renal dysfunction in subtotal nephrectomy rats, improving glomerular filtration rate and reducing proteinuria without affecting blood pressure.. Early outgrowth cell-derived factors exert additive renoprotective effects on top of angiotensin-converting enzyme inhibitor therapy in experimental chronic kidney disease, providing the rationale for clinical trials of early outgrowth cell-based therapies for chronic kidney disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Culture Media, Conditioned; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Endothelial Cells; Glomerular Filtration Rate; Kidney; Protective Agents; Rats, Inbred F344; Renal Insufficiency, Chronic; Stem Cells

Drug-induced liver injury (DILI) is a major safety concern during drug development and remains one of the main reasons for withdrawal of drugs from the market. Although it is crucial to develop methods that will detect potential hepatotoxicity of drug candidates as early and as quickly as possible, there is still a lack of sensitive and specific biomarkers for DILI that consequently leads to a scarcity of reliable hepatotoxic data. Hence, in this study, we assessed characteristic molecular signatures in rat liver treated with drugs (pyrazinamide, ranitidine, enalapril, carbamazepine and chlorpromazine) that are known to cause DILI in humans. Unsupervised hierarchical clustering analysis of transcriptome changes induced by DILI-causing drugs resulted in three different subclusters on dendrogram, i.e., hepatocellular, cholestatic and mixed type of DILI at early time points (2 days), and multiclassification analysis suggested 31 genes as discernible markers for each DILI pattern. Further analysis for characteristic molecular signature of each DILI pattern provided a molecular basis for different modes of DILI action. A proteomics study of the same rat livers was used to confirm the results, and the two sets of data showed 60 matching classifiers. In conclusion, the data of different DILI-causing drug treatments from genomic analysis in a rat model suggest that DILI-specific molecular signatures can discriminate different patterns of DILI at an early exposure time point, and that they provide useful information for mechanistic studies that may lead to a better understanding of the molecular basis of DILI.

Topics: Animals; Biomarkers; Carbamazepine; Chemical and Drug Induced Liver Injury; Chlorpromazine; Disease Models, Animal; Dose-Response Relationship, Drug; Electrophoresis, Gel, Two-Dimensional; Enalapril; Gene Expression; Liver; Male; Oligonucleotide Array Sequence Analysis; Proteomics; Pyrazinamide; Ranitidine; Rats; Rats, Sprague-Dawley; Transcriptome

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

Chronic kidney disease (CKD) is associated with cardiac hypertrophy that leads to increased cardiovascular morbidity and mortality. To date, use of the renin-angiotensin-aldosterone system blockade has been the main treatment modality. However, renin-angiotensin-aldosterone system blockade by the angiotensin converting enzyme inhibitors (ACEi) can only partially reverse the cardiac hypertrophy without having a significant impact on all-cause mortality as evidenced by meta-analyses from clinical trials. It is imperative to elucidate the molecular pathogenesis of CKD-related cardiomyopathy for potential targets in further treatment.. Male Sprague-Dawley rats that underwent subtotal nephrectomy (SNX) rats were established as the CKD model. A hemodynamic study was used to evaluate the left ventricle (LV) structural and functional alterations. We used proteomic techniques to profile the LV protein changes among sham-operated rats, SNX rats, and SNX rats with 6 months of ACEi enalapril interventions. The differentially expressed proteins were further annotated by functional and network analyses.. As compared to the sham-operated rats, the SNX rats had 25 upregulated and 46 decreased protein expression. The top canonical pathways identified by ingenuity pathway analysis for the CKD cardiomyopathy were mitochondrial dysfunction, oxidative phosphorylation, fatty acid β oxidation, protein ubiquitination, and ketolysis. The most relevant functions extracted from these networks contained 27 and 23 focused proteins, respectively. They were related to cellular assembly and organization, RNA posttranscriptional modification, and protein synthesis. After ACEi intervention for 6 weeks, the residual canonical pathways identified by ingenuity pathway analysis that mediated the CKD-related cardiomyopathy were mitochondrial dysfunction, ketolysis, phenylalanine degradation IV, and putrescine degradation III. There were decreased Sirt3 and SNRNP, and increased monoamine oxidase and SAHH expression in the LV of SNX rats that could not be reversed by the ACEi.. Our studies provide a repertoire of potential biomarkers related to cardiac hypertrophy in CKD. There are still residual disturbed molecules/pathways despite ACEi intervention. Further studies are warranted to investigate these potential novel targets to alleviate CKD-related cardiomyopathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Western; Cardiomyopathies; Disease Models, Animal; Enalapril; Heart Ventricles; Hemodynamics; Male; Nephrectomy; Proteomics; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic

Diabetic nephropathy (DN) is a serious complication of longstanding diabetes affecting up to 30% of all diabetes patients and is the main cause of end-stage kidney disease globally. Current standard treatment e.g. ACE-inhibitors like enalapril merely offers a delay in the progression leading to DN. Herein, we describe in two preclinical models evidence to local effects on the inflammatory signatures after intervention treatment with enalapril which provides enhanced understanding of the mechanism of ACE inhibitors. Enalapril transiently reduced albuminuria in both the db/db and the STZ-induced DN models with established disease, without modulating the HbA1c%. Albuminuria was strongly associated with loss of leukocytes, particularly B cells, but also of sub-populations of macrophages and CD4(+) T cells. The remaining kidney macrophages were polarized into a M2-like sub-population with reduced surface expression of the M1-like macrophage marker CD11c and enhanced expression of galectin-3. Enalapril treatment counteracted the reduction of leukocytes in the diabetic kidney towards levels noted in the non-diabetic kidney. Particularly, a subset of macrophages was increased and a clear expansion of CD4(+) and CD8(+) T cells was observed. However, enalapril failed to modulate the B cell compartment. Interestingly, enalapril treatment resulted in a re-polarization of the macrophages towards a M1-like phenotype characterized by elevated levels of CD11c with moderate down-regulation of the M2 marker galectin-3. The data demonstrate that ACE inhibition in pre-clinical models of DN shows a transient beneficial effect on albuminuria which is unexpectedly associated with restoration of T cells and M1-like macrophages in the kidney.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; B-Lymphocytes; CD11c Antigen; Cell Differentiation; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Enalapril; Galectin 3; Humans; Kidney; Lymphocyte Count; Macrophages; Male; Mice; Mice, 129 Strain; Mice, Mutant Strains; T-Lymphocytes

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

We evaluated testicular morphology and spermatozoid parameters in spontaneously hypertensive rats treated with enalapril.. Spontaneously hypertensive rats were assigned to a hypertensive nontreated group and a hypertensive enalapril treated group. Wistar-Kyoto normotensive rats served as controls. Systolic blood pressure was measured weekly. Spermatozoid concentration, motility and viability were determined in samples collected from the epididymal tail. Testicular morphology was analyzed by morphometric methods. All data were compared using ANOVA and the Tukey post test with p <0.05 considered significant.. Systolic blood pressure in the enalapril treated group was similar to that in controls but lower than in the nontreated group. Sperm concentration in the enalapril treated group was similar to that in controls and greater than in the nontreated group. Testicular vascular volumetric density decreased in the nontreated group while in enalapril treated rats this parameter was similar to that in controls. Volumetric density of the seminiferous epithelium in the enalapril treated group was higher than in the nontreated group and controls, indicating a possibly positive effect of enalapril on spermatogenesis.. In this animal model hypertension caused morphological changes in the testis and upon spermatozoid production. Enalapril treatment partially protected the testicles from these alterations, restoring normal spermatozoid production.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Enalapril; Hypertension; Infertility, Male; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sperm Count; Spermatozoa; Testis

We examined whether reversal of high fat diet, stimulating weight loss, compared to two treatments previously shown to have beneficial effects, could improve glucose utilization and peripheral neuropathy in animal models of obesity and type 2 diabetes. Rats were fed a high fat diet and treated with a low dose of streptozotocin to create models of diet induced obesity or type 2 diabetes, respectively. Afterwards, rats were transferred to a normal diet or treated with enalapril or dietary enrichment with menhaden oil for 12 weeks. Obesity and to a greater extent type 2 diabetes were associated with impaired glucose utilization and peripheral neuropathy. Placing obese rats on a normal diet improved glucose utilization. Steatosis but not peripheral neuropathy was improved after placing obese or diabetic rats on a normal diet. Treating obese and diabetic rats with enalapril or a menhaden oil enriched diet generally improved peripheral neuropathy endpoints. In summary, dietary improvement with weight loss in obese or type 2 diabetic rats was not sufficient to correct peripheral neuropathy. These results further stress the need for discovery of a comprehensive treatment for peripheral neuropathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Obesity Agents; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diet, Fat-Restricted; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Enalapril; Fish Oils; Hypoglycemic Agents; Male; Neuralgia; Non-alcoholic Fatty Liver Disease; Obesity; Rats, Sprague-Dawley; Streptozocin; Weight Loss

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

Vitamin D attenuates uremic cardiac hypertrophy, possibly by suppressing the myocardial renin-angiotensin system (RAS) and fibroblast growth factors (FGFs). We compared the suppression of cardiac hypertrophy and myocardial expression of RAS and FGF receptor genes offered by the vitamin D analog paricalcitol (Pc) or the angiotensin-converting enzyme inhibitor enalapril (E) in experimental uremia.. Rats with 5/6 nephrectomy received Pc or E for 8 weeks. Renal function, systolic blood pressure, and cardiac hypertrophy were evaluated. Myocardial expression of RAS genes, brain natriuretic peptide (BNP), and FGF receptor-1 (FGFR-1) were determined using quantitative reverse-transcription (pRT)-PCR.. Blood pressure, proteinuria, and serum creatinine were significantly higher in untreated uremic animals. Hypertension was significantly reduced by E but only modestly by Pc; however, cardiac hypertrophy in the untreated group was similarly attenuated by Pc or E. Upregulation of myocardial expressions of renin, angiotensinogen, FGFR-1, and BNP in untreated uremic animals was reduced similarly by Pc and E, while the angiotensin II type 1 receptor was downregulated only by E.. Uremic cardiac hypertrophy is associated with activation of the myocardial RAS and the FGFR-1. Downregulation of these genes induced by Pc and E results in similar amelioration of left ventricular hypertrophy despite the different antihypertensive effects of these drugs.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Disease Models, Animal; Down-Regulation; Enalapril; Ergocalciferols; Fibroblast Growth Factors; Hypertension; Male; Myocardium; Nephrectomy; Rats, Sprague-Dawley; Receptor, Fibroblast Growth Factor, Type 1; Renin-Angiotensin System; RNA, Messenger; Uremia

Enalapril, an angiotensin-converting enzyme (ACE) inhibitor, has pleiotropic effects such as anti-inflammatory effects. This study investigated the effect of enalapril on the nuclear factor-kappa B (NF-κB) pathway and on experimental colitis.. The human intestinal epithelial cell (IEC) line COLO 205 and peritoneal macrophages from C57BL/6 wild-type mice and IL-10-deficient (IL-10(-/-)) mice were prepared and subsequently stimulated with lipopolysaccharide (LPS) alone or LPS plus enalapril. The effect of enalapril on NF-κB signaling was examined by western blotting to detect IκBα phosphorylation/degradation; an electrophoretic mobility shift assay (EMSA) to assess the DNA binding activity of NF-κB; and ELISAs to qualify IL-8, TNF-α, IL-6, and IL-12 production. In in vivo studies, dextran sulfate sodium (DSS)-induced acute colitis in wild-type mice and chronic colitis in IL-10(-/-) mice were treated with or without enalapril. Colitis was quantified by histologic scoring, and the phosphorylation of IκBα in the colonic mucosa was assessed using immunohistochemistry.. Enalapril significantly inhibited LPS-induced IκBα phosphorylation/degradation, NF-κB binding activity, and pro-inflammatory cytokine production in both IEC and peritoneal macrophages. The administration of enalapril significantly reduced the severity of colitis, as assessed based on histology in both murine colitis models. Furthermore, in colon tissue, the up-regulation of IκBα phosphorylation with colitis induction was attenuated in enalapril-treated mice.. Enalapril may block the NF-κB signaling pathway, inhibit the activation of IECs and macrophages, and attenuate experimental murine colitis by down-regulating IκBα phosphorylation. These findings suggest that enalapril is a potential therapeutic agent for inflammatory bowel disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Blotting, Western; Cell Line; Colitis; Disease Models, Animal; Down-Regulation; Enalapril; Humans; I-kappa B Proteins; Interleukin-10; Intestinal Mucosa; Lipopolysaccharides; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Severity of Illness Index; Signal Transduction

The antihypertensive treatment in patients with metabolic syndrome is unclear. We therefore used a rat model of the metabolic syndrome and compared the effects of enalapril, an angiotensin-converting-enzyme inhibitor, with candoxatril, a neutral endopeptidase inhibitor that inhibits degradation of atrial natriuretic peptide and, in addition to lowering blood pressure, exerts metabolically beneficial activity. Ten male Sprague Dawley rats were fed regular rat chow for 5 weeks. Fifty male Sprague Dawley rats were fed a high-fructose diet for 3 weeks, followed by addition of enalapril, 10 mg/Kg/d, or candoxatril, 25, 50, or 100 mg/Kg/d, for 2 weeks. Systolic blood pressure, plasma triglyceride level, and insulin level were measured at baseline and after 3 weeks and 5 weeks. Three weeks of a high-fructose diet led to a significant increase in all metabolic parameters. Candoxatril and enalapril lowered systolic blood pressure significantly (candoxatril -10 ± 1 to -22 ± 1 mm Hg and enalapril -27 ± 2 mm Hg). High-dose candoxatril and enalapril significantly decreased plasma triglyceride levels (by 17.8% and 32.8%, respectively), but only high-dose candoxatril decreased plasma insulin levels significantly (by 25.3%). High-dose candoxatril is a metabolically favorable option for lowering blood pressure in a rat model of metabolic syndrome.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Disease Models, Animal; Enalapril; Indans; Insulin; Male; Metabolic Syndrome; Propionates; Rats; Rats, Sprague-Dawley; Triglycerides

Most patients with essential hypertension do not exhibit substantial renal damage. Renal autoregulation by preventing glomerular transmission of systemic pressures has been postulated to mediate this resistance. Conversely, malignant nephrosclerosis (MN) has been postulated to develop when severe hypertension exceeds a critical ceiling. If the concept is valid, even modest blood pressure (BP) reductions to below this threshold regardless of antihypertensive class (1) should prevent MN and (2) lead to the healing of the already developed MN lesions. Both predicates were tested using BP radiotelemetry in the stroke-prone spontaneously hypertensive rats receiving 1% NaCl as drinking fluid for 4 weeks. Severe hypertension (final 2 weeks average systolic BP, >200 mm Hg) and MN (histological damage score 36±5; n=27) developed in the untreated stroke-prone spontaneously hypertensive rats but were prevented by all antihypertensive classes (enalapril [n=15], amlodipine [n=13], or a hydralazine/hydrochlorothiazide combination [n=15]) if the final 2-week systolic BP remained <190 mm Hg. More impressively, modest systolic BP reductions to 160 to 180 mm Hg (hydralazine/hydrochlorothiazide regimen) initiated at ≈4 weeks in additional untreated rats after MN had already developed (injury score 35±4 in the right kidney removed before therapy) led to a striking resolution of the vascular and glomerular MN injury over 2 to 3 weeks (post-therapy left kidney injury score 9±2, P<0.0001; n=27). Proteinuria also declined rapidly from 122±9.5 mg/24 hours before therapy to 20.5±3.6 mg 1 week later. These data clearly demonstrate the barotrauma-mediated pathogenesis of MN and the striking capacity for spontaneous and rapid repair of hypertensive kidney damage if new injury is prevented.

Topics: Amlodipine; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Drug Therapy, Combination; Enalapril; Humans; Hydralazine; Hydrochlorothiazide; Hypertension; Male; Nephrosclerosis; Rats; Rats, Inbred SHR; Reference Values; Treatment Outcome

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Bradykinin is the end-product of the kallikrein/kinin system, which has been recognized as an endogenous target for combating CNS inflammation. Angiotensin-converting enzyme (ACE) inhibitors influence the kallikrein/kinin system and reportedly have immunomodulatory characteristics. The objectives of this study were to determine whether bradykinin is involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and whether bradykinin control by the ACE inhibitor could be a therapeutic target in MS. The ACE inhibitor enalapril (1·0 or 0·2 mg/kg/day) was administered orally to EAE mice and the serum levels of bradykinin and cytokines in EAE mice were analysed. As a result, the administration of enalapril increased serum bradykinin levels, decreased the clinical and pathological severity of EAE and attenuated interleukin-17-positive cell invasion into the CNS. Additionally, bradykinin receptor antagonist administration reduced the favourable effects of enalapril. Our results suggest that bradykinin is involved in the pathomechanism underlying CNS inflammation in EAE, possibly through inhibiting cell migration into CNS. Control of the kallikrein/kinin system using ACE inhibitors could be a potential therapeutic strategy in MS.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Cytokines; Demyelinating Diseases; Disease Models, Animal; Enalapril; Encephalomyelitis, Autoimmune, Experimental; Female; Kallikreins; Mice; Multiple Sclerosis; Severity of Illness Index; Th17 Cells

Coronary heart disease (CHD) is the number one cause of death in the US. The adipokine adiponectin has been studied intensively for presenting and inversed association with almost every stage of CHD. For instance, the evaluation of molecules capable of enhancing endogenous adiponectin expression is well justified. In this study, we investigated the effect of the vitamin D receptor activator (VDRA) paricalcitol and the angiotensin-converting enzyme inhibitor (ACEI) enalapril on adiponectin expression, lipid profiles, adenosine monophosphate activated protein kinase (AMPK) expression, monocyte chemo-attractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNFα),cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), antioxidant capacity, CuZn-superoxide dismutase (CuZn-SOD), Mn-SOD, NADPH p22phox subunits, inducible nitric oxidesynthase (iNOS), endothelial marker eNOS, and 81 atherosclerosis-related genes in ApoE-deficient mice.. Seven-week-old ApoE-deficient mice were treated for 16 weeks as follows: Group 1, ApoE vehicle control (intraperitoneal [i.p.] 100 µl propylene glycol); Group 2, ApoE-paricalcitol (200 ng i.p., 3/week); Group 3, ApoE-Enalapril (30 mg/kg daily); Group 4, ApoE-paricalcitol + enalapril (described dosing); and Group 5, wild-type control (C57BLV).. All treated groups presented significant changes in circulating and cardiac adiponectin, cardiac cholesterol levels, AMPK, MCP-1, TNF-α, COX-2, iNOS, eNOS, CuZn-SOD, Mn-SOD and p22phox. There were 15 genes that differed in their expression, 5 of which are involved in cardioprotection and antithrombotic mechanisms: Bcl2a1a, Col3a1, Spp1 (upregulated), Itga2, and Vwf (downregulated).. Together, our data presented a novel role for VDRA and ACEI in reducing factors associated with CHD that may lead to the discovery of new therapeutic venues.

Topics: Adiponectin; Angiotensin-Converting Enzyme Inhibitors; Animals; Apolipoproteins E; Blotting, Western; Coronary Artery Disease; Disease Models, Animal; Drug Therapy, Combination; Enalapril; Ergocalciferols; Female; Gene Expression Regulation; Mice; Mice, Inbred C57BL; Oxidative Stress; Polymerase Chain Reaction; Receptors, Calcitriol; RNA

Endothelial dysfunction is now widely recognized as an early marker of cardiovascular disease, making its treatment, or complete avoidance, an emerging, interesting therapeutic target. This study investigated the ability of the highly intriguing amino acid L-arginine to influence endothelial function. Its therapeutic potential is also compared to that of known cardiovascular medications, namely nitroglycerin [a nitric oxide (NO) donor] and enalapril [an angiotensin-converting enzyme (ACE) inhibitor]. Fifty male New Zealand rabbits were included in the study, divided into 5 equal groups: control, hypercholesterolemia (untreated), hypercholesterolemia (+L-arginine), hypercholesterolemia (+enalapril), and hypercholesterolemia (+nitroglycerin). Biochemical investigations included measurement of circulating NOx, malondialdehyde (MDA), and lipid profile markers, as well as dimethylarginine dimethylaminohydrolase (DDAH) and ACE activities. Furthermore, aortic ACE activity and blood platelet aggregation were estimated. A histopathological examination and intimal thickness measurement were also conducted. Compared to the untreated hypercholesterolemic group, all agents were capable of positively influencing MDA levels, platelet aggregation and intimal thickness; however, only the L-arginine group was capable of beneficially and significantly altering both NOx levels and serum and aortic ACE activities. No agents were capable of modulating serum DDAH activity inhibited by hypercholesterolemia. Based on the results of this study, L-arginine appears to be a novel cardio-protective agent, illustrated by its ability to ameliorate the deleterious effects of hypercholesterolemia on endothelial function, in a manner comparable to, and sometimes more potent than, commonly used cardiovascular medications.

Topics: Amidohydrolases; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Cardiotonic Agents; Cardiovascular Diseases; Dietary Supplements; Disease Models, Animal; Enalapril; Endothelium, Vascular; Heart; Hypercholesterolemia; Male; Malondialdehyde; Nitric Oxide; Nitroglycerin; Oxidative Stress; Rabbits

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

Accumulating evidence suggests a role for angiotensin-converting enzymes involving the angiotensin II-receptor 1 (AT1-R) and the cyclooxygenase pathway in carcinogenesis. The effects of ASS and enalapril were assessed in vitro and in a transgenic mouse model of pancreatic neuroendocrine neoplasms (pNENs). The effects of enalapril and ASS on proliferation and expression of the AGTR1A and its target gene vascular endothelial growth factor (Vegfa) were assessed in the neuroendocrine cell line BON1. Rip1-Tag2 mice were treated daily with either 0.6 mg/kg bodyweight of enalapril i.p., 20 mg/kg bodyweight of ASS i.p., or a vehicle in a prevention (weeks 5-12) and a survival group (week 5 till death). Tumor surface, weight of pancreatic glands, immunostaining for AT1-R and nuclear factor kappa beta (NFKB), and mice survival were analyzed. In addition, sections from human specimens of 20 insulinomas, ten gastrinomas, and 12 non-functional pNENs were evaluated for AT1-R and NFKB (NFKB1) expression and grouped according to the current WHO classification. Proliferation was significantly inhibited by enalapril and ASS in BON1 cells, with the combination being the most effective. Treatment with enalapril and ASS led to significant downregulation of known target genes Vegf and Rela at RNA level. Tumor growth was significantly inhibited by enalapril and ASS in the prevention group displayed by a reduction of tumor size (84%/67%) and number (30%/45%). Furthermore, daily treatment with enalapril and ASS prolonged the overall median survival compared with vehicle-treated Rip1-Tag2 (107 days) mice by 9 and 17 days (P=0.016 and P=0.013). The AT1-R and the inflammatory transcription factor NFKB were abolished completely upon enalapril and ASS treatment. AT1-R and NFKB expressions were observed in 80% of human pNENs. Enalapril and ASS may provide an approach for chemoprevention and treatment of pNENs.

Topics: Adenoma, Islet Cell; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Animals; Antineoplastic Agents; Aspirin; Cell Line, Tumor; Cyclooxygenase Inhibitors; Disease Models, Animal; Enalapril; Female; Humans; Male; Mice, Transgenic; Middle Aged; NF-kappa B; Receptor, Angiotensin, Type 1; Tumor Burden; Vascular Endothelial Growth Factor A; Young Adult

Despite the beneficial effects of type 4 dipeptidyl peptidase (DPP-4) inhibitors on glucose levels, its effects on diabetic nephropathy remain unclear.. This study examined the long-term renoprotective effects of DPP-4 inhibitor linagliptin in db/db mice, a model of type 2 diabetes. Results were compared with the known beneficial effects of renin-angiotensin system blockade by enalapril. Ten-week-old male diabetic db/db mice were treated for 3 months with either vehicle (n = 10), 3 mg linagliptin/kg per day (n = 8), or 20 mg enalapril/kg per day (n = 10). Heterozygous db/m mice treated with vehicle served as healthy controls (n = 8).. Neither linagliptin nor enalapril had significant effects on the parameters of glucose metabolism or blood pressure in diabetic db/db mice. However, linagliptin treatment reduced albuminuria and attenuated kidney injury. In addition, expression of podocyte marker podocalyxin was normalized. We also analysed DPP-4 expression by immunofluorescence in human kidney biopsies and detected upregulation of DPP-4 in the glomeruli of patients with diabetic nephropathy, suggesting that our findings might be of relevance for human kidney disease as well.. Treatment with DPP-4 inhibitor linagliptin delays the progression of diabetic nephropathy damage in a glucose-independent and blood-pressure-independent manner. The observed effects may be because of the attenuation of podocyte injury and inhibition of myofibroblast transformation.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Enalapril; Glucose; Hypoglycemic Agents; Kidney; Kidney Glomerulus; Linagliptin; Male; Mice; Mice, Inbred Strains; Renin-Angiotensin System

An inhibition in the renin-angiotensin system (RAS) is one of the most widely used therapies to treat chronic kidney disease. However, its effect is occasionally not sufficient and additional treatments may be required. Recently, we reported that nicorandil exhibited renoprotective effects in a mouse model of diabetic nephropathy. Here we examined if nicorandil can provide an additive protection on enalapril in chronic kidney disease. Single treatment with either enalapril or nicorandil significantly ameliorated glomerular and tubulointerstitial injury in the rat remnant kidney while the combination of these two compounds provided additive effects. In addition, an increase in oxidative stress in remnant kidney was also blocked by either enalapril or nicorandil while the combination of the drugs was more potent. A mechanism was likely due for nicorandil to preventing manganase superoxide dismutase (MnSOD) and sirtuin (Sirt)3 from being reduced in injured kidneys. A study with cultured podocytes indicated that the antioxidative effect could be mediated through sulfonylurea receptor (SUR) in the mitochondrial KATP channel since blocking SUR with glibenclamide reduced MnSOD and Sirt3 expression in podocytes. In conclusion, nicorandil may synergize with enalapril to provide superior protection in chronic kidney disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Blood Pressure; Cell Line; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Enalapril; KATP Channels; Kidney; Male; Mice; Nephrectomy; Nicorandil; Oxidative Stress; Podocytes; Potassium Channel Blockers; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Sirtuin 3; Sulfonylurea Receptors; Superoxide Dismutase; Time Factors

Angiotensin (Ang II) II is known to promote oxidative stress in acute myocardial infarction (AMI). Inhibition of renin angiotensin system (RAS) or blockade of Ang II receptors may therefore be effective in reducing oxidative stress during AMI. The study evaluates and compares the protective effect of Angiotensin Converting Enzyme (ACE) inhibitor and AT1 receptor blocker in adrenaline induced oxidative stress in rats. Rats were treated with two successive injections of adrenaline subcutaneously at a dose of 2 mg/kg administered 24 hours apart. In other two groups of rats enalapril (30 mg/kg) or valsartan (30 mg/kg) were given orally once daily through intragastric tube for 2 weeks and then two injections of adrenaline were administered 24 hours apart. Serum Aspertate Transaminase (AST), plasma Malonde Aldehyde (MDA), erythrocyte GSH and serum vitamin E levels were measured 24 hours after the 2nd injection of adrenaline in all the groups. Administration of adrenaline caused significant increase (p < 0.001) in serum AST and plasma MDA levels and decrease (p < 0.001) in erythrocyte GSH and serum vitamin E levels. Pre-treatment of enalapril or valsartan for 14 days reduced (p < 0.001) serum AST and plasma MDA levels and increased the concentration of erythrocyte GSH in enalapril pre-treated group (p < 0.01) and in valsartan pre-treated group (p < 0.05). Pre-treatment of enalapril or valsartan also increased (p < 0.01) serum vitamin E levels in adrenaline treated rats. However, no significant difference was noted between the effect of enalapril and valsartan on serum AST, plasma MDA, erythrocyte GSH and serum vitamin E levels. It may be concluded that both enalapril and valsartan offered cardioprotection in adrenaline induced oxidative stress, but the protection afforded by valsartan was not superior to enalapril.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Epinephrine; Female; Male; Oxidative Stress; Rats; Rats, Long-Evans; Tetrazoles; Valine; Valsartan

To investigate the protective effect of angiotensin-converting enzyme (ACE)-inhibitory peptide LAP on the left common carotid artery remodeling in spontaneously hypertensive rats (SHRs).. A cohort of male SHRs were randomly divided into three groups (n = 10 for each group): pseudo-experimental group, enalapril-treated group as a positive control group, ACE-inhibitory peptide LAP-treated group. After the experiment, the left common carotid artery from each rat was removed for morphological evaluation.. It was observed that the vascular medial thickness, media thickness/lumen diameter, medial cross-sectional area and mean nuclear area of smooth muscle cells of the left common carotid artery in the LAP group or enalapril group were significantly lower than those in the pseudo-experimental group, while there was no significant difference in these parameters observed between the LAP group and enalapril group. Additionally, the vascular area percentage of collagen fibers of the left common carotid artery in the LAP group and enalapril group was significantly lower than that of the pseudo-experimental group.. The protective vessel remodeling effect in SHRs was observed with ACE-inhibitory peptide LAP in SHRs by decreasing blood pressure, inhibiting smooth muscle cell hypertrophy and reducing the proliferation of collagen fibers.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Carotid Artery, Common; Carotid Intima-Media Thickness; Cell Proliferation; Disease Models, Animal; Enalapril; Fibrillar Collagens; Heart Rate; Hypertension; Hypertrophy; Male; Muscle, Smooth, Vascular; Peptides; Rats; Rats, Inbred SHR

Elevated plasma aldosterone concentrations in patients have been linked to a spectrum of cardiovascular diseases. Mineralocorticoid receptor antagonists provide additional benefits in patients with heart failure. However, whether aldosterone and the mineralocorticoid receptor are involved in aortic aneurysm is unknown.. We report that administration of deoxycorticosterone acetate (DOCA) and salt or aldosterone and salt, but not DOCA or salt alone, to C57BL/6 male mice induced abdominal and thoracic aortic aneurysm formation and rupture in an age-dependent manner. DOCA and salt- or aldosterone and salt-induced aortic aneurysm mimicked human aortic aneurysm with respect to elastin degradation, inflammatory cell infiltration, smooth muscle cell degeneration and apoptosis, and oxidative stress. Aortic aneurysm formation did not correlate with the increase in blood pressure induced by DOCA and salt. Systemic administration of the angiotensin-converting enzyme inhibitor, enalapril, or angiotensin type 1 receptor antagonist, losartan, did not affect DOCA and salt-induced aortic aneurysm. In contrast, the mineralocorticoid receptor antagonists, spironolactone or eplerenone, significantly attenuated DOCA and salt- or aldosterone and salt-induced aortic aneurysm.. The current study describes a novel aortic aneurysm animal model induced by mineralocorticoid receptor agonist and high salt, and reveals a previously unrecognized but potentially significant role of aldosterone in the pathogenesis of aortic aneurysm. These findings imply that mineralocorticoid receptor antagonists may be effective in the treatment of some aortic aneurysms.

Topics: Aldosterone; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Aortic Rupture; Apoptosis; Blood Pressure; Desoxycorticosterone; Disease Models, Animal; Elastin; Enalapril; Eplerenone; Losartan; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Muscle, Smooth, Vascular; Oxidative Stress; Receptors, Mineralocorticoid; Sodium Chloride, Dietary; Spironolactone; Time Factors

In this study, we investigated the role of nitric oxide synthase (NOS) isoforms in the enhanced enalapril-evoked hypotension in ethanol-fed female rats by examining the effect of the selective inhibitors of eNOS [N(5)-(1-iminoethyl)-l-ornithine; l-NIO], nNOS (N(ω)-propyl-l-arginine; NPLA), or iNOS (1400W) inhibition on the cardiovascular effects of enalapril in ethanol- (5% w/v) fed rats and in their pair-fed controls. In liquid diet-fed control rats, enalapril- (10 mg/kg) evoked hypotension was abolished by l-NIO (20 mg/kg), but not by NPLA (1 mg/kg) or 1400W (5 mg/kg), suggesting a preferential role for eNOS in this response. Enalapril had no effect on spectral indices of hemodynamic variability or +dP/dtmax (myocardial contractility). However, in ethanol-fed rats, the greater enalapril-evoked hypotension was associated with reductions in (i) +dP/dtmax, (ii) low-frequency/high-frequency ratio of interbeat intervals (IBILF/HF), suggesting cardiac parasympathetic dominance, and (iii) low-frequency spectral band of systolic blood pressure (BP), a marker of vasomotor sympathetic tone. While NPLA or 1400W attenuated the enalapril-evoked hemodynamic and autonomic responses in ethanol-fed rats, l-NIO virtually abolished the hypotensive response and was more efficacious in rectifying autonomic responses to enalapril. Together, these findings implicate NOS isoforms, particularly eNOS, in the altered cardiovascular autonomic control that leads to the augmented enalapril-evoked hypotension in ethanol-fed female rats.

Topics: Alcohol Drinking; Animals; Arterial Pressure; Autonomic Nervous System; Cardiovascular System; Disease Models, Animal; Enalapril; Enzyme Inhibitors; Ethanol; Female; Heart Rate; Hypotension; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Time Factors

The discovery of angiotensin-converting enzyme 2 (ACE2) has greatly modified understanding of the renin-angiotensin system (RAS).. To investigate the cardiac expression of ACE2 and ACE in spontaneously hypertensive rats (SHRs) and the effects of enalapril on them.. Fifteen SHRs were randomly assigned to two groups: an SHR control group (n=7), treated with vehicle; and an enalapril group (n=8), treated with enalapril (15 mg/kg/day). After 4 weeks of treatment, the rats were killed and the left ventricular tissue was dissected. Reverse transcription-polymerase chain reaction and Western blot protein staining were performed to detect expression of ACE2 and ACE messenger ribonucleic acid (mRNA) and protein. Ten Wistar Kyoto rats (WKYs) served as the normotensive control group, which were treated with vehicle.. Compared with in normotensive WKYs, cardiac expression of ACE mRNA and protein in SHRs was increased (1.68±0.34 vs. 0.33±0.12, P<0.05 and 1.21±0.14 vs. 0.71±0.11, P<0.05, respectively), whereas cardiac expression of ACE2 mRNA and protein was decreased (0.50±0.15 vs. 1.16±0.24, P<0.05 and 0.71±0.24 vs. 1.22±0.14, P<0.05, respectively). After treatment with enalapril, the levels of ACE mRNA and protein were decreased (0.44±0.19 vs. 1.68±0.34, P<0.01 and 0.87±0.13 vs. 1.21±0.14, P<0.05, respectively), the level of ACE2 mRNA was increased (1.77±0.49 vs. 0.50±0.15, P<0.05) but the level of ACE2 protein remained unchanged.. In SHRs, the expression of cardiac ACE was remarkably increased, whereas ACE2 was notably decreased. Reduction of ACE and elevation of ACE2 might be one of the mechanisms underlying the antihypertensive function of enalapril.

Topics: Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Blotting, Western; Disease Models, Animal; Enalapril; Female; Gene Expression Regulation, Enzymologic; Hypertension; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

This study determined the role of angiotensin-converting enzyme (ACE) on the development of angiotensin I-induced atherosclerosis and the contribution of leukocyte-specific expression of this enzyme.. To define the contribution of ACE-dependent activity to angiotensin II synthesis in atherosclerotic development, male low-density lipoprotein receptor(-/-) mice were fed a fat-enriched diet and infused with either angiotensin I or angiotensin II. The same infusion rate of these peptides had equivalent effects on atherosclerotic development. Coinfusion of an ACE inhibitor, enalapril, ablated angiotensin I-augmented atherosclerosis but had no effect on angiotensin II-induced lesion development. ACE protein was detected in several cell types in atherosclerotic lesions, with a predominance in macrophages. This cell type secreted angiotensin II, which was ablated by ACE inhibition. To study whether leukocyte ACE contributed to atherosclerosis, irradiated male low-density lipoprotein receptor(-/-) mice were repopulated with bone marrow-derived cells from either ACE(+/+) or ACE(-/-) mice and fed the fat-enriched diet for 12 weeks. Chimeric mice with ACE deficiency in bone marrow-derived cells had modestly reduced atherosclerotic lesions in aortic arches but had no effects in aortic roots.. ACE mediates angiotensin I-induced atherosclerosis, and ACE expression in leukocytes modestly contributes to atherosclerotic development in hypercholesterolemic mice.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Atherosclerosis; Bone Marrow Transplantation; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Enalapril; Hypercholesterolemia; Leukocytes; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptidyl-Dipeptidase A; Receptors, LDL; Transplantation Chimera

Recently, we showed that administration of the angiotensin-converting enzyme inhibitor enalapril to aged rats attenuated muscle strength decline and mitigated apoptosis in the gastrocnemius muscle. The aim of the present study was to investigate possible mechanisms underlying the muscle-protective effects of enalapril. We also sought to discern the effects of enalapril mediated by nitric oxide (NO) from those independent of this signaling molecule. Eighty-seven male Fischer 344 × Brown Norway rats were randomly assigned to receive enalapril (n = 23), the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; n = 22), enalapril + L-NAME (n = 19), or placebo (n = 23) from 24 to 27 months of age. Experiments were performed on the tibialis anterior muscle. Total NOS activity and the expression of neuronal, endothelial, and inducible NOS isoforms (nNOS, eNOS, and iNOS) were determined to investigate the effects of enalapril on NO signaling. Transcript levels of tumor necrosis factor-alpha (TNF-α) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) were assessed to explore actions of enalapril on inflammation and mitochondrial biogenesis, respectively. Protein expression of energy-sensing and insulin signaling mediators, including protein kinase B (Akt-1), phosphorylated Akt-1 (pAkt-1), mammalian target of rapamycin (mTOR), AMP-activated protein kinase subunit alpha (AMPKα), phosphorylated AMPKα (pAMPKα), and the glucose transporter GLUT-4, was also determined. Finally, the generation of hydrogen peroxide (H2O2) was quantified in subsarcolemmal (SSM) and intermyofibrillar (IFM) mitochondria. Enalapril increased total NOS activity, which was prevented by L-NAME co-administration. eNOS protein content was enhanced by enalapril, but not by enalapril + L-NAME. Gene expression of iNOS was down-regulated by enalapril either alone or in combination with L-NAME. In contrast, protein levels of nNOS were unaltered by treatments. The mRNA abundance of TNF-α was reduced by enalapril relative to placebo, with no differences among any other group. PCG-1α gene expression was unaffected by enalapril and lowered by enalapril + L-NAME. No differences in protein expression of Akt-1, pAkt-1, AMPKα, pAMPKα, or GLUT-4 were detected among groups. However, mTOR protein levels were increased by enalapril compared with placebo. Finally, all treatment groups displayed reduced SSM, but not IFM H2O2 production relative to placebo. Our data ind

Topics: Adaptation, Physiological; Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Energy Metabolism; Male; Muscle, Skeletal; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxidative Stress; Rats; Rats, Inbred BN; Rats, Inbred F344

No proven pharmacological therapies to delay or reverse age-related diastolic dysfunction exist. We hypothesized that late-life low-dose (non-blood-pressure-lowering) angiotensin-converting enzyme inhibition vs. angiotensin II receptor blockade would be equally efficacious at mitigating diastolic dysfunction in the senescent Fischer 344 × Brown Norway rat. Enalapril (10 mg/kg/day; n = 9) initiated at 24 months of age and continued for 6 months, increased myocardial relaxation (e'), reduced Doppler-derived indices of filling pressure (E/e'), favorably lowered the ratio of phospholamban-SERCA2 and reduced oxidative stress markers, Rac1 and nitrotyrosine, in aged hearts. Treatment with losartan (15 mg/kg/day; n = 9) similarly mitigated signs of cardiac oxidative stress, but impairments in diastolic function persisted when compared with untreated rats (n = 7). Our findings favor the idea that the lusitropic benefit of low-dose angiotensin-converting enzyme inhibitor initiated late in life may be related to an antioxidant-mediated modulation of SERCA2, resulting in improved relaxation rather than via overt effects on cardiac structure or blood pressure.

Topics: Aging; Analysis of Variance; Animals; Arterial Pressure; Diastole; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Echocardiography, Doppler; Enalapril; Heart Function Tests; Heart Rate; Losartan; Male; Myocardial Contraction; Oxidative Stress; Random Allocation; Rats; Rats, Inbred BN; Rats, Inbred F344; Reference Values; Sensitivity and Specificity; Ventricular Function, Left

Topics: Animals; Celecoxib; Dialysis Solutions; Disease Models, Animal; Enalapril; Female; Humans; Male; Mice; Peritoneal Dialysis; Peritoneal Diseases; Peritoneum; Pharmaceutical Preparations; Prospective Studies; Pyrazoles; Rats; Rosiglitazone; Sensitivity and Specificity; Sulfonamides; Thiazolidinediones

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

Antihypertensive treatment may reduce prolonged QT duration in hypertension. Generally, the reductions of blood pressure and/or of cardiac mass are believed to be the responsible factors. However, drugs are not equivalent in QT modulation despite similar antihypertensive and antihypertrophic action. We investigated the effect of a calcium channel blocker, lacidipine and an angiotensin-converting enzyme inhibitor, enalapril on QT duration in rats. Normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were treated with lacidipine (at the dose of 1.5 mg/kg per day for WKY and 3 mg/kg per day for SHR) or enalapril (5 mg/kg per day for WKY and 10 mg/kg per day for SHR) during 8 weeks. Tail-cuff systolic blood pressure (sBP), left ventricular weight (LVW), vascular function of isolated aorta and mesenteric artery and duration of QT (and QTc) interval on Frank electrocardiograms were evaluated. As expected, untreated SHR showed elevated sBP, impaired vascular reactivity, increased LVW and prolonged QT when compared with WKY (p < 0.05). After treatment, both agents markedly improved vascular reactivity and reduced sBP in SHR (p < 0.05). Additionally, enalapril reduced LVW in both hypertensive (by 17%; p < 0.05) and normotensive rats (by 13%; p < 0.05) and, consequently, corrected QT duration in SHR. Interestingly, lacidipine also reduced LVW in SHR (by 9%; p < 0.05), but without influence on prolonged QT. Moreover, lacidipine had no effect on LVW in WKYs but prolonged their QT interval (by 10%; p < 0.05). In conclusion, lacidipine did not reverse a progressive prolongation of QT in SHR, despite sBP lowering and LVW reduction. Thus, the lowering of blood pressure and/or reduction of LVW are not sufficient per se to normalize ventricular repolarization in hypertensive cardiac disease. More likely, modulation of QT prolongation by antihypertensive drugs is a function of their complex action on blood pressure, vascular function, cardiac mass and on reflex neurohumoral activation.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Disease Models, Animal; Enalapril; Heart Ventricles; Hypertension; Male; Mesenteric Arteries; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Diabetic nephropathy is a complication of diabetes mellitus leading to end-stage renal disease. Oxidative stress and inflammation play a major role in the pathogenesis of diabetic nephropathy. Green tea, known for its antioxidant and anti-inflammatory properties, has been shown to be renoprotective. We hypothesized that (+)-catechin (CTN), a component of green tea, is responsible for the renoprotection. Our investigation of the therapeutic potential of CTN in streptozotocin-induced diabetic rats demonstrated for the first time that the effects of CTN treatment were comparable with the effects of an angiotensin-converting enzyme inhibitor (ACEi) enalapril for the treatment of albumin excretion. After 12 weeks of CTN treatment with 35 mg/d in the drinking water, urinary albumin excretion and plasma creatinine concentrations in all the diabetic treatment groups were reduced, compared with the diabetic group with no treatment. Urine creatinine and creatinine clearance were higher in diabetic groups treated with CTN and ACEi compared with the diabetic group with no treatment. Endothelin 1, lipid peroxidation, concentration of alanine transferase enzyme, and expression of fibronectin were lower in all the treatment groups compared with the diabetic group with no treatment. Concentrations of free thiols were higher in the CTN-treated group compared with the diabetic rats with no treatment. Our findings suggest that CTN has renoprotective properties comparable with ACEi, and coadministration of CTN and enalapril might be useful in reducing albumin excretion as well as improving endothelial function. (+)-Catechin might be successfully used in the future for clinical situations where ACEi is poorly tolerated or contraindicated.

Topics: Alanine Transaminase; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Antioxidants; Camellia sinensis; Catechin; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Enalapril; Endothelin-1; Fibronectins; Lipid Peroxidation; Male; Oxidative Stress; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Sulfhydryl Compounds

Brain renin-angiotensin system hyperactivity has been implicated in the development and maintenance of hypertension. We reported previously in the brain that aminopeptidase A and aminopeptidase N are involved in the metabolism of angiotensin II and angiotensin III, respectively. By using in vivo specific and selective aminopeptidase A and aminopeptidase N inhibitors, we showed that angiotensin III is one of the main effector peptides of the brain renin-angiotensin system, exerting a tonic stimulatory control more than blood pressure in hypertensive rats. Aminopeptidase A, the enzyme generating brain angiotensin III, thus represents a potential target for the treatment of hypertension. We demonstrated here the antihypertensive effects of RB150, a prodrug of the specific and selective aminopeptidase A inhibitor, EC33, in spontaneously hypertensive rats, a model of human essential hypertension. Oral administration of RB150 in conscious spontaneously hypertensive rats inhibited brain aminopeptidase A activity, demonstrating the central bioavailability of RB150 and its ability to generate EC33 into the brain. Oral RB150 treatment dose-dependently reduced blood pressure in spontaneously hypertensive rats with an ED(50) of 30 mg/kg, lasting for several hours. This decrease in blood pressure is partly attributed to a decrease in sympathetic tone, reducing vascular resistance. This treatment did not modify systemic renin-angiotensin system activity. Concomitant oral administration of RB150 with a systemic renin-angiotensin system blocker, enalapril, potentiated the RB150-induced blood pressure decrease achieved in <2 hours. Thus, RB150 may be the prototype of a new class of centrally active antihypertensive agents that might be used in combination with classic systemic renin-angiotensin system blockers to improve blood pressure control.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Brain; Disease Models, Animal; Disulfides; Dose-Response Relationship, Drug; Enalapril; Enzyme Inhibitors; Glutamyl Aminopeptidase; Heart Rate; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System; Sulfonic Acids

Previous studies have shown protective effects of brain natriuretic peptide (BNP) against the postmyocardial infarction (MI) remodelling process. The transcription factor NF-κB is known to play an important role after MI.. To investigate if NF-κB is involved in the protective effects of BNP against adverse post-MI remodelling.. Rats were randomly assigned to five groups: sham-operation; MI by coronary ligation; MI treated with chronic BNP infusion; MI treated with enalapril; MI treated with BNP+enalapril. Rats were closely monitored for survival rate analysis. Rats from each group were sacrificed on days 3, 7 and 28 postoperation.. The results showed that chronic continuous BNP infusion achieved similar effects to enalapril therapy, as evidenced by improved survival rate within the 28-day observation period compared with MI group rats; this effect was closely associated with preserved cardiac geometry and performance. The treatment combination did not offer extra benefits in terms of survival rate. Both BNP and enalapril therapy produced higher heart tissue concentrations of cyclic guanosine monophosphate and lower expression levels of inflammatory cytokines, including tumour necrosis factor-α, interleukin-1 and interleukin-6. These benefits were associated with lower phosphorylation levels of NF-κB subunits IκBα, p50 and p65. While enalapril significantly inhibited extracellular matrix remodelling via regulation of the protein expression ratio of matrix metalloproteinase/tissue inhibitor of metalloproteinase and the activity of matrix metalloproteinase, these variables were not affected by BNP, indicating that the two therapies involve different mechanisms.. Chronic BNP infusion can provide beneficial effects against adverse post-MI remodelling.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovascular Agents; Collagen; Cyclic GMP; Disease Models, Animal; Enalapril; Hemodynamics; I-kappa B Proteins; Inflammation Mediators; Infusion Pumps, Implantable; Infusions, Intravenous; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocardial Infarction; Myocardium; Natriuretic Peptide, Brain; NF-kappa B p50 Subunit; NF-KappaB Inhibitor alpha; Phosphorylation; Rats; Rats, Sprague-Dawley; Time Factors; Tissue Inhibitor of Metalloproteinase-1; Transcription Factor RelA; Ventricular Function, Left; Ventricular Remodeling

The hypertensive double-transgenic (dTG) rat strain, expressing human renin and angiotensinogen, develops severe hypertension and organ damage and 50% of individuals die by 7 weeks of age. Here, we characterise a variation of this model in which animals present stable hypertension.. The effect of renin-angiotensin system blockers on blood pressure was determined with adult dTG rats treated with enalapril from 3 to 12 weeks of age. Tissue expression levels of renin and angiotensinogen were determined in dTG rats and rhesus monkeys by quantitative PCR.. Upon withdrawal from enalapril, mean arterial pressure (MAP) rose to 160-180 mmHg, with 95% of the female dTG rats surviving for 6 to 12 months, In Sprague-Dawley (SD) rats and rhesus monkeys, renin mRNA was absent or weakly expressed in most tissues, except for the kidneys and adrenals. In dTG rats, human renin expression was high in many additional tissues. The expression of human angiotensinogen in dTG rats followed a similar tissue pattern to SD and rhesus monkey angiotensinogen. Oral dosing of aliskiren, enalapril or losartan provided a similar maximal reduction in MAP and duration of efficacy in telemetrised dTG rats.. Enalapril-pretreated dTG rats are suitable for long-term MAP monitoring and sequential evaluation of human renin inhibitors.

Topics: Amides; Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Enalapril; Female; Fumarates; Gene Expression Regulation; Heart Rate; Humans; Hypertension; Macaca mulatta; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; RNA, Messenger; Tissue Distribution

Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less effective. Both drugs attenuated canonical transforming growth factor-β (TGFβ) signaling in the aorta, but losartan uniquely inhibited TGFβ-mediated activation of extracellular signal-regulated kinase (ERK), by allowing continued signaling through AT2. These data highlight the protective nature of AT2 signaling and potentially inform the choice of therapies in MFS and related disorders.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Aortic Aneurysm; Aortic Rupture; Disease Models, Animal; Disease Progression; Enalapril; Losartan; MAP Kinase Signaling System; Marfan Syndrome; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Receptor, Angiotensin, Type 2; Signal Transduction; Transforming Growth Factor beta

The purpose of this work was to test whether brain-penetrating angiotensin-converting enzyme (ACE) inhibitors (e.g., perindopril), as opposed to non-brain-penetrating ACE inhibitors (e.g., enalapril and imidapril), may reduce the cognitive decline and brain injury in Alzheimer's disease (AD). We first compared the effect of perindopril, enalapril, and imidapril on cognitive impairment and brain injury in a mouse model of AD induced by intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ)₁₋₄₀. Perindopril, with significant inhibition of hippocampal ACE, significantly prevented cognitive impairment in this AD mouse model. This beneficial effect was attributed to the suppression of microglia/astrocyte activation and the attenuation of oxidative stress caused by iNOS induction and extracellular superoxide dismutase down-regulation. In contrast, neither enalapril nor imidapril prevented cognitive impairment and brain injury in this AD mouse. We next examined the protective effects of perindopril on cognitive impairment in PS2APP-transgenic mice overexpressing Aβ in the brain. Perindopril, without affecting brain Aβ deposition, significantly suppressed the increase in hippocampal ACE activity and improved cognition in PS2APP-transgenic mice, being associated with the suppression of hippocampal astrocyte activation and attenuation of superoxide. Our data demonstrated that the brain-penetrating ACE inhibitor perindopril, as compared to non-brain-penetrating ACE inhibitors, protected against cognitive impairment and brain injury in experimental AD models.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Angiotensin-Converting Enzyme Inhibitors; Animals; Astrocytes; Disease Models, Animal; Enalapril; Hippocampus; Imidazolidines; Mice; Mice, Inbred ICR; Mice, Transgenic; Microglia; Nitric Oxide Synthase Type II; Oxidative Stress; Peptide Fragments; Peptidyl-Dipeptidase A; Perindopril; Superoxide Dismutase

Mounting evidence suggest that tissue levels of angiotensin (ANG) II are maintained in animals submitted to chronic angiotensin-converting enzyme (ACE) inhibitor treatment. We examined the expression levels of transcripts for elastase-2, a chymostatin-sensitive serine protease identified as the alternative pathway for ANG II generation from ANG I in the rat vascular tissue and the relative role of ACE-dependent and -independent pathways in generating ANG II in the rat isolated carotid artery rings of spontaneously hypertensive rats (SHR) and Wistar normotensive rats (WNR) treated with enalapril for 7 days. Enalapril treatment decreased blood pressure of SHR only and resulted in significantly more elastase-2 mRNA expression in carotid artery of both enalapril-treated WNR and SHR. Captopril induced a comparable rightward shift of concentration-response curves to ANG I in vehicle and enalapril-treated rats, although this effect was of lesser magnitude in SHR group. Chymostatin induced a rightward shift of the dose response to ANG I in vehicle-treated and a decrease in maximal effect of 22% in enalapril-treated WNR group. Maximal response induced by ANG I was remarkably reduced by chymostatin in enalapril-treated SHR carotid artery (by 80%) compared with controls (by 23%). Our data show that chronic ACE inhibition was associated with augmented functional role of non-ACE pathway in generating ANG II and increased elastase-2 gene expression, suggesting that this protease may contribute as an alternative pathway for ANG II generation when ACE is inhibited in the rat vascular tissue.

Topics: Analysis of Variance; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Carotid Arteries; Disease Models, Animal; Enalapril; Hypertension; Immunohistochemistry; Male; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Rats, Wistar; RNA, Messenger; Serine Endopeptidases; Time Factors; Up-Regulation; Vasoconstriction

Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Yet the pathogenic mechanisms underlying the development of DN are not fully defined, partially due to lack of suitable models that mimic the complex pathogenesis of renal disease in diabetic patients. In this study, we describe early and late renal manifestations of DN and renal responses to long-term treatments with rosiglitazone or high-dose enalapril in ZSF1 rats, a model of metabolic syndrome, diabetes, and chronic renal disease. At 8 weeks of age, obese ZSF1 rats developed metabolic syndrome and diabetes (hyperglycemia, glucosuria, hyperlipidemia, and hypertension) and early signs of renal disease (proteinuria, glomerular collagen IV deposition, tubulointerstitial inflammation, and renal hypertrophy). By 32 weeks of age, animals developed renal histopathology consistent with DN, including mesangial expansion, glomerulosclerosis, tubulointerstitial inflammation and fibrosis, tubular dilation and atrophy, and arteriolar thickening. Rosiglitazone markedly increased body weight but reduced food intake, improved glucose control, and attenuated hyperlipidemia and liver and kidney injury. In contrast, rosiglitazone markedly increased cardiac hypertrophy via a blood pressure-independent mechanism. High-dose enalapril did not improve glucose homeostasis, but normalized blood pressure, and nearly prevented diabetic renal injury. The ZSF1 model thus detects the clinical observations seen with rosiglitazone and enalapril in terms of primary and secondary endpoints of cardiac and renal effects. This and previous reports indicate that the obese ZSF1 rat meets currently accepted criteria for progressive experimental diabetic renal disease in rodents, suggesting that this may be the best available rat model for simulation of human DN.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Weight; Diabetic Nephropathies; Disease Models, Animal; Enalapril; Humans; Hypoglycemic Agents; Kidney; Liver; Male; Metabolic Syndrome; Myocardium; Obesity; PPAR gamma; Rats; Rosiglitazone; Thiazolidinediones

The attempts to develop new treatments for acute ischemic stroke have been fraught with costly and spectacularly disappointing failures. Repurposing of safe, older drugs provides a lower risk alternative. Vascular protection is a novel strategy for improving stroke outcome. Promising targets for vascular protection after stroke have been identified, and several of these targets can be approached with "repurposed" old drugs, including statins, angiotensin receptor blockers (ARBs), and minocycline. We tested the vascular protection (ability to reduce hemorrhagic transformation) of three marketed drugs (candesartan, minocycline, and atorvastatin) in the experimental stroke model using three different rat strains [Wistar, spontaneously hypertensive rats (SHR) and type 2 diabetic Goto-Kakizaki (GK) rats]. All agents decreased the infarct size, improved the neurological outcome and decreased bleeding. Mechanisms identified include inhibition of MMP-9, activation of Akt, and increased expression of proangiogenic growth factors. Premorbid vascular damage (presence of either diabetes or hypertension) increased the likelihood of vascular injury after ischemia and reperfusion and improved the response to vascular protection.

Topics: Animals; Anticholesteremic Agents; Antihypertensive Agents; Atorvastatin; Benzimidazoles; Biphenyl Compounds; Brain Infarction; Diabetes Mellitus, Type 2; Disease Models, Animal; Enalapril; Enzyme-Linked Immunosorbent Assay; Functional Laterality; Hemoglobins; Hemorrhage; Heptanoic Acids; Male; Matrix Metalloproteinase 9; Pyrroles; Rats; Rats, Inbred SHR; Rats, Wistar; Reperfusion; Stroke; Tetrazoles; Vascular System Injuries

This study aimed to investigate renal arterial resistive index measurements and urine electrolytes before and after enalapril therapy in a rat model of unilateral ureteropelvic obstruction. The transforming growth factor (TGF)-β1 response of the renal tissue was also investigated.. 30 Wistar albino rats were randomly allocated into 5 groups (n=6). Group C rats served as controls. Group S rats had only laparotomy. Group E rats were only treated with enalapril. Rats in group UP and group UPE underwent laparotomy to create a left unilateral moderate partial obstruction. 2 weeks after establishing partial ureteropelvic junction obstruction, group UPE rats were treated with enalapril. Urine was collected over 24 h in all groups. Intrarenal arterial resistive index measurements were performed before and 2 weeks after surgery and after enalapril treatment in group UPE, and before and after enalapril treatment in group E. Rats were sacrificed by intracardiac puncture and left kidneys were harvested to evaluate levels of mRNA TGF-β1.. There was no significant difference in ARI values in group E. In group UPE, the difference between ARI values before and after surgery was statistically significant; the difference between ARI values after surgery and after enalapril treatment was also statistically significant. There was no statistically significant intra-group difference in urine electrolyte levels for UP group or UPE group. There was no difference in renal mRNA TGF-β1 levels.. Enalapril maintained renal blood flow by decreasing the arterial resistive index and maintained renal tubular function by protecting urine concentration and dilution ability in a rat model with unilateral ureteropelvic junction obstruction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Electrolytes; Enalapril; Kidney; Rats; Rats, Wistar; Renal Artery; Renal Circulation; Transforming Growth Factor beta1; Ureteral Obstruction; Vascular Resistance

The study aimed to predict effective human jejunal permeability (P(eff)) using a biophysical model based on parametrized paracellular, aqueous boundary layer, and transcellular permeabilities, and the villus-fold surface area expansion factor (k(VF)). Published human jejunal data (119 P(eff), 53 compounds) were analyzed by a regression procedure incorporating a dual-pore size paracellular model. Transcellular permeability, scaled by k(VF), was equated to that of Caco-2 at pH 6.5. The biophysical model predicted human jejunal permeability data within the experimental uncertainty. This investigation revealed several surprising predictions: (i) many molecules permeate predominantly (but not exclusively) by the paracellular route, (ii) the aqueous boundary layer thickness in the intestinal perfusion experiments is larger than expected, (iii) the mucosal surface area in awake humans is apparently nearly entirely accessible to drug absorption, and (iv) the relative "leakiness" of the human jejunum is not so different from that observed in a number of published Caco-2 studies.

Topics: Animals; Disease Models, Animal; Dogs; Humans; Jejunal Diseases; Kidney Diseases; Models, Biological; Permeability; Porosity; Regression Analysis

There are no chemopreventive strategies for pancreatic cancer or its precursor lesions, pancreatic intraepithelial neoplasia (PanINs). Recent evidence suggests that aspirin and inhibitors of angiotensin-I converting enzyme (ACE inhibitors) have potential chemopreventive properties. In this study, we used a genetically engineered mouse model of pancreatic cancer to evaluate the chemopreventive potential of these drugs.. Drug treatment was initiated at the age of 5 weeks. LsL-Kras(G12D); Pdx1-Cre or LsL-Kras(G12D); LsL-Trp53(R172H); Pdx1-Cre transgenic mice were randomly assigned to receive either mock treatment, aspirin, enalapril, or a combination of both. After 3 and 5 months, animals were killed. The effect of aspirin and enalapril was evaluated by histopathological analyses, immunostaining, and real-time PCR.. After 3 and 5 months of treatment, enalapril and aspirin were able to significantly delay progression of mPanINs in LsL-Kras(G12D); Pdx1-Cre mice. Furthermore, development of invasive pancreatic cancer in LsL-Kras(G12D); LsL-Trp53(R172H); Pdx1-Cre transgenic mice was partially inhibited by enalapril and aspirin. Invasive pancreatic cancer was identified in 15 of 25 (60%) LsL-Kras(G12D); LsL-Trp53(R172H); Pdx1-Cre untreated control mice, but in only three of 17 (17.6%, p=0.01) mice treated with aspirin, in four of 17 (23.5%, p=0.03) in mice treated with enalapril alone, and in five of 16 (31.2%, p=0.11) mice treated with a combination of both drugs. Using real-time PCR we found a significant downregulation of the target genes VEGF and RelA demonstrating our ability to achieve effective pharmacological levels of aspirin and enalapril during pancreatic cancer formation in vivo.. Using a transgenic mouse model that imitates human pancreatic cancer, this study provides first evidence that aspirin and enalapril are effective chemopreventive agents by delaying the progression of PanINs and partially inhibiting the formation of murine pancreatic cancer. This study together supports the hypothesis that aspirin and ACE inhibitors might be a valid chemopreventive strategy.

Topics: Amylases; Angiotensin-Converting Enzyme Inhibitors; Animals; Anticarcinogenic Agents; Aspirin; Carcinoma in Situ; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Enalapril; Gene Expression Regulation, Neoplastic; Mice; Mice, Transgenic; Neoplasm Invasiveness; NF-kappa B; Pancreatic Neoplasms; Receptor, Angiotensin, Type 1

Although accelerated atherosclerosis and arteriosclerosis are the main causes of cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients, the molecular pathogenesis remains largely obscure. Our study of the aortic function in a typical CKD model of subtotal nephrectomy (SNX) rats demonstrated phenotypes that resemble CKD patients with aortic stiffness. The 2-DE analysis of rat aortas followed by MS identified 29 up-regulated and 53 down-regulated proteins in SNX rats. Further Western blot and immunohistochemistry analyses validated the decreased HSP27 and increased milk fat globule epidermal growth factor-8 (MFG-E8) in SNX rats. Functional classification of differential protein profiles using KOGnitor revealed that the two major categories involved in aortic stiffness are posttranslational modification, protein turnover, chaperones (23%) and cytoskeleton (21%). Ingenuity Pathway Analysis highlighted cellular assembly and organization, and cardiovascular system development and function as the two most relevant pathways. Among the identified proteins, the clinical significance of the secreted protein MFG-E8 was confirmed in 50 CKD patients, showing that increased serum MFG-E8 level is positively related to aortic stiffness and renal function impairment. Drug interventions with an inhibitor of the angiotensin converting enzyme, enalapril, in SNX rats improved aortic stiffness and decreased MFG-E8 depositions. Together, our studies provide a repertoire of potential biomarkers related to the aortic stiffness in CKD.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antigens, Surface; Aorta; Disease Models, Animal; Enalapril; HSP27 Heat-Shock Proteins; Humans; Kidney Diseases; Male; Milk Proteins; Nephrectomy; Proteomics; Rats; Rats, Sprague-Dawley

Topics: Animals; Anticarcinogenic Agents; Aspirin; Disease Models, Animal; Drug Therapy, Combination; Enalapril; Humans; Mice; Pancreatic Neoplasms

Reactive oxygen species are known to be derived from NADPH oxidase in several tissues. Angiotensin II was suggested to be involved in the activation of NADPH oxidase; however, its role in the gastric mucosa is unclear. We examined the roles of angiotensin II receptor and NADPH oxidase in ischemia/reperfusion-induced gastric damage in rats. Under urethane anesthesia, male Sprague-Dawley rat stomachs were mounted in an ex-vivo chamber, had 100 mM HCl applied to them, and then a catheter was passed through the femoral vein. Ischemia/reperfusion was accompanied by blood collection and reperfusion through the catheter. Losartan, candesartan, valsartan, which are AT1 receptor blockers (ARB); PD123319, an AT2 receptor blocker; enalapril, an ACE inhibitor; or diphenylene iodonium, a NADPH oxidase inhibitor, was given i.v. 10 mins, and beta-NADPH, a NADPH oxidase substrate, was given i.v. 5 mins before reperfusion. The gastric damage by ischemia/reperfusion was attenuated by treatment with any of ARB or enalapril, but was not affected by PD123319. The increase in gastric H(2)O(2) production and microvascular permeability by ischemia/reperfusion was also suppressed by treatment with any of ARB or enalapril. In rat gastric mucosa, the NADPH oxidase subunit p47(phox) was detected. Additionally, diphenylene iodonium had similar effects to ARB against ischemia/reperfusion-caused gastric damage, increased H(2)O(2) production, and microvascular permeability. Ischemia/reperfusion activated NADPH oxidase in the gastric mucosa, and the activation was significantly attenuated by treatment with losartan or diphenylene iodonium. These results suggest that ischemia/reperfusion generated reactive oxygen species are derived from NADPH oxidase activation via AT1 receptor in rat stomachs.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Enzyme Inhibitors; Gastric Mucosa; Hydrogen Peroxide; Male; NADPH Oxidases; Onium Compounds; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury

The RAS (renin-angiotensin system) is classically involved in BP (blood pressure) regulation and water-electrolyte balance, and in the central nervous system it has been mostly associated with homoeostatic processes, such as thirst, hormone secretion and thermoregulation. Epilepsies are chronic neurological disorders characterized by recurrent epileptic seizures that affect 1-3% of the world's population, and the most commonly used anticonvulsants are described to be effective in approx. 70% of the population with this neurological alteration. Using a rat model of epilepsy, we found that components of the RAS, namely ACE (angiotensin-converting enzyme) and the AT1 receptor (angiotensin II type 1 receptor) are up-regulated in the brain (2.6- and 8.2-fold respectively) following repetitive seizures. Subsequently, epileptic animals were treated with clinically used doses of enalapril, an ACE inhibitor, and losartan, an AT1 receptor blocker, leading to a significant decrease in seizure severities. These results suggest that centrally acting drugs that target the RAS deserve further investigation as possible anticonvulsant agents and may represent an additional strategy in the management of epileptic patients.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Anticonvulsants; Blood Pressure; Disease Models, Animal; Drug Evaluation, Preclinical; Enalapril; Epilepsy; Female; Hippocampus; Losartan; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Angiotensin-converting enzyme (ACE) inhibitors are widely used as blood pressure medications in hypertensive individuals. However, ACE inhibitors also play an integral role in the breakdown of neuronal substance P, which has been recently implicated in the development of functional deficits following traumatic brain injury (TBI). The present study therefore examined the effects of ACE inhibitors on histological and motor outcome following TBI. Male Sprague-Dawley rats were treated with Captopril, Enalapril or equal volume saline for 7 days prior to the induction of diffuse TBI using the impact acceleration model. At 5h post-injury, animals administered Captopril demonstrated significantly increased substance P immunoreactivity compared to vehicle controls (p<0.01), and increased dark cell change that persisted to 7 days post-trauma. Captopril also resulted in exacerbated motor deficits compared to vehicle treated animals (p<0.05) as assessed by the rotarod test over a 7-day post-traumatic period. Administration of the alternative ACE inhibitor, Enalapril, likewise exacerbated motor deficits, confirming a class effect of ACE inhibitors rather than a compound effect specific to Captopril. We conclude that ACE inhibitors are deleterious to outcome following TBI, presumably by impairing the degradation of substance P and increasing substance P mediated neuronal injury.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Brain Injuries; Captopril; Cerebral Cortex; Disease Models, Animal; Enalapril; Gene Expression Regulation; Male; Motor Activity; Movement Disorders; Rats; Rats, Sprague-Dawley; Rotarod Performance Test; Substance P

The prevalence of left ventricular hypertrophy (LVH) is frequent in patients with end-stage renal disease following chronic renal failure (CRF). We investigated the therapeutic efficacy of curcumin, the principal curcuminoid of the Indian curry spice turmeric, in attenuation of LVH and sought to delineate the associated signaling pathways in blunting the hypertrophic response in nephrectomized rats. Adult Sprague-Dawley rats underwent nephrectomy (Nx) by removal of 5/6 of the kidneys. Four groups were studied for 7 wk: 1) control (sham), 2) Nx, 3) Nx + curcumin (150 mg/kg bid), and 4) Nx + enalapril (15 mg/kg bid) as positive control. Subtotal nephrectomy caused renal dysfunction, as evidenced by a gradual increase in proteinuria and elevation in blood urea nitrogen and plasma creatinine. Nx rats showed a significant hypertrophic response and increased diameter of inferior vena cava at inspiration, which was inhibited by treatment with curcumin or enalapril. Moreover, the Nx rats demonstrated changes in the signaling molecules critically involved in the hypertrophic response. These include increased glycogen synthase kinase-3β phosphorylation, β-catenin expression, calcineurin, phosphorylated (p) nuclear factor of activated T cells, pERK, and p-cAMP-dependent kinase. Both curcumin and enalapril variably but effectively deactivated these pathways. Curcumin attenuates cardiac hypertrophy and remodeling in nephrectomized rats through deactivation of multiple hypertrophic signaling pathways. Considering the safety of curcumin, these studies should facilitate future clinical trials in suppressing hypertrophy in patients with CRF.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Urea Nitrogen; Calcineurin; Creatinine; Curcumin; Disease Models, Animal; Enalapril; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Nephrectomy; NFATC Transcription Factors; Rats; Rats, Sprague-Dawley; Ventricular Remodeling

Angiotensin-converting enzyme (ACE) inhibitors have clinically been widely used as anti-hypertensive agents. In the present study, we compared the effects of a centrally active ACE inhibitor, perindopril, with those of non-centrally active ACE inhibitors, imidapril and enalapril, on cognitive performance in amyloid beta(Abeta) (25-35)-injected mice, a rodent model of Alzheimer's disease. We also determined the brain ACE activity in order to elucidate the relationship between the cognitive function and ACE inhibition in the brain. Abeta(25-35)-injected mice showed a cognitive impairment in spontaneous alteration and object recognition tests, the indices of immediate working memory and relatively long-term recognition memory, respectively. As indicated by these tests, the oral administration of perindopril (0.1, 0.3 or 1mg/kg/day) significantly reversed the cognitive impairment in these mice, whereas neither imidapril (0.3, 1 or 3mg/kg/day) nor enalapril (1, 3 or 10mg/kg/day) had any effect on cognitive performance. Perindopril (1mg/kg/day), imidapril (3mg/kg/day), or enalapril (10mg/kg/day) all inhibited the plasma ACE activities by more than 90%. Using the same dosing regimen, only perindopril inhibited the brain ACE activities by more than 50%, whereas imidapril and enalapril showed much less potent effects. These results suggest that perindopril ameliorated the cognitive impairment in the Alzheimer's disease model mice through the inhibition of brain ACE activity, but not peripheral ACE activity. Based on our observations, we concluded that a centrally active ACE inhibitor, perindopril, may therefore have a beneficial effect on Alzheimer's disease as well as hypertension.

Topics: Alzheimer Disease; Angiotensin-Converting Enzyme Inhibitors; Animals; Behavior, Animal; Cognition; Disease Models, Animal; Enalapril; Exploratory Behavior; Humans; Imidazolidines; Memory; Memory, Long-Term; Mice; Peptidyl-Dipeptidase A; Perindopril; Recognition, Psychology

Leptin receptor-deficient db/db mice develop human type 2 diabetes mellitus, hypertension, and obesity with disrupted circadian blood pressure (BP) rhythm. Whether leptin is the sole mechanism mediating autonomic imbalance and hypertension is unclear. To explore this notion further, we measured BP by radiotelemetry combined with fast Fourier transformation and assessed autonomic function pharmacologically before and after renin-angiotensin system blockade with enalapril. The resting period BP (117+/-3 versus 108+/-1.0 mm Hg) and heart rate (HR; 488+/-12 versus 436+/-8 bpm) were higher in db/db mice compared with db/+ mice. BP and HR amplitudes were lower in db/db mice compared with db/+ mice. BP response to trimetaphan (-43+/-5 versus -27+/-3 mm Hg) and HR response to metoprolol (-59+/-12 versus -5+/-4 bpm) were greater in db/db mice than in db/+ mice. The HR response to atropine was blunted in db/db mice (59+/-17 versus 144+/-24 bpm), as were baroreflex sensitivity and HR variability. Enalapril improved autonomic regulation in db/db mice. Stimulation of central alpha-2 adrenoreceptors enhanced both parasympathetic HR control and baroreflex sensitivity in db/db mice. We suggest that functional, rather than structural, alpha-2 adrenoceptor changes and the renin-angiotensin system are involved in the increased sympathetic and decreased parasympathetic tones in db/db mice. Our data suggest that db/db mice exhibit features found in humans with type 2 diabetic autonomic neuropathy and could serve as a model for this complication.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autonomic Nervous System; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Models, Animal; Enalapril; Heart; Heart Rate; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Receptors, Leptin

One ultimate goal of hypertension therapy is to cause permanent reversal ("regression") of already established hypertension. Our aim was to examine whether high-dose "pulse" treatment with a renin-angiotensin system inhibitor could cause regression of established hypertension and to link this action to reversal of arteriolar hypertrophy and changes in vascular matrix metalloproteinase activities. First, 16-week-old male spontaneously hypertensive rats (n=60) were pulse treated for 2 weeks with high-dose angiotensin-converting enzyme inhibitor (enalapril), angiotensin receptor blocker (candesartan), calcium channel blocker (nifedipine), or vasodilator (hydralazine) with or without salt restriction, and the long-term effects on blood pressure were examined. Second, spontaneously hypertensive rats were treated with angiotensin receptor blocker or calcium channel blocker, and the effects on renal gene expressions, arteriolar structure, and vascular matrix metalloproteinase were compared. Treatment of spontaneously hypertensive rats with different antihypertensive agents caused apparently similar reductions in blood pressure during the course of the pulse treatment, within the limitations of the tail-cuff method. After cessation of medications, blood pressure in the rats treated with renin-angiotensin system inhibitor remained reduced by >30 to 40 mm Hg for 4 months. No such effect was seen with calcium channel blocker or vasodilator. The 2-week angiotensin receptor blocker treatment induced a marked reversal of the arteriolar hypertrophy specifically in the small (30 to 100 microm) renal arterioles, together with increased expression and activity of matrix metalloproteinase-13. In conclusion, transient high-dose pulse treatment with angiotensin receptor blocker caused changes in vascular matrix metalloproteinase activity, specific reversal of renal arteriolar hypertrophy, and regression of hypertension in spontaneously hypertensive rats.

Topics: Aldosterone; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Arterioles; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Hydralazine; Hypertension; Hypertrophy; Kidney; Male; Matrix Metalloproteinase 13; Nifedipine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Tetrazoles; Vasodilator Agents

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

TNF-alpha and NF-kappaB play important roles in the development of inflammation in chronic renal failure (CRF). In hepatic cells, curcumin is shown to antagonize TNF-alpha-elicited NF-kappaB activation. In this study, we hypothesized that if inflammation plays a key role in renal failure then curcumin should be effective in improving CRF. The effectiveness of curcumin was compared with enalapril, a compound known to ameliorate human and experimental CRF. Investigation was conducted in Sprague-Dawley rats where CRF was induced by 5/6 nephrectomy (Nx). The Nx animals were divided into untreated (Nx), curcumin-treated (curcumin), and enalapril-treated (enalapril) groups. Sham-operated animals served as a control. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was significantly reduced by curcumin and enalapril treatment. However, only enalapril significantly improved blood pressure. Compared with the control, the Nx animals had significantly higher plasma and kidney TNF-alpha, which was associated with NF-kappaB activation and macrophage infiltration in the kidney. These changes were effectively antagonized by curcumin and enalapril treatment. The decline in the anti-inflammatory peroxisome proliferator-activated receptor gamma (PPARgamma) seen in Nx animals was also counteracted by curcumin and enalapril. Studies in mesangial cells were carried out to further establish that the anti-inflammatory effect of curcumin in vivo was mediated essentially by antagonizing TNF-alpha. Curcumin dose dependently antagonized the TNF-alpha-mediated decrease in PPARgamma and blocked transactivation of NF-kappaB and repression of PPARgamma, indicating that the anti-inflamatory property of curcumin may be responsible for alleviating CRF in Nx animals.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Blood Urea Nitrogen; Cells, Cultured; Creatinine; Curcumin; Disease Models, Animal; Enalapril; Hypertension, Renal; Kidney Failure, Chronic; Macrophages; Mesangial Cells; Nephrectomy; Nephritis; NF-kappa B; PPAR gamma; Proteinuria; Rats; Rats, Sprague-Dawley; Transfection; Tumor Necrosis Factor-alpha

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

Blockade of the renin-angiotensin system (RAS), the standard treatment for chronic proteinuric nephropathy, slows but may not halt progression of the disease, particularly when therapy is started late. Because vasopressin may also play a role in the progression of renal disease, we measured the effect of a dual V(1a) and V(2) vasopressin receptor antagonist (RWJ-676070) alone or combined with angiotensin-converting enzyme inhibition or angiotensin II type 1 receptor blockade on proteinuria and renal disease progression during overt nephropathy. Twenty-one days after renal mass reduction, a time of established injury, rats were given vehicle, RWJ-676070, enalapril, losartan, RWJ-676070 plus enalapril, or losartan in drinking water for an additional 39 days. RWJ-676070 returned the blood pressure to pre-treatment levels, which were significantly lower than those in vehicle-treated rats. Enalapril, losartan, and the combined therapies reduced blood pressure to a greater extent. RWJ-676070 afforded a partial antiproteinuric effect, which was enhanced by the addition of enalapril or losartan. Renal functional impairment, and glomerular and tubular changes were partially ameliorated by RWJ-676070; parameters significantly improved with either enalapril or losartan alone and improved to a greater extent with the combined therapies. Our findings suggest that vasopressin receptor antagonists could be of additional therapeutic value in the treatment of chronic proteinuric nephropathy.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Biomarkers; Blood Pressure; Body Weight; Chronic Disease; Disease Models, Animal; Disease Progression; Diuresis; Drinking; Drug Therapy, Combination; Eating; Enalapril; Hormone Antagonists; Kidney; Kidney Diseases; Losartan; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin; Renin-Angiotensin System; Spiro Compounds; Time Factors

To assess the role of the renin-angiotensin (RAS) and adrenergic systems in the development and progression of dilated cardiomyopathy in the Syrian cardiomyopathic hamster (SCH), echocardiographic parameters were evaluated in 6-month-old animals after 5 months of treatment with enalapril (25 mg/kg/day) plus losartan (10 mg/kg/day), or with carvedilol (1 mg/kg/day). Cardiac output indexes (COI) increased by 53% after RAS blockade and by 20% after beta-blockade in SCH. Moreover, LVEDV and LVESV decreased 30% and 62%, respectively (P < .05) during RAS blockade, whereas ejection fraction (EF) increased by 48%. By contrast, carvedilol reduced LVESV by only 28% (P < .05) and increased EF by only 15% (P < .05). These results suggest that RAS activation plays a critical role in the development of cardiac dysfunction in SCH and that suppression of RAS may be more effective than beta-blockade in retarding the development of cardiomyopathy in SCH. Owing to timing (pre-heart failure stage) and to the single dose protocol, the implications of this study for human subjects remain to be clarified.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Carbazoles; Cardiac Output; Cardiomyopathy, Dilated; Carvedilol; Cricetinae; Disease Models, Animal; Disease Progression; Enalapril; Losartan; Male; Mesocricetus; Propanolamines; Renin-Angiotensin System; Stroke Volume; Time Factors; Ultrasonography; Ventricular Function, Left

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

Acute intravenous infusion of ranolazine (Ran), an anti-ischemic/antiangina drug, was previously shown to improve left ventricular (LV) ejection fraction (EF) without a concomitant increase in myocardial oxygen consumption in dogs with chronic heart failure (HF). This study examined the effects of treatment with Ran alone and in combination with metoprolol (Met) or enalapril (Ena) on LV function and remodeling in dogs with HF. Dogs (n = 28) with microembolization-induced HF were randomized to 3 mo oral treatment with Ran alone [375 mg twice daily (bid); n = 7], Ran (375 mg bid) in combination with Met tartrate (25 mg bid; n = 7), Ran (375 mg bid) in combination with Ena (10 mg bid; n = 7), or placebo (PL; Ran vehicle bid; n = 7). Ventriculographic measurements of LV end-diastolic volume (EDV) and end-systolic volume (ESV) and LV EF were obtained before treatment and after 3 mo of treatment. In PL-treated dogs, EDV and ESV increased significantly. Ran alone prevented the increase in EDV and ESV seen in the PL group and significantly increased EF, albeit modestly, from 35 +/- 1% to 37 +/- 2%. When combined with either Ena or Met, Ran prevented the increase in EDV, significantly decreased ESV, and markedly increased EF compared with those of PL. EF increased from 35 +/- 1% to 40 +/- 1% with Ran + Ena and from 34 +/- 1% to 41 +/- 1% with Ran + Met. Ran alone or in combination with Ena or Met was also associated with beneficial effects at the cellular level on histomorphometric parameters such as hypertrophy, fibrosis, and capillary density as well as the expression for pathological hypertrophy and Ca2+ cycling genes. In conclusion, Ran prevented progressive LV dysfunction and global and cellular myocardial remodeling, and Ran in combination with Ena or Met improved LV function beyond that observed with Ran alone.

Topics: Acetanilides; Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiotonic Agents; Disease Models, Animal; Disease Progression; Dogs; Drug Therapy, Combination; Enalapril; Heart Failure; Metoprolol; Myocardium; Piperazines; Proteins; Ranolazine; Ventricular Dysfunction, Left; Ventricular Remodeling

Encapsulating peritoneal sclerosis (EPS) is a clinical syndrome associated with symptoms of ileus and irreversible sclerosis of both visceral and parietal peritoneum. Peritoneal dialysis (PD) patients rarely develop EPS, a severe life-threatening condition of unknown pathogenesis. Angiotensin II is known to promote fibrosis and inflammation in various tissues. Renin-angiotensin system (RAS) blockade provides advantages in the course of diseases such as hypertension, chronic kidney disease, and proteinuria. We have also previously shown that RAS blockade has beneficial effects on hypertonic (3.86%) PD solution-induced peritoneal alterations. Because it shares the same characteristics as other fibrotic processes, peritoneal fibrosis can benefit from RAS blockade.. To determine the advantages of RAS blockade in regression of EPS.. We divided 56 nonuremic albino Wistar rats into 6 groups: control group (n = 10), daily intraperitoneal (IP) injection of 2 mL isotonic saline for 3 weeks; CG group (n = 10), daily IP injection of 2 mL/200 g chlorhexidine gluconate (CG) for 3 weeks; resting group (n = 10), daily IP injection of CG (0 - 3 weeks) plus peritoneal rest (4 - 6 weeks). After 3 weeks of being injected with CG (0 - 3 weeks), a fourth group (n = 9) was treated with 100 mg/L enalapril (ENA group); a fifth group (n = 10) was treated with 80 mg/L valsartan (VAL group), and a sixth group (n = 7) was treated with 100 mg/L enalapril + 80 mg/L valsartan (ENA+VAL group) in drinking water for an additional 3 weeks (4 - 6 weeks). At the end, a 1-hour peritoneal equilibration test was performed with 25 mL 3.86% PD solution. Dialysate-to-plasma ratio of urea (D/P urea), dialysate WBC count, ultrafiltration volume (UF), and morphological changes of parietal peritoneum were examined.. Exposure to CG for 3 weeks resulted in alterations in peritoneal transport (increased D/P urea, decreased UF volume; p < 0.05) and morphology (increased inflammation, neovascularization, fibrosis, and peritoneal thickness; p < 0.05). Peritoneal rest had some beneficial effect only on UF failure and dialysate cell count (p < 0.05). However, RAS blockade was more effective than peritoneal rest with respect to UF volume, vascularity (p < 0.05), and peritoneal thickness (p > 0.05). Dual blockade of RAS had no additional beneficial effects.. We suggest that RAS blockade either with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be a more effective option than resting in the management of EPS.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Chlorhexidine; Disease Models, Animal; Enalapril; Female; Peritoneal Dialysis; Peritoneum; Rats; Rats, Wistar; Sclerosis; Tetrazoles; Valine; Valsartan

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

Cardiomyopathic Syrian hamsters (Bio TO-2 dilated strain) constitute an animal model of congestive heart failure, which progressively develops an alteration of cardiac function leading to decreased arterial blood pressure and musculo-cutaneous blood flow associated with a complex process of cardiac remodeling including left ventricle dilation, wall thinning, and greater collagen density. The protocols described in this unit are designed to assess the pharmacological effects of new therapeutic strategies on cardiac and systemic hemodynamics, morphometry (body and target organs weight), cardiac remodeling (left ventricle dilation and collagen density), and survival in this model of dilated cardiomyopathy. Examples of results obtained with enalapril, an angiotensin I converting enzyme inhibitor, are provided for illustrative purposes.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomyopathy, Dilated; Cricetinae; Disease Models, Animal; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Enalapril; Heart Failure; Hemodynamics; Male; Mesocricetus; Organ Size; Random Allocation; Survival Analysis; Ventricular Remodeling

We evaluated the effects of angiotensin II (Ang II) blockers, losartan, an Ang II receptor blocker, and enalapril, an angiotensin converting enzyme inhibitor, on the development of autoimmune thyroiditis in nonobese diabetic (NOD) mice, an animal model of Hashimoto's thyroiditis (HT). Mice were assigned into three groups, untreated, losartan-treated (30 mg/kg/day), and enalapril-treated (10 mg/kg/day) groups. Thyroiditis was induced by iodide ingestion (experiment 1) or mouse thyroglobulin (Tg) immunization (experiment 2). Both procedures effectively induced thyroiditis. While iodide ingestion failed to induce anti-mouse Tg antibody (TgAb) production, Tg immunization resulted in a significant increase in serum TgAb levels. In both experiments, neither losartan nor enalapril interfered with the development of thyroiditis and TgAb production. These results suggest that Ang II may not be associated with the development of autoimmune thyroiditis in NOD mice. Thus, the Ang II blockade may not have therapeutic potential in HT.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Hashimoto Disease; Losartan; Mice; Mice, Inbred NOD; Sodium Iodide; Thyroglobulin

Obese Zucker rats, animal model for the metabolic syndrome, develop a diabetes-like neuropathy that is independent of hyperglycemia. The purpose of this study was to determine whether drugs used to treat cardiovascular dysfunction in metabolic syndrome also protect nerve function.. Obese Zucker rats at 20 weeks of age were treated for 12 weeks with enalapril or rosuvastatin. Lean rats were used as controls. Vasodilation in epineurial arterioles was measured by videomicroscopy. Endoneurial blood flow (EBF) was measured by hydrogen clearance and nerve conduction velocity was measured following electrical stimulation of motor or sensory nerves.. Enalapril treatment decreased serum angiotensin-converting enzyme (ACE) activity and both drugs reduced serum cholesterol levels. In obese Zucker rats at 32 weeks of age superoxide levels were elevated in the aortas and epineurial arterioles, which were reduced by treatment with either drug. Nitrotyrosine levels were increased in epineurial arterioles and reduced with enalapril treatment. EBF was decreased and corrected by treatment with either drug. Motor nerve conduction velocity was decreased and significantly improved with enalapril treatment. Obese Zucker rats were hypoalgesic in response to a thermal stimulus and this was significantly improved with either treatment. Treatment with either enalapril or rosuvastatin significantly reversed the decrease in acetylcholine-mediated vascular relaxation of epineurial arterioles in obese Zucker rats.. Even though obese Zucker rats have normal glycemia vascular and neural dysfunctions develop with age and can be improved by treatment with either enalapril or rosuvastatin.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Arterioles; Cardiovascular System; Disease Models, Animal; Enalapril; Fluorobenzenes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Metabolic Syndrome; Motor Neurons; Neural Conduction; Neurons, Afferent; Nociceptors; Obesity; Peripheral Nerves; Pyrimidines; Rats; Rats, Zucker; Rosuvastatin Calcium; Sciatic Nerve; Sulfonamides; Superoxides; Tyrosine; Vasodilator Agents

The aim of this work was to formulate transdermal therapeutic system (TTS) of an antihypertensive drug, enalapril maleate (EM) using a new penetration enhancer, piperidine hydrochloride (PH), belonging to the class of Dihydropyridines. The TTS of EM was prepared by solvent evaporation technique using polymers Eudragit E100 and polyvinyl pyrrolidone K-30 in varying ratios, 5% w/w dibutylphthalate as plasticizer and 10% w/w PH as penetration enhancer. The TTS was evaluated for in-vitro drug release using paddle over disc method and ex-vivo skin permeation using modified Keshary and Chein diffusion cell. The interaction studies were carried out by comparing the results of assay, UV and TLC analysis for pure drug and medicated and TTS formulation. Skin irritation potential of TTS was assessed by visual examination of treated rat skin. Stability studies were conducted according to ICH guidelines at a temperature of 40+/-0.5 degrees C and 75+/-5% RH. The optimized formulation was evaluated for preclinical bioavailability and antihypertensive efficacy using albino rat model. The optimized formulation provided 87.3% drug release in-vitro and a flux of 380 microg/cm(2)/hr over a period of 48 hours. No chemical interaction was found between the drug and excipients and there were no signs of skin irritation on application of patch. The optimized formulation was stable with a tentative shelf life of two years. Significant fall in BP (p<0.001) was observed in experimental hypertensive rats which was maintained for 2 days. There was 3 fold improvement in bioavailability with TTS vis-à-vis marketed tablet (AUC(0 to t) : 1253.9 ng.h/ml vs. 422.88 ng.h/ml). These preclinicial studies indicate the feasibility of matrix-type TTS of EM for 2 day management of hypertension. Further studies on human beings are warranted to establish clinical utility of the above TTS.

Topics: Acrylates; Administration, Cutaneous; Animals; Antihypertensive Agents; Biological Availability; Blood Pressure; Disease Models, Animal; Drug Stability; Drug Storage; Enalapril; Excipients; Female; Hypertension; Male; Permeability; Piperidines; Polymers; Povidone; Rats; Skin Absorption

The present study examined the levels of Angiotensin II type 1 receptor (AT(1)) and type 2 receptor (AT(2)) in the brain stem and cerebral cortex of the stroke-prone spontaneously hypertensive rat (SHR-sp) after long-term treatment with three types of antihypertensive drugs: valsartan, enalapril, and amlodipine. In both tissues, expression of the AT(1) was decreased by administration of each drug. Expression of the AT(2) was decreased in the cerebral cortex by drug administration, but did not change in the brain stem. This study may contribute to elucidating the relationship between AT(1) and AT(2) expressions and the effect of antihypertensive drugs in SHR-sp brain.

Topics: Amlodipine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Brain Stem; Calcium Channel Blockers; Cerebral Cortex; Disease Models, Animal; Down-Regulation; Enalapril; Hypertension; Male; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; RNA, Messenger; Stroke; Tetrazoles; Time Factors; Valine; Valsartan

To investigate the mechanisms underlying the depressed sarcolemmal (SL) Na(+)-K(+)-ATPase activity in congestive heart failure (CHF), different isoforms and gene expression of Na(+)-K(+)-ATPase were examined in the failing left ventricle (LV) at 8 weeks after myocardial infarction (MI). In view of the increased activity of renin-angiotensin system (RAS) in CHF, these parameters were also studied after 5 weeks of treatment with enalapril (10 mg x kg-1 x day-1), an angiotensin-converting enzyme inhibitor, and losartan (20 mg.kg-1.day-1), an angiotensin II type 1 receptor antagonist, starting at 3 weeks after the coronary ligation in rats. The infarcted animals showed LV dysfunction and depressed SL Na(+)-K(+)-ATPase activity. Protein content and mRNA levels for Na(+)-K(+)-ATPase alpha2 isoform were decreased whereas those for Na(+)-K(+)-ATPase alpha3 isoform were increased in the failing LV. On the other hand, no significant changes were observed in protein content or mRNA levels for Na(+)-K(+)-ATPase alpha1 and beta1 isoforms. The treatment of infarcted animals with enalapril or losartan improved LV function and attenuated the depression in Na(+)-K(+)-ATPase alpha2 isoform as well as the increase in alpha3 isoform, at both the protein and mRNA levels; however, combination therapy with enalapril and losartan did not produce any additive effects. These results provide further evidence that CHF due to MI is associated with remodeling of SL membrane and suggest that the blockade of RAS plays an important role in preventing these alterations in the failing heart.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Gene Expression Regulation, Enzymologic; Heart Failure; Hemodynamics; Losartan; Male; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; RNA, Messenger; Sarcolemma; Sodium-Potassium-Exchanging ATPase; Time Factors; Ventricular Dysfunction, Left; Ventricular Remodeling

We investigated the effects of chronic oral antihypertensive treatment on functional and structural capillary rarefaction in spontaneously hypertensive rats (SHR). Wistar Kyoto rats (WKY) were used as a normotensive control group. In untreated rats, intravital videomicroscopy showed that functional capillary density was lower in SHR skeletal muscle (WKY 395 +/- 17 and SHR 258 +/- 13 capillaries/mm, P < 0.01) and ear skin (WKY 391 +/- 18 and SHR 210 +/- 15 capillaries/mm, P < 0.01). A linear relationship was seen between skeletal muscle and skin capillary densities (r = 0.654, P < 0.0001). Histologic analysis showed that SHR had a lower capillary-to-fiber ratio in the skeletal muscle (WKY 1.74 +/- 0.08 and SHR 1.40 +/- 0.06, P < 0.01). Capillary volume density-to-fiber volume density ratio in the left ventricle of SHR was also reduced (WKY 0.55 +/- 0.09 and SHR 0.42 +/- 0.09, P < 0.01). The animals were treated with the angiotensin-converting enzyme (ACE) inhibitor enalapril, the angiotensin II type I receptor (AT1) receptor antagonist losartan, the beta-blocker atenolol, or the calcium channel blocker nifedipine, resulting in similar reductions in systolic blood pressure (19.8%, 19.1%, 17.4%, and 18.2%, respectively, P > 0.05). Atenolol did not induce any change in functional capillary density of SHR. Losartan and nifedipine completely reversed functional capillary rarefaction in both muscle and cutaneous tissues, whereas enalapril significantly increased functional capillary density only in the skin. The skeletal muscle capillary-to-fiber ratio was normalized by enalapril, losartan, and nifedipine. Treatments with enalapril or losartan normalized the cardiac structural capillary rarefaction of SHRs, whereas atenolol and nifedipine had no effect. Our results suggest that different pharmacologic classes of antihypertensive drugs with similar effect on blood pressure differ in terms of their effect on the microcirculation.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Atenolol; Blood Pressure; Capillaries; Disease Models, Animal; Enalapril; Heart Ventricles; Hypertension; Losartan; Male; Microcirculation; Microscopy, Video; Muscle, Skeletal; Nifedipine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Skin

We investigated the effects of co-administration of an angiotensin-converting enzyme inhibitor (ACEI) and angiotensin type 1 receptor blocker (ARB) on nitric oxide (NO) bioavailability in genetically hyperlipidemic rabbits with our newly developed NO sensor. Plasma NO was measured using the new NO sensor in the abdominal aorta of anesthetized Watanabe heritable hyperlipidemic (WHHL) rabbits. Acetylcholine (ACh)-stimulated (20 microg in 5 min into the aortic arch) NO production was recorded after an 8 week per os pretreatment with 1) vehicle (control), 2) the ACEI enalapril (E: 3 mg/kg/day), 3) the ARB losartan (L: 30 mg/kg/day) and 4) enalapril (1.5 mg/kg/day)+losartan (15 mg/kg/day) (E+L). Intra-aortic infusion of ACh produced an increase in plasma NO concentration, which was significantly greater with all the drug treatments than with the control. E increased ACh-induced NO significantly more than L (by 6.9 nmol/L, and 4.7 nmol/L, respectively). E+L increased ACh-induced NO by 9.5 nmol/L, significantly more than either E or L. Plasma peroxynitrite concentration was 1.2 pmol/mg protein in the control group and significantly less than in the E- and L-group. The lowest peroxynitrite concentration was observed in the E+L group (0.5 pmol/mg protein), which was significantly lower than in the E-group and the L-group. Optical coherence tomography and histology of the thoracic aorta revealed that the plaque area decreased significantly more with the combination than with the monotherapy (p<0.01). In conclusion, the combined treatment with an ACEI and an ARB may have additive protective effects on endothelial function as well as atherosclerotic change.

Topics: Acetylcholine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Abdominal; Atherosclerosis; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Heart Rate; Hyperlipidemias; Losartan; Male; Nitric Oxide; Peroxynitrous Acid; Rabbits; Tyrosine; Vasodilator Agents

Experiments were designed to test the hypothesis that antioxidant treatment would increase the anti-hypertensive actions of endogenous kinins during angiotensin converting enzyme (ACE) inhibition. Four groups of rats, all given angiotensin II (Ang II) for 2 weeks, were studied: 1) control, 2) enalapril, 3) tempol or 4) both tempol and enalapril. Ang II significantly increased systolic blood pressure (BP) when compared with the baseline (170+/-8 vs. 128+/-4 mm Hg, P<0.05). Neither enalapril nor tempol alone was able to attenuate the elevation in BP (165+/-7 and 164+/-6 mm Hg, respectively). In contrast, combined administration of tempol and enalapril prevented the increase in BP (137+/-5 mm Hg). Plasma 8-isoprostane increased in Ang II-infused rats when compared with control untreated rats (69+/-14 vs. 23+/-0.5 pg/ml, P<0.05). Tempol alone or tempol plus enalapril significantly attenuated the increase in plasma 8-isoprostane (29+/-6 and 34+/-7 pg/ml, respectively). In additional experiments, we used the bradykinin B(2) antagonist, icatibant to determine if increased B(2) receptor contributes to the anti-hypertensive effect of combined tempol and enalapril in Ang II-infused rats. Icatibant decreased the ability of this combination to lower arterial pressure. Additionally, a significant increase in B(1) receptor protein expression in renal cortex of Ang II-infused rats was observed compared to control suggesting that bradykinin receptor activation could account for the effect of enalapril to enhance the actions of tempol. These data support the hypothesis that combined reduction of superoxide along with enhanced endogenous kinins may facilitate blood pressure lowering in Ang II hypertension.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Antioxidants; Blood Pressure; Bradykinin; Chronic Disease; Cyclic N-Oxides; Dinoprost; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Enalapril; Hydrogen Peroxide; Hypertension; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptors, Bradykinin; Spin Labels; Superoxides; Time Factors

To determine whether the responses of total peripheral resistance and arterial pressure to vasoconstrictor agents are amplified as renovascular hypertension develops in dogs.. After baseline measurements, the effects of renal artery stenosis (1K, 1C hypertension) were studied in groups of untreated and enalapril-treated dogs early (1-3 weeks) and later (4-6 weeks) as the hypertension developed. Both resting and open-loop haemodynamic measurements were made and the effects of acute intravenous infusions of vasopressin (0.25, 0.5 and 1.25 ng/kg per min) and phenylephrine (0.125, 0.25 and 0.50 microg/kg per min on arterial pressure, cardiac output and calculated total peripheral resistance responses were measured.. Renal artery stenosis induced an increase in arterial blood pressure in both groups of dogs, with similar changes in haemodynamics also observed in open-loop conditions. The slopes of arterial pressure and peripheral resistance responses to vasopressin and phenylephrine were not significantly changed in early or late hypertension, in either the untreated or enalapril-treated groups.. Hypertension from renal artery stenosis in dogs was due to nonautonomic, nonangiotensin II mechanisms. There was no evidence of vascular amplification of the effects of vasoconstrictor agents, indicating that this did not play a role in the development of hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine Vasopressin; Blood Pressure; Captopril; Cardiac Output; Disease Models, Animal; Dogs; Enalapril; Ganglionic Blockers; Hypertension, Renovascular; Male; Pentolinium Tartrate; Phenylephrine; Vascular Resistance; Vasoconstrictor Agents

The aim of this study was to investigate the effects of untreated and treated hypertension on abdominal wall healing.. Thirty-two spontaneously hypertensive rats (SHR) were randomly allocated into two groups: H (n = 16), untreated and E (n = 16), treated with enalapril (40 mg/kg per day). Group C (n = 16) was a nonhypertensive control group. The animals of each group were submitted to a midline laparotomy and randomly divided, according to the day on which they were killed (7th or 14th postoperative day), into subgroups of 8 animals, as follows: H-7, H-14, E-7, E-14, C-7 and C-14. On the day of their deaths, two strips of the anterior abdominal wall were collected. One strip was submitted to breaking strength measurement and the other to hydroxyproline determination.. No mortalities or complications were observed in the six subgroups. The breaking strength in E-7 subgroup was significantly lower than in C-7 (P < 0.05). The tissue hydroxyproline levels were similar in all six subgroups (P > 0.05).. Untreated hypertension had no effect on the abdominal wall healing of rats. Hypertensive animals treated with enalapril showed a significant decrease in abdominal wound-breaking strength on the 7th postoperative day.

Topics: Abdominal Wall; Animals; Antihypertensive Agents; Biomechanical Phenomena; Disease Models, Animal; Enalapril; Hypertension; Laparotomy; Rats; Rats, Inbred SHR; Wound Healing

Uremia accelerates atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice. We examined whether this effect may be preventable by pharmacological blockade of the renin-angiotensin system (RAS).. Uremia was induced in apoE-/- mice by 5/6 nephrectomy (NX). Treatment with the angiotensin converting enzyme inhibitor enalapril (2 or 12 mg/kg/d) from week 4 to 36 after NX reduced the aortic plaque area fraction from 0.23+/-0.02 (n=20) in untreated mice to 0.11+/-0.01 (n=21) and 0.08+/-0.01 (n=23), respectively (P<0.0001); the aortic plaque area fraction was 0.09+/-0.01 (n=22) in sham-operated controls. Enalapril from week 20 to 44 after NX also retarded the progression of atherosclerosis. Plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) and concentrations of IgM antibodies against oxidized low density lipoprotein (OxLDL) increased after NX (P<0.01). Enalapril (12 mg/kg/d) attenuated these increases (P<0.05) and reduced aortic expression of vascular cell adhesion molecule (VCAM)-1 mRNA (P<0.05). Atherosclerosis in NX mice was also reduced by losartan (an angiotensin II receptor-blocker), but not when blood pressure was lowered with hydralazine (a non-RAS-dependent vasodilator).. The results suggest that inhibition of RAS abolishes the proatherogenic effect of uremia independent of its blood pressure-lowering effect, possibly because of antiinflammatory and antioxidative mechanisms.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibodies, Anti-Idiotypic; Aorta, Thoracic; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Blood Pressure; Disease Models, Animal; Disease Progression; Drosophila Proteins; Enalapril; Follow-Up Studies; Gene Expression; Immunoglobulin G; Immunoglobulin M; Intercellular Adhesion Molecule-1; Lipoproteins, LDL; Losartan; Mice; Nephrectomy; Oxidation-Reduction; Peptidyl-Dipeptidase A; Prognosis; Receptors, Cell Surface; Renin-Angiotensin System; RNA, Messenger; Uremia; Vascular Cell Adhesion Molecule-1

There is evidence that acutely elevated blood pressure (BP) after stroke is associated with increased cerebral hemorrhage and edema. Previous experiments in our laboratory have shown that candesartan 1 mg/kg administered after reperfusion in a model of hypertension after experimental ischemic stroke reduces neurovascular damage and improves outcome. These results could be either mediated by BP lowering or a BP-independent cerebrovascular protective effect.. To determine the contribution of BP lowering to the neurovascular protection previously reported with candesartan after stroke.. Male Wistar rats (280-305 g) underwent 3 h of middle cerebral artery occlusion (MCAO). At reperfusion, either hydralazine 1 mg/kg (n = 8), enalapril 5 mg/kg (n = 7) or enalapril 10 mg/kg (n = 8) were administered intravenously. BP was measured by telemetry for 2 days before and 24 h after MCAO. After neurological function was assessed, brain tissue was processed for infarct size and hemoglobin content analyses.. Mean arterial pressure (MAP) increased from 92 to 124 mmHg immediately upon MCAO and decreased to 112 mmHg after reperfusion, remaining elevated for 24 h (P < 0.0001) in the saline group. Hydralazine reduced MAP (P = 0.048) and infarct size (53 versus 30%, P = 0.0083), and there was a trend towards decreased hemoglobin content. Enalapril 5 mg/kg did not significantly change MAP or other outcomes. Enalapril 10 mg/kg reduced MAP (P < 0.0001) and infarct size (53 versus 29%, P = 0.003). There was an intermediate effect on both hemoglobin content and neurological function, neither one was significant. The time course of BP lowering varied with each treatment.. Acute BP lowering after reperfusion in acute ischemic stroke is an effective strategy to achieve neurovascular protection. The rate, extent and mechanism of BP lowering may determine the magnitude of protection.

Topics: Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Area Under Curve; Benzimidazoles; Biomarkers; Biphenyl Compounds; Blood Pressure; Brain Ischemia; Cerebrovascular Circulation; Circadian Rhythm; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Hemoglobins; Hydralazine; Infarction, Middle Cerebral Artery; Male; Rats; Rats, Wistar; Reperfusion; Telemetry; Tetrazoles

Monotherapy with angiotensin-converting enzyme inhibitors has been shown to be beneficial in suppressing the progression of experimentally induced kidney diseases. Whether such therapy provides additional benefits when combined with vitamin D or an analog of vitamin D has not been established. Rats were made uremic by 5/6 nephrectomy and treated as follows: Uremic + vehicle (UC), uremic + enalapril (30 mg/L in drinking water; E), uremic + paricalcitol (19-nor; 0.8 microg/kg, three times a week), and uremic + enalapril + paricalcitol (E + 19-nor). A group of normal rats served as control (NC). BP was significantly elevated in the UC and 19-nor groups compared with the NC group but was indistinguishable from normal in the E and E + 19-nor groups. The decrease in creatinine clearance and the increase in the excretion of urinary protein that were observed in the UC group were ameliorated by the use of E alone or by E + 19-nor (P < 0.05 versus UC). The glomerulosclerotic index was significantly decreased in both the 19-nor (P < 0.01) and E + 19-nor groups (P < 0.01) compared with the UC group. Tubulointerstitial volume was significantly decreased in both the E (P < 0.05) and E + 19-nor groups (P < 0.01) compared with the UC group. Both macrophage infiltration (ED-1-positive cells) and production of the chemokine monocyte chemoattractant protein-1 were significantly blunted in E + 19-nor compared with E group. TGF-beta1 mRNA and protein expression were increased in the UC group (mRNA: 23.7-fold; protein: 29.1-fold versus NC). These increases were significantly blunted in the 19-nor group (mRNA: 7.1-fold; protein: 8.0-fold versus NC) and virtually normalized in the E + 19-nor group (protein: 0.8-fold versus NC). Phosphorylation of Smad2 was also elevated in the UC group (7.6-fold versus NC) but less so in the 19-nor-treated rats (5.5-fold versus NC). When rats were treated with E + 19-nor, the phosphorylation of Smad2 was normal (1.1-fold versus NC). Thus, 19-nor can suppress the progression of renal insufficiency via mediation of the TGF-beta signaling pathway, and this effect is amplified when BP is controlled via renin-angiotensin system blockade.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Enalapril; Ergocalciferols; Female; Macrophages; Nephrectomy; Parathyroid Hormone; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Insufficiency; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta1; Uremia; Vitamin D

1. The aim of the present study was to evaluate the effect of treatment with enalapril on the sensitivity of cardiopulmonary reflexes 30 days after myocardial infarction in Wistar rats. 2. Animals were divided into four groups: (i) sham operated, receiving vehicle (SHAM); (ii) infarcted, receiving vehicle (0.9% NaCl; INF); (iii) sham operated, receiving enalapril (SHAME); and (iv) infarcted, receiving enalapril (INFE). 3. Enalapril was administered at a dose of 10 mg/kg per day. Serotonin (4-32 microg/kg, i.v.) was administered in order to activate the Bezold-Jarisch reflex, which was estimated as the percentage of reduction in heart rate. 4. The volume-sensitive cardiopulmonary reflex was induced by saline overload and evaluated as the percentage increase in sodium and volume renal excretion. At the end of the experiments, rats were killed and hearts excised to estimate the size of the infarction. The weight of the kidneys, lungs, liver and cardiac chambers as ratios of bodyweight was used to estimate the extent of hypertrophy. 5. The results showed an impairment in the sensitivity of the cardiopulmonary reflexes in the INF group compared with the SHAM and SHAME groups. We observed right ventricle and pulmonary hypertrophy, a reduction in mean and systolic arterial pressure and an increase in heart rate in INF animals. In the INFE group, nearly all the parameters were normal compared with the INF group, except for systolic arterial pressure, which was only partially improved. 6. The main finding of the present study was that treatment with enalapril normalized the sensitivity of the cardiopulmonary reflexes, which could be due, in part, to the reduction of cardiac hypertrophy. The present study provides information about the beneficial effects of the angiotensin-converting enzyme inhibitors by normalizing the cardiopulmonary reflexes involved with the regulation of volume and sodium, as well as control of arterial pressure and heart rate in infarcted animals.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Baroreflex; Blood Pressure; Cardiomegaly; Chronic Disease; Disease Models, Animal; Enalapril; Heart Rate; Kidney; Lung; Male; Myocardial Infarction; Natriuresis; Rats; Rats, Wistar; Reflex; Sympathetic Nervous System; Urination; Water-Electrolyte Balance

The purpose of this study was to investigate the renoprotective effect of telmisartan on the advanced stages of nephropathy in rats with 5/6 nephrectomy (5/6 Nx). Telmisartan was orally administered for 12 weeks to rats that previously underwent 5/6 Nx or sham operations. After completion of the administration period, the degree of renal injury was examined histopathologically using indices of glomerulosclerosis and lesions of the renal tubule and interstitium. An immunohistochemical staining for transforming growth factor-beta (TGF-beta1) was also performed. The suppression of urinary protein was statistically significant in surviving animals dosed with telmisartan. The enalapril group's urinary protein was also significantly suppressed for these same parameters in surviving animals. Histopathologically, telmisartan significantly decreased the progression of glomerulosclerosis and the interstitial cell infiltration at all doses tested. As assessed by immunohistochemical staining the TGF-beta1 reactivity in the glomerular tissue tended to decrease in the telmisartan group when compared to the vehicle group. Thus, telmisartan ameliorates the progressive nephropathy in the remaining kidney after 5/6 Nx by non-haemodynamic as well as antihypertensive actions of the drug.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Benzoates; Blood Pressure; Diabetic Nephropathies; Disease Models, Animal; Enalapril; Kidney; Nephrectomy; Rats; Telmisartan

The results of experiments on isolated preparations of aorta and portal vein of rats with chronic deficiency of mesencephalo-striatal dopamine have shown that endothelium-dependent reactions of dilatation were inhibited. If rats with dopamine deficiency received enalapryl (20 mg/kg) these reactions partly recovered. A possible conclusion may be that in conditions of cerebral dopamine deficiency the functional state of endothelium got worse, and endothelium-dependent dilatation of vascular smooth muscles was inhibited. The use of inhibitor of angiotensin-converting enzyme enalapryl resulted in a significant restoration of the above vascular reactions.

Topics: Animals; Aorta, Thoracic; Corpus Striatum; Disease Models, Animal; Dopamine; Enalapril; In Vitro Techniques; Mesencephalon; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Norepinephrine; Parkinsonian Disorders; Rats; Rats, Inbred WKY; Time Factors; Vasoconstrictor Agents; Vasodilation

Pharmacological and genetic interference with the renin-angiotensin system (RAS) seems to alter voluntary ethanol consumption. However, understanding the influence of the RAS on ethanol dependence and its treatment requires modeling the neuroadaptations that occur with prolonged exposure to ethanol. Increased ethanol consumption was induced in rats through repeated cycles of intoxication and withdrawal. Expression of angiotensinogen, angiotensin-converting enzyme, and the angiotensin II receptor, AT1a, was examined by quantitative reverse transcription polymerase chain reaction. Increased ethanol consumption after a history of dependence was associated with increased angiotensinogen expression in medial prefrontal cortex but not in nucleus accumbens or amygdala. Increased angiotensinogen expression also demonstrates that the astroglia is an integral part of the plasticity underlying the development of dependence. The effects of low central RAS activity on increased ethanol consumption were investigated using either spirapril, a blood-brain barrier-penetrating inhibitor of angiotensin-converting enzyme, or transgenic rats (TGR(ASrAOGEN)680) with reduced central angiotensinogen expression. Spirapril reduced ethanol intake in dependent rats compared to controls. After induction of dependence, TGR(ASrAOGEN)680 rats had increased ethanol consumption but to a lesser degree than Wistar rats with the same history of dependence. These data suggest that the central RAS is sensitized in its modulatory control of ethanol consumption in the dependent state, but pharmacological or genetic blockade of the system appears to be insufficient to halt the progression of dependence.

Topics: Adaptation, Physiological; Alcoholism; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Animals, Genetically Modified; Central Nervous System; Disease Models, Animal; Enalapril; Ethanol; Humans; Neuronal Plasticity; Rats; Rats, Wistar; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Antisense

We aimed to compare the effect of angiotensin converting enzyme (ACE) inhibitors captopril (containing thiol group) and enalapril (without thiol group) on the development of spontaneous hypertension and to analyze mechanisms of their actions, particularly effects on oxidative stress and NO production. Six-week-old SHR were divided into three groups: control, group receiving captopril (50 mg/kg/day) or enalapril (50 mg/kg/day) for 6 weeks. At the end of experiment, systolic blood pressure (SBP) increased by 41 % in controls. Both captopril and enalapril prevented blood pressure increase, however, SBP in the captopril group (121+/-5 mmHg) was significantly lower than that in the enalapril group (140+/-5 mmHg). Concentration of conjugated dienes in the aorta was significantly lower in the captopril group compared to the enalapril group. Captopril and enalapril increased NO synthase activity in the heart and aorta to the similar level. Neither captopril nor enalapril was, however, able to increase the expression of eNOS. Both ACE inhibitors increased the level of cGMP. However, cGMP level was significantly higher in the aorta of captopril group. We conclude that captopril, beside inhibition of ACE, prevented hypertension by increasing NO synthase activity and by simultaneous decrease of oxidative stress which resulted in increase of cGMP concentration.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Captopril; Cardiomegaly; Cyclic GMP; Disease Models, Animal; Enalapril; Hypertension; Male; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Rats; Rats, Inbred SHR; Sulfhydryl Compounds; Time Factors; Up-Regulation

Endotoxin [or lipopolysaccharide (LPS)] increases levels of superoxide in blood vessels and impairs vasomotor function. Angiotensin II plays an important role in the generation of superoxide in several disease states, including hypertension and heart failure. The goal of this study was to determine whether the activation of the renin-angiotensin system contributes to oxidative stress and endothelial dysfunction after endotoxin. We examined the effects of enalapril (an angiotensin-converting enzyme inhibitor) or L-158809 (an angiotensin receptor blocker) on increases of superoxide and vasomotor dysfunction in mice treated with LPS. C57BL/6 mice were treated with either enalapril (60 mg.kg(-1).day(-1)) or L-158809 (30 mg.kg(-1).day(-1)) for 4 days. After the third day, LPS (10-20 mg/kg) or vehicle was injected intraperitoneally, and one day later, vasomotor function of the aorta was examined in vitro. After precontraction with PGF(2alpha), the maximal responses to sodium nitroprusside were similar in the aorta from normal and LPS-treated mice. In contrast, the relaxation to acetylcholine was impaired after LPS (54 +/- 5% at 10(-5), mean +/- SE) compared with vessels treated with vehicle (88 +/- 1%; P < 0.05). Enalapril improved (P < 0.05) relaxation in response to acetylcholine to 81 +/- 6% after LPS. L-158809 also improved relaxation in response to acetylcholine to 77 +/- 4% after LPS. Superoxide (measured with lucigenin and hydroethidine) was increased (P < 0.05) in aorta after LPS, and levels were reduced (P < 0.05) following enalapril and L-158809. Thus, after LPS, enalapril and L-158809 reduce superoxide levels and improve relaxation to acetylcholine in the aorta. The findings suggest that activation of the renin-angiotensin system contributes importantly to oxidative stress and endothelial dysfunction after endotoxin.

Topics: Acetylcholine; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Endothelium, Vascular; Endotoxemia; Imidazoles; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Nitroprusside; Oxidative Stress; Renin-Angiotensin System; Superoxides; Tetrazoles; Vasodilation; Vasodilator Agents

Neprilysin (NEP) is a zinc metalloproteinase that degrades enkephalins, endothelins, and the Alzheimer's disease amyloid beta (Abeta) peptides. NEP-deficient mice possess increased levels of brain Abeta(1-40) and Abeta(1-42). The objective of this study was to determine whether tissue NEP specific activity differs according to age and/or across mouse strains, especially those strains predisposed toward formation of Abeta-amyloid plaques following overexpression of the human Alzheimer amyloid precursor protein (APP). The C57Bl/6J mouse strain appears to be relatively susceptible to cerebral amyloidosis, whereas the Swiss Webster (SW) strain appears more resistant. We investigated whether NEP specific activity in brain and kidney homogenates from SW and C57 mice of 6, 40, and 80 weeks old varied according to mouse strain, age, and gender. Among the variables tested, NEP specific activity varied most dramatically across mouse strain, with the kidney and brain of SW mice displaying the highest activities. Aging was associated with a reduction in brain NEP specific activity in both strains. Gender-specific differences were identified in kidney but not in brain. We conclude that aging- and strain-dependent differences in NEP specific activity may play a role in the differential susceptibility of some mouse strains for developing cerebral amyloidosis following human APP overexpression.

Topics: Age Factors; Alzheimer Disease; Amyloidosis; Analysis of Variance; Animals; Disease Models, Animal; Disease Susceptibility; Enalapril; Enzyme Activation; Enzyme Inhibitors; Female; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neprilysin; Sex Factors; Species Specificity

It is suggested that appropriate chronic exercise (EX) may produce improvements of the physical strength in patients with chronic renal failure (CRF). Because acute exercise causes proteinuria and decreases the renal blood flow and glomerular filtration rate, it is necessary to consider the influence of EX on renal function. Therefore, we assessed the renal and peripheral effects of moderate to intense EX as well as the effects of the combination of EX and enalapril (ENA) in a rat model of CRF.. Male 5/6-nephrectomized Wistar-Kyoto rats were divided into six groups according to the following treatment: 1) no exercise (C); 2) ENA (2 mg/kg/day, subcutaneously); 3) moderate exercise with treadmill running (20 m/min for 60 min/day, 5 days/week) (EXm); 4) intense exercise with treadmill running (28 m/min for 60 min/day, 5 days/week) (EXi); 5) EXm+ENA; and 6) sham operation (S). The rats were then treated for 12 weeks.. Both EX and ENA blocked the development of hypertension, blunted increases in proteinuria, reduced serum creatinine and blood urea nitrogen, and improved the index of glomerular sclerosis (IGS) and the relative interstitial volume of the renal cortex (RIV). Moreover, IGS and RIV in the EXm+ENA group were the lowest among all other nephrectomized groups. Furthermore, EXm+ENA enhanced capillarization as well as the proportion of type-I fiber in the soleus muscle.. These results suggest that EX and ENA have renoprotective effects. The findings also suggest that EXm+ENA provided greater renoprotective effects than those of ENA alone, and that EXm+ENA had some additional peripheral effects without any complications in this rat model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Enalapril; Glomerular Filtration Rate; Hypertension; Kidney; Kidney Cortex; Kidney Failure, Chronic; Male; Muscle, Skeletal; Nephrectomy; Physical Conditioning, Animal; Proteinuria; Rats; Rats, Inbred WKY

The renin-angiotensin-aldosterone system (RAAS) has been implicated in the pathophysiology of salt-induced hypertension. Angiotensin converting enzyme inhibitors, angiotensin II-type 1 receptor blockers, and aldosterone receptor blockers are used to treat hypertension and congestive heart disease. In addition to their blood pressure lowering effects, they appear to protect against myocardial, renal, and vascular damage. In various models of hypertension, generation of reactive oxygen species is increased in the vasculature and that treatment with antioxidants or superoxide dismutase mimetics (e.g., tempol) improves vascular function and structure and reduces blood pressure. The purpose of this study was to examine the effects of enalapril, an angiotensin II converting enzyme inhibitor; eplerenone, a selective aldosterone receptor antagonist; and tempol, a superoxide dismutase mimetic, on salt-induced hypertension in Dahl Salt-Sensitive rats. The rats were placed on a high salt (HS; 8%) diet for 3 weeks prior to switching to a normal salt (0.3%) diet for an additional 3 weeks. While on the normal salt (NS) diet, rats were treated with enalapril (30 mg/kg/day in the drinking water), eplerenone (100 mg/kg/day by gavage), tempol (1 mM/day in the drinking water), eplerenone + enalapril, eplerenone + enalapril + tempol, or without drug treatment (control). After 3 weeks on HS diet, systolic blood pressure rose from 127 +/- 7 to 206 +/- 11 mm Hg and remained elevated when switched to NS diet. Subsequently, treatment with eplerenone alone or in combination with enalapril and tempol produced a stepwise reduction in systolic blood pressure reaching -80 mm Hg; however, enalapril and tempol alone produced more modest pressure reduction (approximately -35 mmHg). Plasma levels of prostacyclin and nitric oxide were elevated in rats treated with enalapril and eplerenone alone or in combination. Enalapril and eplerenone alone and in combination reduced heart and kidney levels of angiotensin II and aldosterone when compared with control. Renal and heart levels of reduced glutathione were diminished by eplerenone alone; however, enalapril tended to attenuate the effect of eplerenone on reduced glutathione levels in the heart. The findings from this study suggest that eplerenone reduces salt-induced hypertension by increasing endothelium-derived relaxing factors, inhibiting RAAS components and oxidative stress. (353words).

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Blood Pressure; Cyclic N-Oxides; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Enalapril; Eplerenone; Epoprostenol; Hypertension; Male; Nitric Oxide; Oxidative Stress; Rats; Rats, Inbred Dahl; Sodium Chloride; Spin Labels; Spironolactone; Treatment Outcome

Pax2 is a transcription factor with important functions during kidney development . Ectopic expression of Pax2 in podocytes has been reported in various glomerular diseases , but the functional relevance remains unknown. We developed an inducible mouse model that allows activation of Pax2 specifically in podocytes. Persistent expression of Pax2 did not interfere with the initial differentiation of podocytes, but mice ectopically expressing PAX2 developed end-stage renal failure soon after birth. Similarly, activation of PAX2 in healthy adult animals resulted in renal disease within 3 weeks after podocyte-specific induction of a deleter Cre. PAX2 activation caused repression of the podocyte key regulator molecule Wt1 and consequently a dramatic reduction of nephrin expression. Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1. Finally, treatment of mice with an angiotensin-converting enzyme (ACE) inhibitor normalized renal function and induced upregulation of the important structural molecule nephrin via a Wt1-independent pathway. Our data demonstrate the functional significance of PAX2 reexpression in mature podocytes for the development of glomerular diseases and suggest that reactivation of PAX genes in terminally differentiated cells leads to a more dedifferentiated phenotype.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Gene Expression Regulation; Kidney Failure, Chronic; Male; Membrane Proteins; Mice; PAX2 Transcription Factor; Podocytes; Proteinuria; WT1 Proteins

Five-sixths-nephrectomized rats present renal functional and histological abnormalities which are attenuated by enalapril treatment. c-Jun N-terminal kinase (JNK), a mitogen-activated protein kinase, and nuclear factor-kappaB (NF-kappaB) pathways can be activated by angiotensin II which has been implicated in renal injury. The aim of this study was to investigate the effect of enalapril on the expression of NF-kappaB and JNK in renal cortices of five-sixths-nephrectomized rats.. Of the 65 rats studied, 25 underwent five-sixths nephrectomy and received no treatment, 15 underwent five-sixths nephrectomy and received enalapril, 15 were sham operated and received no treatment, and 10 were sham operated and received enalapril. On postoperative days 15 and 90, systolic blood pressure, glomerular filtration rate, and albumin excretion were determined. The rats were then killed and the kidneys removed for histology and immunohistochemistry.. In five-sixths-nephrectomized rats, we observed functional and structural renal alterations, as well as greater NF-kappaB/JNK expression and higher macrophage counts. Enalapril treatment reduced all of these changes.. The protective effect of enalapril on the kidney of five-sixths-nephrectomized rats might be related to the inhibition of NF-kappaB and JNK activation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Gene Expression; JNK Mitogen-Activated Protein Kinases; Kidney; Kidney Diseases; Nephrectomy; NF-kappa B; Rats; Rats, Wistar; Tissue Distribution

This study compared the antithrombotic effect of plasma angiotensin converting enzyme inhibitors (ACE-Is): captopril (CAP), enalapril (ENA) and tissue ACE-Is: perindopril (PER), quinapril (QUIN) in experimental venous and arterial thrombosis. Normotensive Wistar rats were treated p.o. with CAP (75 mg/kg), ENA (20 mg/kg), PER (2 mg/kg) and QUIN (3 mg/kg) for 10 days. The influence of ACE-Is on coagulation and fibrinolytic systems as well as platelet function was evaluated. The hypotensive effect of ACE-Is was equal in all groups. QUIN maintained the final carotid blood flow at the highest value in comparison to PER and plasma ACE-Is. The arterial thrombus weight was reduced in PER and QUIN groups while venous thrombus weight was also reduced after CAP. Tissue and plasma ACE-Is caused the inhibition of platelet adhesion and aggregation. A reduction of fibrin generation, prolongation of prothrombin time (PT), activated partial thromboplastin time (APTT) and shortening of euglobulin clot lysis time (ECLT) were observed after PER and QUIN treatment. In conclusion, given in equipotent hypotensive doses, tissue ACE-Is exerted more pronounced antithrombotic effect than plasma ACE-Is in experimental thrombosis. The differences between tissue and plasma ACE-Is in terms of their more pronounced inhibition of experimental thrombosis may be related to the intensified activation of fibrinolysis and inhibition of coagulation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Carotid Arteries; Disease Models, Animal; Enalapril; Fibrillar Collagens; Fibrin; Hemostasis; Male; Perindopril; Platelet Adhesiveness; Platelet Aggregation; Quinapril; Rats; Rats, Wistar; Regional Blood Flow; Tetrahydroisoquinolines; Thromboembolism

Angiotensin-converting enzyme (ACE) inhibitors have been associated with an increased risk of acute pancreatitis. The pathogenesis of this condition remains unclear, but an activation of the kinin system and a resultant localized angioedema have been implicated in the initial step leading to acute pancreatic damage. The goal of the present study was to explore the impact of ACE inhibition on pancreatic microcirculation and capillary permeability in normal and insulin-resistant rats.. Chow- or fructose-fed Sprague-Dawley rats were treated with enalapril (dosage, 10 mg.kg.d) or vehicle for 4 weeks before measuring in vivo the extravasation of Evans blue (EB) dye in pancreas. Unanesthetized animals (n = 10-17 per group) were injected with EB 20 mg.kg in the caudal vein 10 minutes before killing, and EB dye was extracted from each pancreas by using formamide.. Relative to controls, enalapril-treated animals showed a 5-fold increase in pancreatic extravasation of EB in the fructose-fed rat model (P < 0.001); smaller changes (2-fold) were observed in the chow-fed animals treated with enalapril (P < 0.001). The increase in pancreatic vasopermeability observed with enalapril in the fructose-fed animals was accompanied by a significant increase in total pancreatic nitric oxide synthase (NOS) activity compared to controls (Delta = +128%; P < 0.001). This increase in NOS activity seemed to be solely attributable to an upregulation of the endothelial NOS isoform because only the eNOS immunoreactive mass (as opposed to nNOS) seemed to be increased in the pancreas of these animals. Treatment with enalapril was not associated with any increase in serum amylase concentrations in either animal subgroup.. Enalapril increases capillary permeability (extravasation of macromolecules) in the pancreas of the fructose-fed rat model. This suggests that ACE inhibition upregulates the eNOS isoform locally, increases vasopermeability of the pancreas, and can therefore result in local edema in the fructose-fed insulin-resistant rat model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Western; Capillary Permeability; Dietary Carbohydrates; Disease Models, Animal; Enalapril; Evans Blue; Fructose; Indicators and Reagents; Insulin Resistance; Male; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Pancreas; Rats; Rats, Sprague-Dawley

Activin A, a member of the transforming growth factor-beta (TGF-beta) superfamily of proteins, shares many biological features with the pro-fibrotic cytokine TGF-beta1, which is primarily responsible for the accumulation of extracellular matrix proteins in renal disease. This study was designed to identify regulators of activin A production in glomerular mesangial cells and test if activin A acts as a pro-fibrotic cytokine in mesangial cells.. The effect of inflammatory cytokines on activin A production and the effect of exogenous activin A on mediators of fibrosis were analysed in cultured rat mesangial cells. Expression of activin A and of established mediators of fibrosis was analysed in a rat model of glomerular fibrosis (anti-Thy1 glomerulonephritis).. In cultured mesangial cells, interleukin-1 and basic fibroblast growth factor, both mediators of glomerular inflammatory injury, dose-dependently increased activin A expression. Incubation with activin A significantly stimulated TGF-beta1, PAI-1 and connective tissue growth factor RNA expression and increased production of extracellular matrix proteins in mesangial cells. In rats with anti-Thy1 glomerulonephritis, expression of glomerular activin A mRNA and protein paralled the expression of TGF-beta and other indices of fibrosis, showing little change from normal on day 1, a marked, 70-fold increase of activin protein production on day 6, and a subsequent decrease at day 12. Antifibrotic therapy with the angiotensin-converting enzyme inhibitor enalapril significantly reduced glomerular activin A production.. Taken together, the results of this study link overexpression of activin A to glomerular matrix protein expansion in vivo and in vitro, suggesting that activin A acts as pro-fibrotic cytokine in renal disease.

Topics: Activins; Animals; Cells, Cultured; Disease Models, Animal; Enalapril; Fibroblast Growth Factor 2; Gene Expression Regulation; Glomerular Mesangium; Inflammation; Inhibin-beta Subunits; Interleukin-1; Male; Rats; Rats, Sprague-Dawley; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Animals; Cardiomyopathy, Hypertrophic; Disease Models, Animal; Enalapril; Rabbits; Ventricular Remodeling

Angiotensin-converting enzyme inhibitors (ACE-Is) prevent target organ damage in several models of hypertension. The aim of this study was to assess the influence of the ACE-I enalapril (10 mg/kg(-1) per day, gavage) on the cardiovascular alterations and production of free radicals induced by chronic infusion of angiotensin II (Ang II, 200 ng/kg(-1) per minute, s.c.) in Sprague-Dawley rats. Enalapril was given concomitantly for the 10 days of Ang II infusion (prevention) or from day 10 to 17 of Ang II infusion (intervention). The influence of the NADPH oxidase inhibitor apocynin (600 mg/L(-1) in drinking water) was evaluated. Enalapril and apocynin had no effect on hypertension in the prevention and intervention studies. Enalapril prevented the increase in heart weight index (HWI), carotid cross-sectional area (CSA) and albuminuria induced by Ang II. Enalapril reduced HWI and albuminuria whereas CSA was not affected in the intervention study. Apocynin had effects comparable to enalapril. Both enalapril and apocynin reduced the overproduction of superoxide anion by the left ventricle and rise in advanced oxidation protein products induced by Ang II. Therefore, the antioxidant but not the antihypertensive effect of enalapril may participate in the prevention and treatment of the Ang II-induced cardiovascular and renal alterations.

Topics: Acetophenones; Albuminuria; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Enalapril; Hypertension; Male; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

Bradykinin is a potent endothelium-dependent vasodilator in the coronary vascular bed. Endothelial mediators released by bradykinin include nitric oxide, prostacyclin and as yet unidentified endothelium-derived hyperpolarising factors. We wished to determine the involvement of nitric oxide and prostaglandin pathways in the cardioprotective actions mediated by bradykinin via the combined inhibition of ACE and aminopeptidase P (APP) in an in vivo rat model of acute ischemia (30 min) and reperfusion (4h). Myocardial infarct size was measured by using the staining agent 2,3,5-triphenyl tetrazolium chloride (TTC). Lipid peroxide levels in serum and in heart tissue were estimated spectrophotometrically. A lead II electrocardiogram was monitored at various intervals throughout the experiment. Infarct size reduction obtained with the combined inhibition of enalapril and apstatin, lisinopril and apstatin was blocked partially but significantly with the prior administration of L-NAME (Nomega-nitro-L-arginine methyl ester) or aspirin, suggesting the involvement of both nitric oxide and prostaglandin pathways in the cardioprotective actions mediated by bradykinin.

Topics: Animals; Aspirin; Bradykinin; Disease Models, Animal; Drug Therapy, Combination; Enalapril; Female; Heart Rate; Injections, Intravenous; Lisinopril; Male; Malondialdehyde; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; NG-Nitroarginine Methyl Ester; Peptides; Rats; Rats, Sprague-Dawley; Staining and Labeling; Tetrazolium Salts

1. Regional haemodynamic responses to a continuous, 4-day infusion of the selective phosphodiesterase type 5 inhibitor, UK-357,903 (0.133 or 1.33 mg x kg(-1) h(-1)) were measured in conscious spontaneously hypertensive rats, and compared with those of enalapril (1 mg x kg(-1) h(-1)). 2. Both doses of UK-357,903 caused modest reductions in mean blood pressure that were not dose-dependent and only significantly different from the vehicle effects on Day 1 of the study (mean -11.8 and -15.3 mmHg for low and high doses, respectively). UK-357,903 had mesenteric and hindquarters vasodilator effects, which were, again, similar for both dose levels and only significantly different from vehicle on Day 1. Neither dose of UK-357,903 affected renal vascular conductance or heart rate. 3. Although the haemodynamic effects of UK-357,903 were not clearly dose-related and some appeared to wane with time, geometric mean plasma levels of UK-357,903 increased in proportion to dose, and were sustained throughout the infusion period. Furthermore, plasma cyclic guanosine monophosphate, a biomarker of phosphodiesterase 5 inhibition, was persistently elevated, and increased with increasing dose. 4. Enalapril caused a fall in mean blood pressure on day 1 (-14.1 mmHg) that was associated with dilatation in renal, mesenteric and hindquarters vascular beds. The haemodynamic effects of enalapril were sustained or increased over the 4-day infusion, although plasma free drug levels were stable. 5. In conclusion, we have shown regional and temporal changes in the haemodynamic effects of UK-357,903, which may be due to activation of compensatory mechanisms, but there were no signs of functional compensation to the cardiovascular effects of enalapril.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Angiotensin I; Animals; Cardiovascular Physiological Phenomena; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Hemodynamics; Hypotension; Infusions, Intravenous; Male; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pyrimidinones; Radioimmunoassay; Rats; Rats, Inbred SHR; Renin; Sulfones; Time Factors

Nitric oxide (NO) production is known to be impaired in heart failure. A new compound (NCX 899), a NO-releasing derivative of enalapril was characterized, and its actions were evaluated in Bio 14.6 cardiomyopathic (CM) hamsters with heart failure. The hamsters were randomized to oral treatment for 4 weeks with vehicle (n=11), NCX 899 (NCX, 25 mg/kg, n=10), or enalapril (25 mg/kg, n=10). In the vehicle group, fractional shortening by echocardiography decreased (-23.6+/-2.0%) and LV end-diastolic dimension) increased (+10.9+/-1.0%), whereas fractional shortening increased (+17.5+/-4.4%) in NCX and was unchanged in the enalapril group (both P<0.01 vs. vehicle). End-diastolic dimension decreased only in NCX. LV contractility (LVdP/dt max and Emax) was significantly greater in NCX than in enalapril or vehicle, while relaxation (Tau) was shortened in both NCX and enalapril vs. vehicle. ACE activity was inhibited equally by NCX and enalapril in the CM hamster, and plasma nitrate levels were increased only in NCX (P<0.05 vs. enalapril and vehicle). In aortic strips endothelium-independent relaxation occurred only with NCX. The superior effects of NO-releasing enalapril (NCX) vs. enalapril alone to enhance vascular effects, increase LV contractility and prevent unfavorable remodeling and are consistent with vascular delivery of exogenous NO. NCX 899 may hold promise for the future treatment of heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Cardiomyopathy, Dilated; Cricetinae; Cytoskeletal Proteins; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Enalapril; Endothelium, Vascular; Enzyme Inhibitors; Heart Failure; Hemodynamics; Male; Membrane Glycoproteins; Mesocricetus; Myocardial Contraction; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitrites; Oxadiazoles; Quinoxalines; Rabbits; Sarcoglycans; Ultrasonography; Vasoconstriction; Ventricular Remodeling

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

Pathological changes in glomerular structure are typically associated with the progression of diabetic nephropathy. The involvement of angiotensin II (AII) in pathogenesis of diabetic nephropathy has been extensively studied and the therapeutic advantages associated with blockade of renin-angiotensin system (RAS), primarily with angiotensin converting enzyme (ACE) inhibitors, has been well-documented. We studied the effect of RAS blockade with an AII receptor antagonist (losartan) vs. an ACE inhibitor (enalapril) on glomerular lesions in KKAy mice, a model of type 2 diabetes mellitus. Losartan was administered at 3 and 10 mg/kg/day and enalapril at 3 mg/kg/day for 14 weeks in the drinking water. The doses of losartan at 10 mg/kg/day was expected to be equivalent to 3 mg/kg/day of enalapril when considering clinical doses for lowering blood pressure. The dose of 3 mg/kg/day of losartan was selected to compare the efficacy at equivalent dose of enalapril. Histologic observation demonstrated suppression of glomerular mesangial expansion and glomerulosclerosis with exudative lesion in the 10 mg/kg/day losartan group when compared to the untreated diabetic controls. A lesser degree of glomerulosclerosis was also observed with losartan and enalapril treatment at 3 mg/kg/day. Ultrastructural examination of renal glomeruli from the high dose losartan group revealed a decreased degree of effacement and/or irregular arrangement of glomerular podocytic foot process. The beneficial effect of RAS inhibition with the AII receptor antagonist losartan on diabetic glomerular lesions was clearly demonstrated in this study. These findings, therefore, provide mechanistic explanation for the clinical utility of losartan for use in the treatment of diabetic nephropathy in man.

Topics: Administration, Oral; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Kidney; Kidney Glomerulus; Losartan; Male; Mice; Mice, Inbred Strains; Mice, Obese; Organ Size; Receptor, Angiotensin, Type 1; Water Supply

Twenty mature male Wistar rats were maintained alive for 40 days, separated in four groups of five rats each: control, L-NAME (LN), L-NAME + Enalapril (LN + E), L-NAME + Verapamil (LN + V). Blood pressure (BP), left ventricular (LV) mass index, and aortic wall parameters were analyzed: aortic wall thickness, tunica media sectional area, surface density of lamellae (Sv[lamellae]), and smooth muscle cell nuclear profiles per section (SMC). At the end of the experiment, the LN group showed high BP and a high LV mass index (cardiac hypertrophy). The control group and the other groups showed significant differences in aortic wall thickness, tunica media sectional area, Sv[lamellae], and SMC. When comparing the LN group with both the LN + E group and the LN + V group, aortic thickness was not different. Tunica media sectional area and SMC differed between the LN group and the LN + E group. There were also differences between the LN group and the LN + V group in SMC. The Sv[lamellae] decreased in the following sequence: control group > LN group = LN + E group > LN + V group. In conclusion, treatment with enalapril and verapamil shows partial efficiency in preventing or treating aortic wall tunica media hypertrophy, suggesting that these alterations are due to a mechanism other than blood pressure control, where nitric oxide synthesis inhibition could be involved.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Blood Pressure; Calcium Channel Blockers; Disease Models, Animal; Drug Therapy, Combination; Enalapril; Heart Ventricles; Male; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Verapamil

75% of patients systematically taking over the period of 6 weeks nonsteroidal anti-inflammatory drugs have their mucous of gastrointestinal tract pathologically changed. This process is called induced NSAID gastropathy. Inhibitors of angiotensin converting enzyme (I-ACE) seems to have gastroprotective effect by enhancing level of endogenous prostaglandins. Besides, an application of I-ACE reduces angiotensin II formation and activates renin-kallicrein-kinin system resulting in nitrogen oxide formation that is in its turn an important component of reparative process of mucous of gastrointestinal tract.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Captopril; Disease Models, Animal; Enalapril; Gastric Mucosa; Indomethacin; Lisinopril; Male; Rats; Stomach Ulcer; Treatment Outcome

Earlier studies have revealed an improvement of cardiac function in animals with congestive heart failure (CHF) due to myocardial infarction (MI) by treatment with angiotensin converting enzyme (ACE) inhibitors. Since heart failure is also associated with attenuated responses to catecholamines, we examined the effects of imidapril, an ACE inhibitor, on the beta-adrenoceptor (beta-AR) signal transduction in the failing heart. Heart failure in rats was induced by occluding the coronary artery, and 3 weeks later the animals were treated with g/(kg x day) (orally) imidapril for 4 weeks. The animals were assessed for their left ventricular function and inotropic responses to isoproterenol. Cardiomyocytes and crude membranes were isolated from the non-ischemic viable left ventricle and examined for the intracellular concentration of Ca2+ [Ca2+]i and beta-ARs as well as adenylyl cyclase (AC) activity, respectively. Animals with heart failure exhibited depressions in ventricular function and positive inotropic response to isoproterenol as well as isoproterenol-induced increase in [Ca2+]i in cardiomyocytes; these changes were attenuated by imidapril treatment. Both beta1-AR receptor density and isoproterenol-stimulated AC activity were decreased in the failing heart and these alterations were prevented by imidapril treatment. Alterations in cardiac function, positive inotropic effect of isoproterenol, beta1-AR density and isoproterenol-stimulated AC activity in the failing heart were also attenuated by treatment with another ACE inhibitor, enalapril and an angiotensin II receptor antagonist, losartan. The results indicate that imidapril not only attenuates cardiac dysfunction but also prevents changes in beta-AR signal transduction in CHF due to MI. These beneficial effects are similar to those of enalapril or losartan and thus appear to be due to blockade of the renin-angiotensin system.

Topics: Adenylyl Cyclases; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Heart Failure; Imidazolidines; Isoproterenol; Kinetics; Losartan; Male; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Renin-Angiotensin System; Signal Transduction

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

We have investigated the protective effect of YM598, a selective endothelin type A receptor antagonist, against an endothelin-1-induced proliferation of rat mesangial cells and renal function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type II diabetes. YM598, but not K-8794, a selective endothelin type B receptor antagonist, inhibited the endothelin-1-induced proliferation of cultured mesangial cells derived from intact Wistar rats in a concentration-dependent manner. YM598 (0.1 or 1 mg/kg), enalapril (5 mg/kg), an angiotensin- converting enzyme inhibitor, or vehicle was administered once daily by gastric gavage to 22-week-old male OLETF rats for 32 weeks. YM598 blunted the development of albuminuria in a dose-dependent manner. A higher dose of YM598 reduced albuminuria comparable with enalapril. Urinary endothelin-1 excretion was greater in the diabetic rats than in the control rats, and was not substantially influenced by the agents. Enalapril, but not YM598, mildly lowered the blood pressure in the diabetic rats, indicating that blood pressure reduction is not involved in the major mechanism of the renoprotective effect of YM598 in OLETF rats. These data suggest that endothelin is involved in the progression of diabetic nephropathy in OLETF rats, and an endothelin type A antagonist is promising for the treatment of diabetic nephropathy.

Topics: Administration, Oral; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Proliferation; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Enalapril; Endothelin A Receptor Antagonists; Endothelin-1; Hyperplasia; Male; Mesangial Cells; Pyrimidines; Rats; Rats, Inbred OLETF; Rats, Wistar; Receptor, Endothelin A; Sulfonamides

The plasma levels of des-aspartate-angiotensin I (DAA-I) in three models of hypertensive rats and hypertensive subjects were determined and compared with their normotensive controls. The rationale for the study was based on our earlier findings showing that DAA-I is a physiological angiotensin peptide that is involved in the pathophysiology of the cardiovascular system. The determination was carried out by the technique of capillary electrophoresis. Plasma level of angiotensin I, angiotensin II, and angiotensin III was also determined as a measurement of the status of the renin-angiotensin system in the different models of hypertension. DAA-I was found to be significantly lower in the spontaneously hypertensive rats (SHR) (46.6 +/- 2.5 pmol/l compared to 66.1 +/- 3.4 pmol/l for the normotensive control Wistar Kyoto rats), renal hypertensive rats (54.2 +/- 5.1 pmol/l compared to 72 +/- 2.5 pmol/l for the normotensive control Sprague-Dawley rats), and essential human hypertensive subjects (15.2 +/- 0.9 pmol/l compared to 19.5 +/- 2.5 pmol/l for the normotensive adult), whilst plasma concentration of angiotensin I and angiotensin II is reflective of the state of the renin-angiotensin system in the particular model of hypertension. When the SHR and human hypertensive subjects were treated with an angiotensin converting enzyme (ACE) inhibitor, the plasma level of DAA-I increased significantly. These findings suggest that the low plasma level of DAA-I could be a characteristic defect of the renin-angiotensin system in the two genetic models of hypertension (SHR and human essential hypertensive subjects). The increase of the nonapeptide following ACE inhibitor treatment could be an important hitherto unrecorded contributory factor to the effectiveness of ACE inhibitors in combating heart pathology.

Topics: Adult; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Chromatography, High Pressure Liquid; Disease Models, Animal; Enalapril; Humans; Hypertension; Male; Middle Aged; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Rats, Wistar

Vascular dysfunction is important in the pathogenesis of peripheral complications of diabetes. However, the effects of diabetes on cerebral blood flow and the role of vascular deficits in the pathogenesis of diabetic encephalopathy are still unknown. The present study examined whether experimental diabetes is associated with reduced cerebral blood flow and whether treatment with enalapril can improve cerebral perfusion and function (blood flow and functional cerebral deficits). Streptozotocin-diabetic rats were treated with the ACE inhibitor enalapril (24 mg/kg) from onset of diabetes. After 14 weeks of diabetes, 12 enalapril treated and 12 untreated diabetic rats, and 12 nondiabetic age-matched control rats were tested in a spatial version of the Morris water maze. After 16 weeks of diabetes, in the same groups, blood flow in the hippocampus and thalamus was measured by hydrogen clearance microelectrode polarography. In a separate study, hippocampal long-term potentiation was measured after 26 weeks of diabetes. Water maze performance and hippocampal long-term potentiation were impaired in diabetic rats. Furthermore, blood flow in diabetic rats was reduced by 30% (P<0.001) in the hippocampus and by 37% (P<0.005) in the thalamus compared to nondiabetic controls. Enalapril treatment significantly improved water maze performance (P<0.05), hippocampal long term potentiation (P<0.05) and hippocampal blood flow (P<0.05). Cerebral perfusion is reduced in diabetic rats compared to controls. Treatment aimed at the vasculature can improve cerebral blood flow, deficits in Morris maze performance and long term potentiation. These findings suggest that vasculopathy plays a role in the development of cerebral dysfunction in diabetic rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Behavior, Animal; Blood Glucose; Cerebral Cortex; Diabetes Mellitus, Experimental; Disease Models, Animal; Enalapril; Hippocampus; Hydrogen; Long-Term Potentiation; Male; Maze Learning; Neuronal Plasticity; Rats; Rats, Wistar; Reaction Time; Regional Blood Flow; Streptozocin; Thalamus; Time Factors

We investigated the systemic and mesenteric cardiovascular effects of administering enalaprilat during resuscitation from hemorrhage. Dogs were hemorrhaged (mean arterial pressure [MAP] 40-45 mmHg for 30 min, then 30-35 mmHg for 30 min) and were then resuscitated with intermittent lactated Ringer's solution (200 mL/kg/h during first 40 min, and 60 mL/kg/h during the following 130 min, MAP 75-80 mmHg). A constant-rate infusion of saline with or without enalaprilat (0.02 mg/kg/h) was initiated after 40 min of resuscitation. Blood flows declined with hemorrhage, increased with resuscitation, and then declined during the initial 40 min of resuscitation. Enalaprilat administration resulted in blood flow increases not seen in the controls (ending values for cardiac index: 2.8 +/- 0.4 L/min/m2 vs. 1.6 +/- 0.3 L/min/m2; celiac arterial flow 314 +/- 66 L/min/m2 vs. 139 +/- 13 mL/min/m2; and portal venous flow 596 +/- 172 L/min/m2 vs. 414 +/- 81 mL/min/m2 for enalaprilat versus controls, respectively). The greater flows with enalaprilat appeared to be due to prevention of the increases in afterload noted in the controls (ending arterial elastance values 3.73 +/- 0.97 mmHg/m2/mL vs. 7.74 +/- 1.80 mmHg/m2/mL for enalaprilat versus controls, respectively). We conclude that administration of a constant-rate infusion of enalaprilat during resuscitation can be used to improve systemic and mesenteric blood flow.

Topics: Animals; Blood Flow Velocity; Blood Pressure; Disease Models, Animal; Dogs; Electrocardiography; Enalapril; Regional Blood Flow; Resuscitation; Shock, Hemorrhagic; Splanchnic Circulation

We examined the effects of KD3-671 (2-propyl-8-oxo-1-[(2'-(H-tetrazole-5-yl)biphenyl-4-yl)methyl]-4,5,6,7-tetrahydrocycloheptimidazole), an angiotensin II type1 receptor antagonist, on an experimental rat model of mesangioproliferative glomerulonephritis, anti-Thy-1 nephritis. Anti-Thy-1 nephritis was induced by intravenous injection of 300 microg/kg of anti-Thy-1.1 monoclonal antibody into rats. KD3-671 (3, 10, 30 mg/kg per day) or enalapril (30 mg/kg per day), an angiotensin II converting enzyme inhibitor, was given p.o. once daily from the day before the antibody injection (the 1st day) to the 15th day after. KD3-671 significantly inhibited an increase in the number of total and proliferating cell nuclear antigen-positive cells and the deposition of alpha-smooth muscle actin and fibronectin in the glomeruli of nephritic rats, but enalapril (30 mg/kg per day) suppressed only the number of total cells and the deposition of alpha-smooth muscle actin in the glomeruli. Moreover, to elucidate the effect of KD3-671 on matrix deposition in the glomeruli, we measured the production of fibronectin in isolated glomeruli obtained from anti-Thy-1 nephritic rats. The glomeruli in anti-Thy-1 nephritic rats produced more fibronectin than that in control rats. KD3-671 (10(-8), 10(-7), 10(-6) M) dose-dependently attenuated fibronectin production in isolated nephritic glomeruli. These findings suggest that KD3-671 may be an effective agent for the treatment of mesangioproliferative glomerulonephritis.

Topics: Actins; Administration, Oral; Angiotensin II Type 1 Receptor Blockers; Animals; Antibodies, Monoclonal; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Fibronectins; Glomerulonephritis, Membranoproliferative; Imidazoles; Isoantibodies; Kidney Glomerulus; Male; Rats; Rats, Sprague-Dawley; Tetrazoles

To observe the regression effect of tetrandrine (Tet) and enalapril (Ena) on vascular morphological changes in renovascular hypertensive (RH) rats.. Renovascular hypertension was induced by two kidney one clip (2K1C) operation. The morphometric measurements were performed in the aorta, caudal artery, renal arterioles, coronary arterioles and mesenteric arterioles.. The wet weight of aorta, caudal artery and femoral artery of RH rats (18 weeks after 2K1C operation) were greater than those of sham-operated rats. The media thickness, lumen diameter, cross section of media, media over lumen ratio and the wet weight of abdomen aorta, caudal artery, coronary arterioles, renal arterioles and mesenteric arterioles were significantly increased, which were more significant in arterioles with the diameter smaller than 70 microns. There were no significant change in the number of the smooth muscle cells (VSMC) in most vessel wall, except in renal arterioles, where the number of smooth muscle cells were significantly increased. After Tet (50 mg.kg-1.d-1, p.o.) or Ena (6 mg.kg-1.d-1, p.o.) treated for 9 weeks from week 9 after 2K1C operation, almost all the changes in the media thickness, the media to lumen ratio, the cross section of media and the wet weight were ameliorated.. In RH rats, mainly a hypertrophic and rearrangement remodeling in the wall of arteries and arterioles was observed with a proliferation of VSMC in renal arterioles. Tet and Ena were shown to regress vascular remodeling by markedly attenuating these changes in renovascular hypertensive rats.

Topics: Alkaloids; Animals; Antihypertensive Agents; Aorta, Abdominal; Arterioles; Benzylisoquinolines; Blood Pressure; Disease Models, Animal; Drugs, Chinese Herbal; Enalapril; Hypertension, Renovascular; Kidney; Male; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley

Vasopeptidase inhibitors are a new class of compounds that inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase. This study determined whether treatment with the vasopeptidase inhibitor omapatrilat (OMA) produced different effects on renal and cardiovascular structure compared with inhibition of ACE by enalapril (ENP) in rats with two-kidney, one clip hypertension (2K1C).. Hypertensive 2K1C rats were randomized into four groups and studied for another 8 weeks: no treatment, OMA, ENP or ENP combined with the diuretic hydrochlorothiazide (ENP + HCTZ). Albuminuria, vascular and renal histology as well as glomerular expression of transforming growth factor-beta (TGF-beta) were determined at the end of the experiment.. OMA decreased blood pressure slightly better than ENP. However, combination of ENP with a diuretic lowered blood pressure equally effective as OMA. OMA was numerically more efficient in reducing cardiovascular and renal hypertensive changes compared with ENP. In contrast, the combination of ENP + HCTZ was as efficient as OMA. However, OMA lowered overexpression of TGF-beta in the non-clipped kidney better than ENP or ENP +HCTZ. Antihypertensive therapy surprisingly decreased renal function as shown by increased plasma creatinine and urea and decreased creatinine clearance.. OMA is marginally more potent compared with ENP alone in lowering blood pressure and preventing cardiovascular and renal injury. This effect may be due to slightly better blood pressure reduction because addition of HCTZ enhances the cardio- and nephroprotective capacity of ENP. In contrast, OMA reduces TGF-beta overexpression in the non-clipped kidney better than ENP or ENP + HCTZ. Therefore, vasopeptidase inhibition is not superior to ACE inhibition in the prevention of cardiovascular and renal damage Goldblatt hypertension.

Topics: Analysis of Variance; Animals; Biopsy, Needle; Blotting, Western; Disease Models, Animal; Enalapril; Enzyme-Linked Immunosorbent Assay; Hypertension, Renal; Immunohistochemistry; Male; Organ Size; Probability; Protease Inhibitors; Pyridines; Random Allocation; Rats; Rats, Inbred Strains; Reference Values; Renal Circulation; Survival Rate; Thiazepines

Our goal was to identify the effects of chronic treatment with enalapril on cerebrovascular dysfunction and endothelial nitric oxide synthase (eNOS) protein in diabetic rats.. Rats were assigned to 1 of 4 groups: nondiabetic, diabetic, nondiabetic/enalapril-treated, and diabetic/enalapril-treated groups. Rats assigned to the nondiabetic groups were injected with vehicle (sodium citrate buffer), and rats assigned to the diabetic groups were injected with streptozotocin (50 mg/kg IP). Enalapril (10 mg/kg per day) was administered in the drinking water and coincided with the injection of vehicle or streptozotocin. Two to 3 months later, we examined responses of pial arterioles to nitric oxide synthase (NOS)-dependent agonists (acetylcholine and ADP) and a NOS-independent agonist (nitroglycerin). After these functional studies, we harvested cerebral microvessels for Western blot analysis of eNOS protein.. We found that acetylcholine- and ADP-induced dilatation of pial arterioles was impaired in diabetic compared with nondiabetic rats. In addition, while enalapril did not alter responses in nondiabetic rats, enalapril prevented diabetes-induced impairment of NOS-dependent vasodilatation. Furthermore, eNOS protein was higher in diabetic than in nondiabetic rats, and enalapril did not produce a further increase in eNOS protein in enalapril-treated diabetic rats compared with untreated diabetic rats.. These results suggest that enalapril prevents cerebrovascular dysfunction in diabetic rats. We speculate that the protective role of enalapril may be independent of an alteration in eNOS protein in cerebral microvessels.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arterioles; Brain; Cerebral Arteries; Cerebrovascular Circulation; Diabetes Mellitus, Experimental; Disease Models, Animal; Enalapril; Male; Microcirculation; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Vascular Patency; Vasodilation; Vasodilator Agents

We have evaluated the effects of an ACE inhibitor, enalapril (ENA) and of an angiotensin II receptor blocker, losartan (LOS), administered either at hypotensive or non-hypotensive dosage, on the cardiac and renal structure of spontaneously hypertensive rats (SHR). Forty-eight rats were included in the study: eight SHR were treated with low-dose (ld, 1 mg/kg/day) ENA; eight with low-dose (ld, 0.5 mg/kg/day) LOS; eight with high-dose (hd, 25 mg/kg/day) ENA; eight with high-dose (hd, 15 mg/kg/day) LOS; while eight Wistar-Kyoto (WKY) and eight SHR were kept untreated (unt). Treatment was given from the 4th to the 12th week of age. Systolic blood pressure (SBP) was measured non-invasively every week. The left ventricular weight to body weight (RLVM) and the left + right kidney weight (RKW) to body weight was measured, and the cardiac and glomerular interstitial collagen content was evaluated using sirius red staining and image analysis. In addition, cardiac metalloproteinases activity (43 kDa MMP, MMP-2, and MMP-9) was evaluated by zymography. A significant reduction in RLVM was observed in SHR given ENA hd or LOS hd. Cardiac collagen was significantly reduced in SHR ENA hd and SHR LOS hd as well as in SHR LOS ld, but not in SHR ENA ld. The 43 kDa MMP collagenase activity was greater in WKY unt compared with SHR unt, being normalized only in SHR ENA hd. The gelatinase activity of MMP-9 showed a trend similar to 43 kDa MMP, but differences between SHR and WKY unt were only of borderline statistical significance. No difference among groups was observed in MMP-2 activity. No significant differences in RKW was observed between groups. However, the collagen content in the glomerular perivascular space was significantly reduced in all treated groups, including those given ld, compared with SHR unt. In conclusion, LOS and ENA showed a similar preventive effect on the increase of RLVM in SHR, but, at least in part, different effects on the extracellular matrix in different organs, being cardiac collagen less sensitive to low dose (ld) ACE inhibition.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Collagen; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Heart; Heart Ventricles; Kidney; Losartan; Matrix Metalloproteinases; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Angiotensin-converting enzyme inhibitors have been shown to reduce morbidity and mortality in patients with heart failure. The angiotensin type-1 blocking and cardioprotective properties of perindopril and enalapril were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Enalapril at 20 mg/kg showed the same angiotensin type-1 blocking action as perindopril at 2 mg/kg in rats with heart failure. Twenty-eight days after immunization, surviving Lewis rats (90/120 = 75%) were divided into six groups and administered perindopril at 0.02, 0.2 and 2 mg/kg per day (Groups P0.02, P0.2 and P2), enalapril at 2 and 20 mg/kg per day (Groups E2 and E20) or vehicle alone (Group V, all groups n = 15). After oral administration for 1 month, four of 15 (27%) rats in Group V, and two (13%) in Groups P0.02 and E2 died. None of the animals in Groups P0.2, P2 and E20, or normal rats (Group N) died. Although both angiotensin-converting enzyme inhibitors improved ventricular function in a dose-dependent manner, the left ventricular end-diastolic pressure and area of myocardial fibrosis were lower, and +/- dP/dt was higher in Group P2 (4.9 +/- 0.6 mmHg, 7.5 +/- 1.4% and +2651 +/- 254/-2622 +/- 189 mmHg/s, respectively) than in Group V (16.7 +/- 1.3, 36 +/- 2.6 and +2659 +/- 176/-2516 +/- 205, respectively) and Group E20 (7.5 +/- 2.5, 15.6 +/- 2.0 and +2018 +/- 110/-2097 +/- 102, respectively). Although the expression levels of transforming growth factor-beta1 and collagen-III mRNA in Group V (36.3 +/- 5.7 and 157.6 +/- 12.7%) were significantly higher than those in Group N (19.6 +/- 3.0 and 65.2 +/- 1.5%, both p < 0.01), they were reduced in Group P2 (21.4 +/- 5.9 and 75.2 +/- 9.3%, both p < 0.01). These results suggest that although enalapril can block increases in blood pressure caused by circulating angiotensin type-1, perindopril at 2 mg/kg may confer greater protection than enalapril at 20 mg/kg against injury from the renin-angiotensin system in heart failure.

Topics: Administration, Oral; Angiotensin I; Animals; Cardiomyopathy, Dilated; Collagen Type III; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Endomyocardial Fibrosis; Gene Expression; Heart Failure; Hemodynamics; Hypertension; Infusions, Intravenous; Male; Pericardial Effusion; Perindopril; Rats; Rats, Inbred Lew; RNA, Messenger; Survival Rate; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Dysfunction, Left; Ventricular Pressure

Vascular endothelial growth factor (VEGF) is involved in angiogenesis, wound healing and inflammation. VEGF exerts its effect via the tyrosine kinase receptors Flt-1 and KDR/Flk-1. We have previously shown that VEGF is up-regulated in a chronic cyclosporine (CsA) nephrotoxicity model. Our current study examined the role of angiotensin II (Ang II) blockade with enalapril (E) or losartan (L) on VEGF in this model.. Pair-fed salt-depleted rats were administered vehicle, CsA, CsA + nilvadipine, CsA + hydralazine/hydrochlorthiazide (HCTZ), CsA + E or CsA + L, and were sacrificed at 7 or 28 days. Physiologic and histologic changes were studied in addition to the mRNA expression of VEGF and its receptors Flt-1 and KDR/Flk-1 by Northern blot, and the protein expression of VEGF by Western blot.. While all groups achieved similar blood pressures and creatinine clearances, the amelioration in nephrotoxicity was observed only with Ang II blockade. VEGF mRNA and protein expressions increased with CsA and became significantly reduced with Ang II blockade. Flt-1 expression was similar in all groups; it decreased early and remained low. On the other hand, KDR/Flk-1 mRNA expression was higher at seven days in all groups, except in the +E and +L groups where it was significantly lower, and then became further down-regulated at 28 days.. The increased VEGF expression in chronic CsA nephrotoxicity seems to be related to up-regulation of Ang II. In addition, VEGF probably exerted its effect via the KDR/Flk-1 receptor. The actions of VEGF in this model remain speculative, but may be related to its effect on macrophage infiltration or matrix deposition.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cyclosporine; Disease Models, Animal; Enalapril; Endothelial Growth Factors; Extracellular Matrix Proteins; Gene Expression; Immunosuppressive Agents; Intercellular Signaling Peptides and Proteins; Kidney Diseases; Losartan; Lymphokines; Male; Rats; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors

Evidence links the insulin resistance syndrome with endothelial dysfunction. Previously, we have described a decreased endothelial nitric oxide synthase (eNOS) activity in both aortic endothelium and cardiac tissue, and an increased proliferation of aortic primary cultured vascular smooth muscle cells (pC-VSMCs), obtained from fructose-fed rats (FFR), an experimental model of syndrome X. Because the participation of the renin-angiotensin system (RAS) in this model is still unclear, the present study examined the effect of chronic administration of an angiotensin converting enzyme (ACE) inhibitor enalapril (E) on pC-VSMCs proliferation and eNOS activity in a conduit artery (aorta) and in resistance vessels (mesenteric vascular bed) from fructose-fed rats. Male Wistar rats were used: Control, FFR, Control + E, and FFR + E (n = 8 in each group). After 8 weeks, tissue samples were obtained and 10% fetal calf serum (FCS) proliferative effect was examined in pC-SMCs of aortic and mesenteric arteries by [(3)H]thymidine incorporation. The eNOS activity was estimated in endothelial lining from both origins by conversion of [(3)H]arginine into [(3)H]citrulline. The FFR aortic and mesenteric pC-VSMCs showed a significantly increased 10% FCS-induced [(3)H]thymidine incorporation compared to controls. The FFR aortic and mesenteric endothelium eNOS activity was significantly decreased. Chronic treatment with E abolished the increased proliferation and restored eNOS activity. These data confirm that changes in VSMCs proliferation and endothelial dysfunction at different levels of the vascular system are involved in syndrome X, and that the inhibition of angiotensin II production can revert those changes, suggesting an important role for RAS and possibly kinins, in the physiopathologic mechanism of this model of syndrome X.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Cells, Cultured; Coronary Vessels; Disease Models, Animal; Enalapril; Fructose; Male; Mesenteric Arteries; Metabolic Syndrome; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rats; Rats, Wistar

The purpose of this study was to determine that the administration of an angiotensin converting enzyme (ACE) inhibitor enalapril would confer protection against doxorubicin-induced experimental heart failure, and attenuate the development of left ventricular dysfunction.. Seventeen dogs were chronically instrumented with an intracoronary catheter and received doxorubicin weekly for 4 weeks. Animals were assigned to two groups: group 1: untreated heart failure; and group 2: simultaneous enalapril administration (5 mg twice a week). Hemodynamic data were obtained at week 0 and 12. Echocardiography was performed weekly.. Survival improved with simultaneous enalapril administration (36% in group 1 vs. 100% in group 2, P=0.04). The increase in the left ventricular end-diastolic pressure was significantly reduced at week 12 (17+/-1 mmHg in group 1 vs. 9+/-1 mmHg in group 2, P=0.0042). The fall in left ventricular stroke work index was significantly prevented (52% in group 1 vs. 21% in group 2, P=0.006). The increase in right ventricular end-diastolic diameter was significantly reduced by enalapril prophylaxis.. Simultaneous treatment with enalapril was beneficial in the prevention of doxorubicin-induced cardiomyopathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antineoplastic Agents; Blood Pressure; Disease Models, Animal; Dogs; Doxorubicin; Enalapril; Heart Failure; Heart Rate; Male; Models, Cardiovascular; Stroke Volume; Time Factors; Treatment Outcome; Vascular Resistance; Ventricular Dysfunction, Left

Topics: Adaptation, Physiological; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Myocardial Ischemia; Rats; Severity of Illness Index; Tachycardia

We sought to determine whether reperfusion and the calcium channel blocker amlodipine or the angiotensin-converting enzyme inhibitor enalapril, during healing over six weeks after myocardial infarction (MI), limit structural vascular remodeling in the noninfarct zone (NIZ).. The effect of reperfusion and amlodipine or enalapril on structural vascular remodeling during healing of MI has not been determined.. We randomly assigned 54 dogs to reperfused or nonreperfused MI, followed by twice-daily doses of oral placebo, amlodipine (5 mg) or enalapril (5 mg) for six weeks and three days off treatment, or to three matching sham groups. We measured in vivo hemodynamic data and left ventricular (LV) function and remodeling (by echocardiography) over the six weeks, as well as ex vivo structural vascular, ventricular and collagen remodeling in the hearts after six weeks.. Compared with placebo and sham groups, both amlodipine and enalapril with or without reperfusion produced LV unloading and limited structural LV remodeling and dysfunction over six weeks in vivo, and also decreased the NIZ resistance vessel media/lumen area ratio at six weeks ex vivo. In addition, amlodipine, but not enalapril, preserved infarct scar collagen and increased the border zone collagen volume fraction and perivascular fibrosis, as well as NIZ resistance vessel media thickness. Enalapril, but not amlodipine, decreased transforming growth factor-beta in the border zone and NIZ.. The results indicate that therapy with amlodipine and enalapril during healing after reperfused MI limits structural vascular remodeling in the NIZ, probably by different mechanisms.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Calcium Channel Blockers; Collagen; Coronary Vessels; Disease Models, Animal; Dogs; Echocardiography; Enalapril; Hydroxyproline; In Vitro Techniques; Myocardial Infarction; Myocardial Reperfusion; Transforming Growth Factor beta; Ventricular Remodeling

The present study was undertaken to investigate the effects of treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril in a mouse model of pulmonary hypertension induced by bleomycin. Bleomycin-induced lung injury in mice is mediated by enhanced tumor necrosis factor-alpha (TNF) expression in the lung, which determines the murine strain sensitivity to bleomycin, and murine strains are sensitive (C57BL/6) or resistant (BALB/c). Bleomycin induced significant pulmonary hypertension in C57BL/6, but not in BALB/c, mice; average pulmonary arterial pressure (PAP) was 26.4 +/- 2.5 mmHg (P < 0.05) vs. 15.2 +/- 3 mmHg, respectively. Bleomycin treatment induced activation of nuclear factor (NF)-kappaB and activator protein (AP)-1 and enhanced collagen and TNF mRNA expression in the lung of C57BL/6 but not in BALB/c mice. Double TNF receptor-deficient mice (in a C57BL/6 background) that do not activate NF-kappaB or AP-1 in response to bleomycin did not develop bleomycin-induced pulmonary hypertension (PAP 14 +/- 3 mmHg). Treatment of C57BL/6 mice with enalapril significantly (P < 0.05) inhibited the development of pulmonary hypertension after bleomycin exposure. Enalapril treatment inhibited NF-kappaB and AP-1 activation, the enhanced TNF and collagen mRNA expression, and the deposition of collagen in bleomycin-exposed C57BL/6 mice. These results suggest that ACE inhibitor treatment decreases lung injury and the development of pulmonary hypertension in bleomycin-treated mice.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Bleomycin; Body Weight; Cardiac Output; Collagen Type I; Disease Models, Animal; Enalapril; Female; Gene Expression; Hemodynamics; Hypertension, Pulmonary; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; NF-kappa B; Pneumonia; Pulmonary Circulation; Receptors, Tumor Necrosis Factor; RNA, Messenger; Specific Pathogen-Free Organisms; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

Structural left ventricular remodeling after myocardial infarction is a complex process with several pathophysiologic descriptors that can be modified by pharmacotherapy. However, the possibility that different classes of antiremodeling agents might exert different effects on different remodeling parameters after reperfused and nonreperfused myocardial infarction has not been systematically studied.. We measured detailed left ventricular remodeling parameters in vivo (echocardiograms) repeatedly over 6 weeks and ex vivo (planimetry) at 6 weeks after myocardial infarction in 36 dogs randomized (factorial design) after reperfused or nonreperfused myocardial infarction to 6 weeks of twice daily oral therapy with the calcium channel blocker amlodipine (5 mg), the angiotensin-converting enzyme inhibitor enalapril (5 mg) or placebo, and 18 matching sham or control animals. Compared to placebo and control groups over 6 weeks, both agents reduced left ventricular loading and limited overall remodeling in both reperfused and nonreperfused groups, but there were pertinent differences. Enalapril limited the increase in left ventricular asynergy in the reperfused group. Both enalapril and amlodipine limited infarct zone thinning in the nonreperfused groups but increased infarct zone thinning in the reperfused groups, despite preserved infarct zone collagen with amlodipine. Enalapril decreased left ventricular diastolic volume and mass more than amlodipine in the reperfused group and increased left ventricular ejection fraction in the nonreperfused group. Both agents limited regional and global shape deformation in reperfused and non-reperfused groups. Diastolic wall stress in the infarct zone decreased with amlodipine, and increased with enalapril and reperfusion.. Different antiremodeling therapies may exert different effects on different remodeling parameters during healing after reperfused myocardial infarction. Significant interactions occur during reperfusion. More than one variable may be needed for the comprehensive assessment of the antiremodeling efficacy of different therapies.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channel Blockers; Cardiac Volume; Cicatrix; Collagen; Disease Models, Animal; Dogs; Enalapril; Heart; Hemodynamics; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Organ Size; Time Factors; Ventricular Remodeling; Wound Healing

Sodium/hydrogen ion exchange is hyperactive in hypertension. Myocardial sodium/hydrogen ion exchange hyperactivity accompanies the regression of cardiac hypertrophy in spontaneously hypertensive rats (SHR) after long term control of blood pressure with enalapril.. To explore whether this effect is shared by other antihypertensive agents or is specific to angiotensin-converting enzyme inhibition.. SHR and normotensive Wistar Kyoto (WKY) rats were treated for five weeks with enalapril (20 mg/kg/day), nifedipine (10 mg/kg/day) or losartan (40 mg/kg/day). Sodium/hydrogen ion exchange activity was estimated in terms of both steady intracellular pH in HEPES buffer and the rate of intracellular pH recovery from intracellular acid loads in isolated superfused 2'-7'-bis(2-carboxyethyl)-5,-(and-6)-carboxyfluorescein, acetoxymethyl ester form-loaded papillary muscles.. Enalapril, nifedipine and losartan decreased systolic blood pressure in SHR to about the same value (140 3, 140 2 and 146 3 mmHg, respectively, at the end the treatment). However, the index of cardiac hypertrophy (heart weight to body weight ratio) was decreased to a smaller value with losartan than with nifedipine or enalapril (2.66 0.09, 3.06 0.05 and 2.86 0.04 mg/g respectively; P<0.05 ANOVA). For the untreated SHR, the index of cardiac hypertrophy was 3.30 0.04 mg/g. Myocardial sodium/hydrogen ion exchange hyperactivity in SHR was normalized by all treatments.. The three treatments regressed cardiac hypertrophy and normalized sodium/hydrogen ion exchange exchange activity in SHR, and losartan was the most effective treatment for reversing cardiac hypertrophy, despite producing effects on blood pressure and sodium/hydrogen exchange activity similar to that of other antihypertensive drugs.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Disease Models, Animal; Enalapril; Hypertension; Losartan; Male; Myocardium; Nifedipine; Rats; Rats, Wistar; Sodium-Hydrogen Exchangers

In Ren-2 rats, plasma active renin and prorenin increase following binephrectomy (BNx) related to increasing plasma potassium. Adrenal is the source of the increasing prorenin but active renin comes mainly from thymus and gut. Trophic influences other than potassium were tested in the present work. Angiotensin did not influence the post-BNx increases in plasma active or prorenin but suppressed resting plasma prorenin from non-adrenal, non-renal sources virtually to zero. ACTH and histamine had no discernible effects. Hexamethonium decreased by 50% the post BNx increase in prorenin but not active renin. In Sprague-Dawley and spontaneously hypertensive rats, low levels of active renin secretion were detected from adrenal but no prorenin. Thus, in anesthetized Ren-2 rats, secreted prorenin is from two sources, i.e. extrarenal and extra-adrenal sites readily suppressible with angiotensin and the adrenal that is partly suppressible by autonomic blockage. This may assist in identifying the origin of extra-renal prorenin secreted in man.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Antihypertensive Agents; Disease Models, Animal; Enalapril; Enzyme Precursors; Female; Ganglionic Blockers; Gene Dosage; Hexamethonium; Histamine; Hypertension; Nephrectomy; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Renin; Vasoconstrictor Agents

Effects of the angiotensin-converting enzyme (ACE) inhibitors, imidapril and enalapril, on kaolin-induced writhing reaction, which is believed to be caused by bradykinin (BK), were examined in mice. The number of writhes was increased significantly by 200 microg/kg of imidapril and by 100 and 200 microg/kg of enalapril. The intensity of writhing reaction was significantly suppressed by 1,000 nmol/kg of icatibant, a selective bradykinin B2 receptor antagonist, in the imidapril-, but not in the enalapril-treated groups. These results suggest that the potentiating effect of enalapril on kaolin-induced writhing reaction is greater than that of imidapril. This might depend on the difference of their inhibitory effects on BK degradation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Enalapril; Imidazoles; Imidazolidines; Kaolin; Male; Mice; Mice, Inbred ICR; Pain

Hyperoxaluria is a recognized cause of tubulointerstitial lesions and it may contribute to chronic renal failure. In previous studies we demonstrated that enalapril was effective against the progression of tubulointerstitial lesions in a 4-week hyperoxaluria rat model. We evaluated whether the action of enalapril on the tubulointerstitial lesions produced by hyperoxaluria persisted for a long period.. Two-month-old male Sprague-Dawley rats were divided into 4 groups of 12 each, including 1--control animals given tap water, 2--animals with hyperoxaluria, 3--animals with hyperoxaluria plus enalapril, 4--animals with enalapril. Hyperoxaluria in groups 2 and 3 rats was induced by administering 1% ethylene glycol, a precursor for oxalates, in the tap water continuously throughout the whole study. Meanwhile, groups 3 and 4 received 20 mg./l. enalapril in the drinking water. At the end of the study renal tubulointerstitial lesions were evaluated by immunostaining using monoclonal antibodies against macrophage infiltrates (ED1), tubulointerstitial alpha-smooth muscle actin and transforming growth factor-beta1. The lesions were quantified by semiquantitative scores. Creatinine clearance and urinary albumin excretion were also determined.. There was no difference in urine oxalate excretion in groups 2 and 3. Group 3 rats treated with enalapril showed fewer tubulointerstitial lesions than nontreated group 2 rats, as indicated by the mean scores plus or minus standard error of mean for inflammatory infiltrate (2.16 +/- 0.2 versus 0.83 +/- 0.16), tubular atrophy (2 +/- 0.27 versus 0.66 +/- 0.14), interstitial fibrosis (2.5 +/- 0.15 versus 0.5 +/- 0.1), glomerular ED1 (1.75 +/- 0.25 versus 0.16 +/- 0.11), interstitial ED1 (2.33 +/- 0.18 versus 0.58 +/- 0.10) tubular transforming growth factor-beta1 (2.09 +/- 0.08 versus 0.91 +/- 0.14), interstitial transforming growth factor-beta 1 (2.33 +/- 0.22 versus 0.66 +/- 0.12), tubulointerstitial alpha-smooth muscle actin (2.91 +/- 0.22 versus 0.83 +/- 0.16), lower urinary albumin excretion (35.5 +/- 2.7 mg. daily versus 10.9 +/- 1) and higher creatinine clearance (2.29 +/- 0.04 ml. per minute versus 2.54 +/- 0.03, all p <0.05).. Based on our results we believe that enalapril would provide a beneficial effect against chronic tubulointerstitial lesions caused by oxalates.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Chronic Disease; Disease Models, Animal; Enalapril; Hyperoxaluria; Immunohistochemistry; Kidney Function Tests; Male; Nephritis, Interstitial; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Sensitivity and Specificity; Treatment Outcome; Urinalysis

Pulmonary arterial hypertension (PAH) is associated with structural changes in the pulmonary vasculature characterized by the proliferation of cellular components of the vessels. ACE inhibitor (ACEI) may have beneficial effects in treating PAH, but its precise mechanism of action in the remodeling process is unclear. p21 is a cyclin-dependent kinase inhibitor that may have a protective role in this process by inhibiting cellular proliferation. Endothelial nitric oxide synthase (eNOS) has also been shown to be protective by its vasodilatory effect. Therefore, we investigated whether expression of p21 and eNOS was modulated by ACEI treatment in a rat model.. Monocrotaline (MCT) was administered to 2 groups of Sprague-Dawley rats fed a high-cholesterol diet, ie, one group received MCT concomitantly with enalapril treatment (MCT(+)/ACEI(+) rats), and the other group did not receive enalapril (MCT(+)/ACEI(-) rats). After 5 weeks, MRI showed right ventricular hypertrophy in MCT(+)/ACEI(-) rats. MCT(+)/ACEI(+) rats showed a preserved right ventricular morphology. Isolated pulmonary perfusion studies showed that ACEI significantly upregulated NO production, as measured by nitrite levels. Addition of N-methyl-D-glucamine dithiocarbamate-Fe solution, an NO-trapping agent, reversed the basal vasodilatory effect of ACEI in the pulmonary vasculature. Immunoblot analysis showed decreased p21 and eNOS expression in the lung in MCT(+)/ACEI(-) rats, whereas their expression was preserved with enalapril treatment.. ACEI suppresses the development of MCT-induced PAH in rats. The mechanism of action might involve the preservation of p21 and eNOS expression. Both p21 and endothelium-derived NO appear to have protective roles in the development of PAH.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Dietary Fats; Disease Models, Animal; Enalapril; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; In Vitro Techniques; Lung; Magnetic Resonance Imaging; Male; Monocrotaline; Nitrates; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitrites; Perfusion; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Signal Transduction

To check wether the deleterious effect of enalaprilat administered before unilateral caroid ligation in the gerbil reported by Fernandez et al. (J Cardiovasc Pharmacol 1994; 24: 937) is not a molecule specific effect but an angiotensin converting enzyme inhibitor class effect.. Survival rate of gerbils (an animal with incomplete Willis hexagona) was measured after unilateral carotid ligation with preadministration (2 hours before by gavage) of saline (0.75 ml) (n = 37); losartan (20 mg/kg) (n = 37), enalaparil (10 mg/kg) (n = 37); a combination of losartan and enalapril at the same dose (n = 37); and of captopril (75 mg/kg) (n = 35).. The survival rate of the gerbils 72 hours after carotid ligation was 65% in control, 62% in losartan, 30% in enalapril, 32% in enalapril + losartan, and 32% in captopril groups. Statistical analysis (log rank test) of the Kaplan-Meier survival curves over 72 hours showed no difference between losartan and controls nor between the various groups treated with ACEI. However survival was significantly lower in the ACEI groups than in the group treated by losartan alone (p < 0.02) or controls (p < 0.02). Intraaortic mean arterial pressure was measured in 6 controls, 6 animals treated with losartan and 6 other treated with enalapril. It was comparable in the losartan and enalapril treated animals (65 +/- 2 mm Hg vs 64 +/- 2) but significantly lower than in the controls (77 +/- 2 mmHg) (p < 0.02).. In contrast to oral preadministration of enalapril and captopril that of losartan does not increase the mortality of the gerbil after unilateral carotid ligation in spite of the same decrease in systemic blood pressure. Although a lower mortality than in controls was not observed with losartan as in the princeps study of Fernandez, these data are consistent with the demonstration by this author that angiotensin II plays a critical protective role in acute ischemia probably by promoting collateral circulation recruitment through non-AT1 receptors stimulation.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Captopril; Cardiovascular Surgical Procedures; Carotid Arteries; Disease Models, Animal; Enalapril; Gerbillinae; Ligation; Losartan; Myocardial Ischemia; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Survival Analysis

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

The effects of chronic treatment with the new sulfhydryl angiotensin-converting enzyme (ACE)-inhibitor, zofenopril, in comparison with the classical sulfhydryl ACE-inhibitor captopril or enalapril or placebo on the development of atherosclerosis were determined in apolipoprotein-E knockout (apoE(-/-)) mice. Groups of 2-month-old male mice received either placebo (N=10), 0.05 mg/kg/day of zofenopril (N=10), 1 mg/kg/day of zofenopril (N=10), 5 mg/kg/day of captopril (N=10) or 0.5 mg/kg/day of enalapril (N=8). After 29 weeks of treatment, computer-assisted imaging analysis revealed that zofenopril reduced the aortic cumulative lesion area by 78% at 0.05 mg/kg/day and by 89% at 1 mg/ml/day of zofenopril compared to that of the placebo (P<0.0001). Captopril reduced by 52% aortic lesions compared to placebo (P<0.01 vs. placebo; P<0.05 vs. zofenopril at both doses). Enalapril did not reduce aortic lesions. Furthermore, 0.05 mg/kg/day of zofenopril reduced susceptibility of plasma LDL to in vitro oxidation compared to captopril, enalapril or placebo, as shown by significant reduction of malondialdehyde content (P<0.001 vs. placebo or enalapril; P<0.05 vs. captopril), as well as by the prolongation of lag-time (P<0.01 vs. placebo or enalapril P<0.05 vs. captopril). More importantly, mice treated with 1 mg/ml/day of zofenopril had a significant decrease in the intimal immunohistochemical presence of oxidation-specific epitopes on oxLDL (NA59 monoclonal antibody, P<0.01), macrophages derived foam cells (F4/80 monoclonal antibody, P<0.05) and native LDL (NP monoclonal antibody, P<0.01) compared to placebo, captopril or enalapril. Thus, chronic treatment with the new sulfhydryl ACE-inhibitor zofenopril has antiatherosclerotic and antioxidant effects in the arterial wall of hypercholesterolemic apoE(-/-) mice. This protection was significantly higher than that reached with captopril and at lower doses of the drug. Treatment with 0.5 mg/kg/day of enalapril did not provide any protective effect.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aortic Valve Stenosis; Apolipoproteins E; Arteries; Arteriosclerosis; Blood Pressure; Captopril; Cholesterol; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Epitopes; Immunohistochemistry; Lipid Peroxidation; Lipoproteins, LDL; Male; Mice; Mice, Knockout; Oxidation-Reduction; Oxidative Stress; Peptidyl-Dipeptidase A; Random Allocation; Sulfhydryl Reagents; Time Factors; Treatment Outcome

Previous studies have shown that angiotensin II (Ang II), by mediating rapid recruitment of collateral circulation, has a protective effect in the setting of acute ischaemia. In an experimental model of acute cerebral ischaemia in the gerbil, Fernandez et al. have reported that the mechanism of the protective effect of Ang 11 is blood pressure (BP)-independent, and that the AT1-receptor antagonist, losartan, but not the ACE inhibitor (ACE-I),enalapril, decreases mortality following unilateral carotid artery ligation. The aim of this study was to examine there producibility of the respective effects of losartan and enalapril, and to verify that these differential effects are drug class-related. Acute cerebral ischaemia was induced in anaesthetised gerbils bv unilateral carotid ligation. The effect of pretreatment with two different ACE-I(enalapril and lisinopril), and two different AT1-receptor antagonists (losartan and candesartan), administered orally or intravenously, on mortality were compared. Kaplan-Meier survival curves at day three were analysed bv a log-rank test. Pretreatment with both enalapril and lisinopril significantly decreased survival at day three compared with controls, while the AT1-receptor antagonists losartan and candesartan, despite similarly lowering BP, did not increase mortality. Coadministration of losartan and enalapril increased mortality to the same extent as enalapril alone. This study confirms that Ang II contributes to protective mechanisms against acute cerebral ischaemia through non AT1-receptor-mediated, BP-independent effects.

Topics: Acute Disease; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Brain Ischemia; Disease Models, Animal; Enalapril; Gerbillinae; Lisinopril; Losartan; Male; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Reproducibility of Results; Stroke; Tetrazoles

We evaluated the effects of chronic inhibition of angiotensin-converting enzyme (ACE) or receptor blockade of angiotensin II type I on the size of myocardial infarcts induced by coronary occlusion-reperfusion in rabbits fed a high-cholesterol or normal diet for 10 weeks. In treated rabbits, myocardial infarction occurred 24 h after the last dose of enalapril or L-158809, an angiotensin II type I receptor antagonist, because of the drugs' waning effects on hemodynamic parameters. The size of the infarct was significantly larger in cholesterol-fed rabbits than in rabbits fed a normal diet. This augmentation of infarct size in cholesterol-fed rabbits was reversed by long-term treatment with enalapril, but not L-158809. The favorable effects of enalapril treatment disappeared after pretreatment with the bradykinin B(2) receptor blocker HOE 140. Long-term enalapril or L-158809 administration did not reduce the size of the infarct in rabbits fed a normal diet. ACE activity in ischemic myocardium significantly exceeded that in nonischemic myocardium and was further increased in cholesterol-fed rabbits, but was significantly reduced by long-term enalapril, but not L-158809. Moreover, treatment with enalapril, but not L-158809, restored acetylcholine-induced endothelium-dependent relaxation of aortic rings from cholesterol-fed rabbits. These results demonstrate that long-term ACE inhibition, but not angiotensin II type I receptor blockade, effectively reduces the size of myocardial infarcts in cholesterol-fed rabbits. The favorable effects of enalapril treatment may involve primarily a bradykinin B(2) receptor-mediated pathway.

Topics: Analysis of Variance; Animals; Cholesterol, Dietary; Disease Models, Animal; Enalapril; Endothelium, Vascular; Hemodynamics; Imidazoles; Male; Myocardial Infarction; Myocardial Reperfusion; Probability; Rabbits; Reference Values; Renin-Angiotensin System; Survival Rate; Tetrazoles

Individually, both late reperfusion and early angiotensin converting enzyme (ACE) inhibitor treatment prevent infarct expansion after acute myocardial infarction.. To examine the effect and mechanism of early post-myocardial infarction ACE inhibitor treatment, when used in combination with late coronary artery reperfusion, on infarct expansion.. Sprague-Dawley rats underwent 8 h of coronary occlusion followed by permanent reperfusion. The treatment group received enalapril, started 1 h after coronary occlusion and continued for 13 days. A control group received placebo. Two weeks after acute myocardial infarction, hemodynamic, morphometric and histologic analyses were performed.. Hemodynamic parameters were similar in both groups (P = NS). Infarct size was similar in the ACE inhibitor and placebo treatment groups (44 +/- 4% compared with 39 +/- 4%, P = NS). Septal thickness was also similar in the two groups (2.8 +/- 0.3 mm compared with 2.7 +/- 0.3 mm, P = NS). The ACE inhibitor-treated group had thicker infarcts than those in the placebo-treated group (0.93 +/- 0.07 mm compared with 0.76 +/- 0.04 mm, P < 0.05) and these infarcts were less expanded (expansion index 1.17 +/- 0.12 compared with 1.57 +/- 0.12, P < 0.05). ACE inhibitor treatment was associated with hypertrophy of viable myocytes within the scar compared with placebo treatment (cell diameter 11.1 +/- 0.5 microns compared with 8.9 +/- 0.4 microns, P < 0.01).. Early post-myocardial infarction ACE inhibitor treatment enhances the benefits of late coronary reperfusion on infarct expansion. The benefits may be related to hypertrophy of still-viable myocytes within the infarcted zone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Female; Hemodynamics; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Necrosis; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Survival Rate; Time Factors; Treatment Outcome

In the present study, myocardial microvessels were investigated by stereology in rats with nitric oxide blockade and concomitant antihypertensive treatment for 40 days. The following five groups (10 rats each) were studied: control; L-NAME; L-NAME + spironolactone; L-NAME + enalapril; L-NAME + verapamil. The blood pressure (BP) increased every week in the L-NAME group; after an initial increase BP decreased in the treated groups and was not different from the control group. Compared to control animals, the myocardium had hypertrophied myocytes and capillary rarefaction; the tunica media and the tunica intima of small arteries were thickened, and an increase in collagen fibrils in L-NAME treated animals was noted. The enalapril, verapamil and spironolactone groups showed uniform myocardium, quite similar to the control group. The volume density of vessels, in comparison with the L-NAME group, was greater in the spironolactone group (57%), in the enalapril group (76%) and in the verapamil group (81%). The length density of vessels was, respectively, 56%, 50%, and 76% greater in the spironolactone, enalapril and verapamil groups than in the L-NAME group. The surface density of the vessels of the L-NAME group was, respectively, 88%, 96%, and 113% lower than in the spironolactone, enalapril and verapamil groups. These results are compatible with the occurrence of angiogenesis in the verapamil rats.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Capillaries; Coronary Circulation; Coronary Vessels; Disease Models, Animal; Enalapril; Enzyme Inhibitors; Heart; Hypertension; Male; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Spironolactone; Verapamil

Cross talk between angiotensin AT1 and alpha1-adrenergic receptors has been reported previously and points to the existence of physiologic regulation between the renin-angiotensin system and the sympathetic nervous system at the receptor level. This regulation may play an important role in the control of blood pressure and may be modified in different cardiovascular pathologies. Nevertheless, neither the physiologic actions nor the clinical relevance of the interaction between these 2 receptors has yet been established. To reveal these aspects in relation to heart failure, the interaction between vascular AT1 and alpha1-adrenergic receptors was evaluated in the Syrian cardiomyopathic hamster model.. The vascular response of each individual receptor to vasoactive agonist was assessed in the presence and absence of antagonists of the other receptor using aortic rings from 11-month-old Syrian cardiomyopathic hamsters. Age-matched golden hamsters were used as controls. In control hamsters, concentration-response curves for the norepinephrine (NE)-induced contraction were significantly displaced to the left after 100 mmol/L losartan incubation. The maximal tension achieved (Emax) values increased by 26+/-4.3% after incubation (P < .05). Similar results were obtained when 20 micromol/L enalapril was used to block angiotensin II (Ang II) synthesis. NE concentration-response curves were also displaced to the left and Emax increased by 27%+/-8.0% (P < .05). The concentrations that induce 50% of the maximal contraction (EC50) were 22.2+/-0.2 nmol/L for untreated and 27.1+/-2.0 nmol/L for losartan-treated aortic rings (n = 8, P > .05). However, EC50 values were significantly reduced in aortic rings treated with enalapril (7.51+/-0.16 nmol/L, n = 8, P < .05). Blockade of alpha1 receptor with 10 micromol/L prazosin increased the response to Ang II by 32% (n = 6, P < .05). In contrast, when these experiments were repeated in aortic rings from cardiomyopathic animals, no interaction between the 2 receptors was observed. NE concentration-response curves, Emax (9.6%+/-2.8% increase after enalapril. and 5.8%+/-6.5% increase after losartan, P > .05) and EC50 values (14.7+/-0.7 nmol/L without treatment, 17.5+/-1.5 nmol/L with enalapril and 11.1+/-0.8 with losartan, n = 8, P > .05) were similar. Furthermore, in cardiomyopathic animals, prazosin did not modify the vascular response to Ang II.. An interaction exists between vascular AT1 and alpha1-adrenergic receptors in control hamsters but not in cardiomyopathic animals. This interaction seems to be bidirectional and counterregulatory. The lack of this regulation may promote a state of enhanced vascular wall activity, which could contribute to the increased vasoconstriction and total peripheral resistance characteristic of heart failure.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Aorta; Cardiomyopathies; Cricetinae; Disease Models, Animal; Enalapril; Humans; Losartan; Male; Mesocricetus; Muscle Contraction; Muscle, Smooth, Vascular; Prazosin; Receptor Cross-Talk; Receptors, Adrenergic, alpha-1; Receptors, Angiotensin; Vascular Resistance

Inhibition of dopamine beta-hydroxylase (DBH) results in a decrease in norepinephrine synthesis. The present study was a randomized, blinded, placebo-controlled investigation of the long-term effects of therapy with the DBH inhibitor nepicastat (NCT) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with chronic heart failure (HF).. Moderate HF (LV ejection fraction [LVEF] 30% to 40%) was produced in 30 dogs by intracoronary microembolization. Dogs were randomized to low-dose NCT (0.5 mg/kg twice daily, n=7) (L-NCT), high-dose NCT (2 mg/kg twice daily, n=7) (H-NCT), L-NCT plus enalapril (10 mg twice daily, n=8) (L-NCT+ENA), or placebo (PL, n=8). Transmyocardial (coronary sinus-arterial) plasma norepinephrine (tNEPI), LVEF, end-systolic volume, and end-diastolic volume were measured before and 3 months after initiating therapy. tNEPI levels were higher in PL compared with NL (86+/-20 versus 13+/-14 pg/mL, P:<0.01). L-NCT alone and L-NCT+ENA reduced tNEPI toward normal (28+/-4 and 39+/-17 pg/mL respectively), whereas HD-NCT reduced tNEPI to below normal levels (3+/-10 pg/mL). In PL dogs, LVEF decreased but was unchanged with L-NCT and increased with L-NCT+ENA. L-NCT and L-NCT+ENA prevented progressive LV remodeling, as evidenced by lack of ongoing increase in end-diastolic volume and end-systolic volume, whereas H-NCT did not. In dogs with HF, therapy with L-NCT prevented progressive LV dysfunction and remodeling. The addition of ENA to L-NCT afforded a greater increase in LV systolic function. NCT at doses that normalize tNEPI may be useful in the treatment of chronic HF.

Topics: Animals; Chronic Disease; Disease Models, Animal; Disease Progression; Dogs; Dopamine beta-Hydroxylase; Dose-Response Relationship, Drug; Enalapril; Enzyme Inhibitors; Heart Failure; Imidazoles; Norepinephrine; Stroke Volume; Thiones; Ventricular Dysfunction, Left; Ventricular Function, Left

Kidney function and structure were compared in control rats (group 1) and in 3 groups of rats made hypertensive by administration of aldosterone and saline for 8 weeks (groups 2, 3, and 4). Group 2 rats received only aldosterone and saline, while group 3 also received losartan and group 4 also received enalapril. Rats in all groups were subjected to uninephrectomy before beginning the experiment. Hypertension and proteinuria in rats given aldosterone and saline were not affected by losartan or enalapril (8-week values for blood pressure in mm Hg: 135+/-3 group 1, 193+/-4 group 2, 189+/-4 group 3, 189+/-5 group 4; P<0.05 groups 2, 3, and 4 versus 1; 8-week values for proteinuria in mg/d: 44+/-8 group 1, 278+/-34 group 2, 267+/-37 group 3, 289+/-36 group 4; P<0.05 groups 2, 3, and 4 versus 1). Vascular, glomerular, and tubulointerstitial injury accompanied hypertension and proteinuria at 8 weeks. Losartan and enalapril did not prevent vascular injury, which was characterized by thickening of arterial and arteriolar walls and by fibrinoid necrosis and thrombotic microangiopathy. Likewise, losartan and enalapril did not reduce the prevalence of glomerular segmental sclerosis (1+/-1% group 1, 10+/-2% group 2, 11+/-2% group 3, 13+/-2% group 4; P<0.05 groups 2, 3, and 4 versus 1) or limit tubulointerstitial injury as reflected by the volume fraction of the cortical interstitium (15+/-1% group 1, 20+/-1% group 2, 21+/-1% group 3, 21+/-1% group 4; P<0.05 groups 2, 3, and 4 versus 1). These findings suggest that local angiotensin II activity does not contribute to the development of renal injury in mineralocorticoid-salt hypertension.

Topics: Administration, Oral; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Disease Models, Animal; Enalapril; Hypertension, Renal; Kidney; Kidney Function Tests; Losartan; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Renal Insufficiency; Sodium Chloride

Angiotensin-converting enzyme (ACE) inhibitor improves the impaired hyperpolarization and relaxation to acetylcholine (ACh) via endothelium-derived hyperpolarizing factor (EDHF) in arteries of spontaneously hypertensive rats (SHR). We tested whether the angiotensin type 1 (AT(1)) receptor antagonist also improves EDHF-mediated responses and whether the combined AT(1) receptor blockade and ACE inhibition exert any additional effects. SHR were treated with either AT(1) receptor antagonist TCV-116 (5 mg. kg(-1). d(-1)) (SHR-T), enalapril (40 mg. kg(-1). d(-1)) (SHR-E), or their combination (SHR-T&E) from 8 to 11 months of age. Age-matched, untreated SHR (SHR-C) and Wistar Kyoto (WKY) rats served as controls (n=8 to 12 in each group). Three treatments lowered blood pressure comparably. EDHF-mediated hyperpolarization to ACh in mesenteric arteries in the absence or presence of norepinephrine was significantly improved in all treated SHR. In addition, the hyperpolarization in the presence of norepinephrine was significantly greater in SHR-T&E than in SHR-E (ACh 10(-5) mol/L with norepinephrine: SHR-C -7; SHR-T -19; SHR-E -15; SHR-T&E -22; WKY -14 mV). EDHF-mediated relaxation, assessed in the presence of indomethacin and N:(G)-nitro-L-arginine, was markedly improved in all treated SHR. Hyperpolarization and relaxation to levcromakalim, a direct opener of ATP-sensitive K(+)-channel, were similar in all groups. These findings suggest that AT(1) receptor antagonists are as effective as ACE inhibitors in improving EDHF-mediated responses in SHR. The beneficial effects of the combined AT(1) receptor blockade and ACE inhibition appears to be for the most part similar to those of each intervention.

Topics: Acetylcholine; Administration, Oral; Angiotensin Receptor Antagonists; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Benzimidazoles; Biological Factors; Biphenyl Compounds; Cromakalim; Disease Models, Animal; Drug Therapy, Combination; Enalapril; Endothelium, Vascular; Enzyme Inhibitors; Hypertension; In Vitro Techniques; Indomethacin; Male; Nitroarginine; Norepinephrine; Potassium Channels; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Tetrazoles

It is unclear whether the previous in vitro evidence of a link between angiotensin II (Ang II) and growth factor receptors can apply to the in vivo situation. In this study, we examined vascular platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptor activation in stroke-prone spontaneously hypertensive rats (SHRSP) and the role of Ang II. Tyrosyl phosphorylation of the growth factor receptors was determined by Western blot analysis coupled with immunoprecipitation. Tyrosyl phosphorylation of the aortic PDGF beta-receptor, but not the EGF receptor, was chronically increased in SHRSP with hypertension, compared with normotensive rats, being accompanied by increased extracellular signal-regulated kinase (ERK) activity. Treatment of SHRSP with ACE inhibitors (perindopril or enalapril) significantly reduced aortic PDGF beta-receptor tyrosyl phosphorylation and ERK activity, whereas treatment with hydralazine failed to reduce these activities. Therefore, these aortic changes in SHRSP were mediated by Ang II in response to vascular ACE. Ang II was infused into rats to examine the effects on aortic growth factor receptors. Chronic Ang II infusion, via the angiotensin type 1 receptor, significantly increased activation of the aortic PDGF beta-receptor but not the EGF receptor. Thus, the aortic PDGF beta-receptor, activated by ACE-mediated Ang II, seems to be responsible for vascular remodeling in hypertensive rats.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Blood Pressure; Disease Models, Animal; Enalapril; ErbB Receptors; Hypertension; Infusions, Intravenous; Male; Mitogen-Activated Protein Kinases; Peptidyl-Dipeptidase A; Perindopril; Phosphorylation; Rats; Rats, Inbred SHR; Receptors, Platelet-Derived Growth Factor

The development of progressive glomerulosclerosis (GS) has been attributed to a number of humoral and hemodynamic factors, however, neither the exact pathomechanism nor the prevention and treatment have been clearly established. Renin-angiotensin system (RAS), interleukin-2 (IL-2)-activated T cells, systemic BP, and serum lipid levels all have been recognized as pathogenetic factors. According to our working hypothesis, a combination therapy with the inhibition of RAS and IL-2 system may be more potent in the prevention of the progression of GS than a monotherapy. After 5/6 subtotal nephrectomy, rats were treated with either the angiotensin-converting enzyme-blocker enalapril (E), the angiotensin II AT1 receptor blocker candesartan cilexetil (CA), the IL-2 synthesis inhibitor tacrolimus (T), or a combination of these agents. Proteinuria, as a functional hallmark of GS, was determined regularly, and at week 16, systolic BP, plasma total cholesterol, and triglyceride (TG) levels were measured and kidneys were harvested for morphologic and immunohistochemical analysis. Combination therapy was more effective (proteinuria: CA + T: 29.3+/-12.8 mg/24 h, E + T: 31.3+/-13.0 mg/24 h; GS: CA + T: 10.7+/-4.1%, E + T: 8.3+/-4.6%, P < 0.01) than monotherapy (proteinuria: T: 49.3+/-17.3 mg/24 h, CA: 53.2+/-18.1 mg/24 h, E: 51.1+/-26.6 mg/24 h; GS: T: 10.9+/-4.4%, CA: 23.8+/-4%, E: 14.2+/-5.3%, P < 0.05, with control values of proteinuria: 77.6+/-27.1 mg/24 h and GS: 28+/-2.9%). The number of infiltrating ED-1 (rat macrophage marker) macrophages (T: 161.5+/-51.2 cells/field of view, CA: 203.6+/-102.3, E: 178.6+/-35.3, CA + T: 140.2+/-63.2, E + T:128.2+/-75.6), and CD-5+ (rat T cell marker) T lymphocytes (CA + T: 261.5+/-103.6, E + T: 236+/-94.8) was significantly reduced by the treatment protocols (controls: ED-1: 356+/-100, CD-5: 482.9+/-154.5). These results indicate that an inhibition of RAS either with angiotensin-converting enzyme or AT1 receptor blockade, together with the inhibition of IL-2 synthesis, is more effective in the prevention of GS than a single treatment alone.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cholesterol; Disease Models, Animal; Enalapril; Glomerulosclerosis, Focal Segmental; Immune System; Immunosuppressive Agents; Interleukin-2; Kidney; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; Tacrolimus; Tetrazoles; Triglycerides

We have investigated the influence of a novel angiotensin II type 1 receptor antagonist, candesartan cilexetil, on the oxidative state of renal tissue and renal function in 5/6 nephrectomized rats, and compared its effects with those of an angiotensin-converting enzyme inhibitor, enalapril. Candesartan cilexetil (1 and 5 mg/kg per day), enalapril (5 mg/kg per day) and vehicle were orally administered once daily for 16 weeks after 5/6 nephrectomy. There was a marked degree of proteinuria evident prior to treatment, an average of 5.69 mg/mg creatinine in the nephrectomized rats, vs 1 to 2 mg/mg creatinine in the control group matched for species and body weight. Inhibition of development of proteinuria by candesartan cilexetil was dose dependent. Enalapril also significantly blunted the rise in urinary protein. Malondi-aldehyde content in the homogenate from the renal cortex increased significantly in the nephrectomized rats compared to control animals. This elevation of malondi-aldehyde content was unaffected by administration of either candesartan cilexetil or enalapril. Antioxidative enzyme (glutathione peroxidase, superoxide dismutase, and catalase) activities in the renal tissue were not affected by any active treatment. Elevation of lipid peroxide in remnant renal tissue suggests that oxidative stress may contribute to the progression of renal injury in the nephrectomized rats. Neither candesartan cilexetil nor enalapril affected antioxidant defenses in renal tissue in nephrectomized rats, indicating that mechanisms other than alteration in oxidative stress are involved in the renoprotective effects of candesartan cilexetil and enalapril.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Catalase; Disease Models, Animal; Disease Progression; Enalapril; Glutathione Peroxidase; Kidney; Kidney Function Tests; Male; Nephrectomy; Organ Size; Oxidation-Reduction; Prodrugs; Proteinuria; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Superoxide Dismutase; Tetrazoles; Thiobarbituric Acid Reactive Substances; Treatment Outcome

Inhibition of the renin-angiotensin system by both angiotensin II type 1 receptor antagonists (AT1As) and angiotensin I-converting enzyme inhibitors (ACEIs) shows renoprotective effects in rats with chronic renal failure when treatment is started in the early phase of renal injury. In this study, we examined the renal protective effects of candesartan cilexetil (TCV-116), an AT1A, and enalapril, an ACEI, in the progressive phase of renal injury in 5/6 nephrectomized rats.. Candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) were orally administered once a day for 4 weeks (the short-term experiment) or 16 weeks (the long-term experiment) to 5/6 nephrectomized rats beginning 15 weeks after the nephrectomy, that is, after they had already showed marked proteinuria.. In vehicle-treated rats, proteinuria, glomerulosclerosis, and interstitial fibrosis developed. Moreover, enhanced expression of transforming growth factor-beta1 (TGF-beta1) in the injured glomeruli was observed. These adverse changes progressed with time, and in the short-term experiment, both drugs inhibited them. In the long-term experiment, the progressive proteinuria and the elevation of blood pressure were similarly attenuated by both drugs. However, candesartan cilexetil significantly inhibited the progression of glomerulosclerosis, the expression of TGF-beta1, and interstitial fibrosis, whereas enalapril did not.. These results indicate that candesartan cilexetil shows potent and long-term preventive effects against the progression of previously developed renal injury.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Blood Urea Nitrogen; Creatinine; Dinoprostone; Disease Models, Animal; Enalapril; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Tetrazoles; Transforming Growth Factor beta

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Kidney Failure, Chronic; Nephrectomy; Oxidative Stress; Rats

Both Long-Evans (LE) and Wistar-Furth (WF) strains of rat are known to be resistant to development of hypertension by mineralocorticoid (MC) treatment. MC-induced hypertension is, in part, mediated by the brain. We have examined another aspect of central MC action, the induction of NaCl appetite in these strains, by using the more common Sprague-Dawley (SD) and Wistar (WS) strains for comparison. In the first experiment, LE and SD rats were administered three treatments known to induce an appetite for NaCl solution in rats. Administration of deoxycorticosterone acetate (DOCA) increased the intake of 0.45 M NaCl in both strains, but the amounts consumed were about 2-fold greater in LE rats than in SD rats. Administration of captopril also increased NaCl intake, but there were no differences between LE and SD rats. NaCl depletion with furosemide induced NaCl appetite in both strains, but the amounts consumed were about 2-fold greater in LE rats than in SD rats. In the second experiment, adult male WF and WS rats were administered DOCA, enalapril, or furosemide and NaCl appetite was determined. Both strains showed comparable NaCl appetite during each of these treatments. However, during a 5-week regimen of DOCA with only NaCl-KCl solution to drink, uninephrectomized WF rats consumed less than WS rats. Thus, despite reported resistance to MC-induced hypertension, neither LE nor WF strains of rats showed correspondingly marked deficits in induced NaCl appetite.

Topics: Analysis of Variance; Animals; Appetite Regulation; Captopril; Desoxycorticosterone; Disease Models, Animal; Drinking; Enalapril; Furosemide; Hypertension; Male; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Rats, Wistar; Sodium Chloride; Species Specificity

This study examined the effects of long-term treatments with the angiotensin-converting enzyme inhibitor, enalapril, and the calcium antagonist, amlodipine, on the morphologic changes, progressive left ventricular dysfunction, and gene expression of the ryanodine receptor (RyR) and phospholamban (PLN) in dilated cardiomyopathy. From the ages of 5 through 20 weeks, dilated cardiomyopathic hamsters, BIO53.58 (BIO), and control hamsters, F1b, orally received either enalapril or amlodipine. Cardiac function was assessed by echocardiography. At the age of 20 weeks, the collagen volume fractions were analyzed by the stereologic method. RyR and PLN messenger RNAs (mRNAs) were examined by Northern blot in the amlodipine group. In BIO, the reduction of left ventricular percentage of fractional shortening was attenuated in the enalapril group (p < 0.05) and amlodipine group (p < 0.001), and the increase in the collagen volume fraction and the loss of myocytes were suppressed in the amlodipine group compared with the untreated group. RyR mRNA level decreased in BIO (p < 0.01) compared with F1b, but PLN mRNA level was unchanged. RyR and PLN mRNA levels were unaffected by the treatment with amlodipine. Enalapril and amlodipine prevent progressive remodeling and reduce cardiac dysfunction in BIO. Amlodipine prevents fibrosis and cell death without modifying RyR and PLN mRNA levels in BIO.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Calcium; Calcium Channel Blockers; Calcium-Binding Proteins; Cardiomyopathies; Cricetinae; Disease Models, Animal; Enalapril; Extracellular Matrix; Gene Expression; Heart; Male; Myocardium; Rats; Ryanodine Receptor Calcium Release Channel; Vasodilator Agents; Ventricular Function, Left

Nitric oxide synthase inhibition in the kidney enhances tubuloglomerular feedback (TGF) responsiveness. This may reflect either the effect of reduced basal nitric oxide (NO) availability or the effect of impaired NO release that is physiologically induced by TGF activation. However, it is unknown whether the latter actually takes place. In this study, it was hypothesized that NO is released (from macula densa cells or endothelium) as part of the normal TGF loop, and mitigates the TGF response. In Sprague Dawley rats, TGF responsiveness was assessed (fall in tubular stop flow pressure, deltaSFP, upon switching loop of Henle perfusion rates from 0 to 40 nl/min) during an intrarenal NO clamp (systemic infusion of nitro-L-arginine, 10 microg/kg per min, followed by intrarenal nitroprusside infusion adjusted to restore renal blood flow [RBF]). This maneuver was presumed to fix intrarenal NO impact at a physiologic level. To validate the approach, TGF responsiveness during an intrarenal angiotensin II (AngII) clamp (systemic infusion of enalaprilat 0.2 mg/kg per min, followed by intrarenal AngII infusion) was also studied. AngII is presumed to modulate but not mediate, TGF, thus not to increase as part of the TGF loop. In untreated animals, RBF was 7.4 +/- 0.4 ml/min, and deltaSFP was 5.7 +/- 1.6 mmHg. Nitro-L-arginine infusion alone reduced RBF to 5.3 +/- 0.5 ml/min (P < 0.05); with nitroprusside infusion, RBF was restored to 8.3 +/- 0.7 ml/min. In this condition (NO clamp), deltaSFP was markedly increased to 19.6 +/- 3.2 mmHg (P < 0.05). By contrast, deltaSFP, which was virtually abolished during enalaprilat alone (0.2 +/- 0.3 mmHg), was not significantly different from controls during AngII clamp (8.2 +/- 1.0 mmHg). These data suggest that NO may well be released upon TGF activation. By contrast, AngII is not dynamically involved in TGF activation, but may modulate the TGF response. Thus, dynamic release of NO during TGF activation mitigates the TGF response, so that it will offset the action of a primary, as yet undefined, vasoconstrictor mediator. The source of this NO, macula densa or endothelium, remains to be elucidated.

Topics: Analysis of Variance; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Enzyme Inhibitors; Feedback; Glomerular Filtration Rate; Kidney Glomerulus; Kidney Tubules; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Pressoreceptors; Rats; Rats, Sprague-Dawley; Reference Values; Renal Circulation

The endothelial vasoconstrictor endothelin (ET) can induce acute renal failure when fibrinolysis and vasodilatory prostanoids (PGs) are inhibited. This study compares therapeutic agents preventing ET-induced acute renal failure in anesthetized female pigs. We investigated the effect of four ET boli (1.5 microg/kg, i.v.) after pretreatment with indomethacin (2 mg/kg) and epsilon-aminocaproicacid (100 + 50 mg/kg) alone (controls, group 1) or during additional nifedipine (10 microg/kg/h; group 2), hirudin (0.5 mg/kg; group 3), or enalapril (2 x 0.15 mg; group 4) on coagulation, PGs, and renal function. The ET-induced blood pressure increase was lower in groups 2 to 4 (lowest in group 3, P < 0.05). PG synthesis was blocked in all groups. The initial hypercoagulability (controls) resulted in disseminated intravascular coagulation that was prevented by hirudin and was attenuated in groups 2 and 4. At the end of the experiment, creatinine clearance was significantly (P < 0.05) decreased. The recovery of renal function two hours after the last ET bolus was most pronounced in the hirudin group. All therapeutic drugs attenuated ET-induced impairment of renal function. Hirudin seems to be the most potent protective drug. Prevention of further ET release evoked by ET-mediated secretion of thrombin might explain this. These results suggest three important pathways for ET's hemodynamic and renal effects.

Topics: Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antithrombins; Blood Pressure; Calcium Channel Blockers; Creatinine; Disease Models, Animal; Enalapril; Endothelins; Female; Hirudins; Indomethacin; Nifedipine; Renal Circulation; Swine; Vasoconstrictor Agents

Activation of the renin-angiotensin system may contribute to the derangement in renal and cardiac function in congestive heart failure. The present study evaluated the effects of eprosartan, a selective angiotensin II receptor antagonist, on renal hemodynamic and excretory parameters and on the development of cardiac hypertrophy in rats with aortocaval fistula, an experimental model of congestive heart failure. Infusion of eprosartan (1.0 mg/kg) in rats with aortocaval fistula produced a significant increase (+34%) in total renal blood flow and a sustained decrease (-33%) in the calculated renal vascular resistance. These effects on renal hemodynamics were more pronounced than those observed in sham-operated control rats and occurred despite a significant fall (-12%) in mean arterial blood pressure. Moreover, eprosartan caused a preferential increase in renal cortical blood perfusion and significantly increased glomerular filtration in rats with congestive heart failure. Chronic administration of eprosartan (5.0 mg/kg per day for 7 days through osmotic minipumps inserted intraperitoneally on the day of operation) resulted in a significant enhancement of urinary sodium excretion compared with nontreated rats with heart failure. Moreover, administration of eprosartan to salt-retaining rats with congestive heart failure resulted in a progressive increase and ultimate recovery in urinary sodium excretion. Finally, early treatment with eprosartan blocked the development of cardiac hypertrophy in rats with aortocaval fistula to a larger extent than the angiotensin-converting enzyme inhibitor enalapril. These findings emphasize the importance of angiotensin II in mediating the impairment in renal function and induction of cardiac hypertrophy in heart failure and further suggest that angiotensin II receptor blockade may be a useful treatment of these consequences in severe cardiac failure.

Topics: Acrylates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiomegaly; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Heart Failure; Hemodynamics; Imidazoles; Kidney; Male; Rats; Rats, Wistar; Renal Circulation; Sodium; Thiophenes

The regional hemodynamic effects of candesartan cilexetil (TCV-116), a selective angiotensin II AT1-receptor antagonist, and enalapril, an angiotensin-converting enzyme inhibitor, were compared in conscious spontaneously hypertensive rats (SHR). A 7-day repeated administration study was carried out. TCV-116 (1 mg/kg, p.o.) and enalapril (10 mg/kg, p.o.) reduced blood pressure to the same extent 5 hr after administration on the 1st and the 7th day. At these points, the cardiac index and organ or tissue blood flow were measured by the non-radioactive colored dye-extraction microsphere technique. Repeated administration of TCV-116, and single and repeated administration of enalapril significantly increased renal blood flow without any changes in the cardiac index. TCV-116 and enalapril also tended to increase splanchnic blood flow following the 1st dose but not the 7th dose. No significant changes in blood flow were observed in the brain, heart, adrenal, skin and skeletal muscle. These results suggest that the antihypertensive effects of TCV-116 and enalapril are attributable to the systemic reduction of vascular resistance caused by the dilatation of blood vessels. These hemodynamic effects of TCV-116, like those of enalapril, may be beneficial in the treatment of hypertension.

Topics: Administration, Oral; Adrenal Glands; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Brain; Coronary Circulation; Disease Models, Animal; Enalapril; Hemodynamics; Hypertension; Male; Microspheres; Muscle, Skeletal; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Regional Blood Flow; Renal Circulation; Skin; Splanchnic Nerves; Tetrazoles; Vascular Resistance

We undertook the present study to examine the effect of the angiotensin-converting enzyme inhibitor enalapril, the angiotensin II antagonist losartan, and calcium antagonist verapamil on systolic pressure and spontaneous blood glucose levels in rats from the Cohen-Rosenthal diabetic hypertensive strain. Genetic hypertension and diabetes developed in this strain after crossbreeding of Cohen diabetic and spontaneously hypertensive rats. The new rat strain was fed their usual copper-poor sucrose diet, which is essential for the development of this model, and for 4 weeks received either enalapril, losartan, or verapamil. Systolic pressure was reduced significantly compared with controls in all treated groups. Chronic treatment with enalapril or verapamil, but not with losartan, succeeded in lowering spontaneous blood glucose, indicating improved diabetic control. Data suggest that angiotensin-converting enzyme inhibition by enalapril, but not angiotensin II antagonism by losartan, can improve glucose metabolism in addition to its hypotensive effect in a genetic diabetic hypertensive rat strain. This confirms that the drop in glucose with converting enzyme inhibition is highly dependent on bradykinin accumulation. Data further suggest that calcium channel blockade by verapamil can also improve glucose metabolism. The question remains whether the reduction in glucose by verapamil was a result of inhibition of glucogenesis.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Disease Models, Animal; Enalapril; Glucose; Hypertension; Imidazoles; Losartan; Male; Rats; Rats, Inbred Strains; Tetrazoles; Verapamil

To compare the effects of the calcium channel blocker amlodipine with those of the angiotensin-converting enzyme (ACE) inhibitor enalapril on left ventricular (LV) remodelling and dysfunction during healing after reperfused anterior myocardial infarction (MI). ACE inhibitors and reperfusion are known to limit LV remodelling after MI. However, the effects of ACE inhibitors and calcium channel blockers on LV remodelling after reperfused MI have not been compared.. Changes in LV topography and function (quantitative echocardiograms) and hemodynamics were measured over six weeks in dogs that were randomized 24 h after reperfusion, done after 2 h of anterior MI, to oral amlodipine (5 mg bid; n = 7), enalapril (5 mg bid; n = 6) or no drug (controls; n = 6) for six weeks. Postmortem LV topography was measured at six weeks.. Scar sizes after six weeks were similar in the three groups. Both enalapril and amlodipine reduced the rate pressure product, but decreases in mean arterial and left atrial pressures were more sustained over six weeks with enalapril. Compared with controls over six weeks, both enalapril and amlodipine preserved LV volumes, global ejection fraction, regional function and infarct segment length, but enalapril blocked the increase in non-infarct wall thickness, attenuated the infarct wall thickness, preserved shape and decreased global LV mass more than amlodipine. Sham-operated dogs (n = 3) showed no significant structural changes.. Both enalapril and amlodipine preserve LV volumes and function during healing after reperfused MI, but enalapril more effectively limits hypertrophy, attenuates infarct wall thickness and preserves shape.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channel Blockers; Disease Models, Animal; Dogs; Drug Evaluation; Enalapril; Heart; Myocardial Infarction; Myocardial Reperfusion; Postoperative Care; Wound Healing

X-linked hereditary nephritis (HN) in Samoyed dogs is a model for human HN (Alport's syndrome). Angiotensin converting enzyme (ACE) inhibitors have been shown to slow the progression of renal disease in animal models and human patients. To determine the effect of ACE inhibitor treatment on X-linked HN in Samoyed dogs, a group of affected and a group of normal males were each randomly divided into two subgroups, which were either treated with an ACE inhibitor or left untreated. ACE inhibitor treatment caused significant increases (P < 0.05) in plasma renin activity in normal and affected dogs, confirming its effectiveness, but did not lower systemic blood pressure. Three of four affected treated dogs had improved weight gains and, overall, treated dogs survived 1.36 times longer than affected untreated dogs (P < 0.05). ACE inhibitor treatment of affected dogs significantly delayed (P < 0.05) the onset of an increase in serum creatinine concentration, tended to delay the decline of glomerular filtration rate and effective renal plasma flow (ERPF), significantly improved (P < 0.05) the ERPF at 110-154 days of age, and significantly slowed (P < 0.01) the rate of increase of proteinuria. Affected treated dogs showed a significant (P < 0.05) transient reduction in glomerular basement membrane splitting. Thus, ACE inhibitor treatment of Samoyed dogs with X-linked HN produced beneficial effects with respect to renal function, renal structure, and survival.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Basement Membrane; Blood Pressure; Creatinine; Disease Models, Animal; Dogs; Enalapril; Genetic Linkage; Glomerular Filtration Rate; Kidney Function Tests; Kidney Glomerulus; Male; Nephritis, Hereditary; Renal Circulation; Renin; X Chromosome

The effects of angiotensin-converting enzyme (ACE) inhibitors was investigated on the development of cerebral vasospasm and on the endothelium-dependent relaxation in the rat subarachnoid hemorrhage (SAH) model. Alacepril or enalapril was used as an ACE inhibitor with or without a thiol moiety in the structure. SAH rats or sham-operated rats were produced by the injection of homologous blood or artificial cerebrospinal fluid into the cisternal magna, respectively. In the SAH rat, cerebral vasospasm was observed at 24 h after blood injection. Acetylcholine (Ach)-induced relaxation in basilar arteries from SAH rats significantly decreased compared to that from sham-operated rats, although the relaxation induced by 3-morpholinosydnonimine, sodium nitroprusside or papaverine did not decrease. These results suggest that the endothelium cell function of basilar arteries in SAH rats is damaged. Alacepril prevented both the development of cerebral vasospasm and the suppression in the Ach-induced relaxation of basilar artery in SAH rats. However, enalapril did not prevent the suppression of Ach-induced relaxation in SAH rats, despite the tendency to prevent cerebral vasospasm. Therefore, it is suggested that the preventive effect of alacepril on cerebral vasospasm could be based on its protective effect on endothelium-dependent relaxation system.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Basilar Artery; Captopril; Disease Models, Animal; Enalapril; In Vitro Techniques; Ischemic Attack, Transient; Male; Muscle Relaxation; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage

The hereditary cardiomyopathic strain of Syrian hamster has been extensively studied as a model of cardiomyopathy of heart failure. We attempted to determine whether an angiotensin converting enzyme (ACE) inhibitor, enalapril, prevents the increase in extracellular collagen matrix which connects the myocytes in cardiomyopathy. Enalapril was administered at an average dosage of 10 mg/kg per day to 10- to 20-week-old hamsters with hypertrophic (Bio 14.6) and dilated (Bio 53.58) cardiomyopathy, as well as to control Syrian hamsters (F1 beta). Collagen concentration estimated by hydroxyproline concentration and the collagen type III:I ratio significantly increased in the hearts of the Bio 14.6 and Bio 53.58 strains at 20 and 40 weeks of age as, compared with those in age-matched F1 beta hamsters. When Bio 14.6 hamsters were given enalapril for 10 weeks from 10 to 20 weeks of age, the collagen concentration, the collagen type III:I ratio and type III collagen mRNA expression were significantly decreased, compared with those in untreated animals of the same strain. After the administration of enalapril, scanning electron microscopic examination also revealed a decrease in fibrillar collagen accumulation in the interstitium and the network surrounding the cardiac myocytes. These prophylactic effects were not observed in the Bio 53.58 strain. These results indicate that the administration of ACE inhibitor prevents type III collagen production in the Bio 14.6 strain but not in the Bio 53.58 strain of Syrian hamster.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomyopathies; Collagen; Cricetinae; Disease Models, Animal; Enalapril; Histocytochemistry; Male; Mesocricetus; Myocardium; RNA

The renin-angiotensin-aldosterone system (RAAS) participates in the injury sustained by the remnant kidney. Our studies assessed the importance of aldosterone in that model and the response of aldosterone to drugs interfering with the RAAS. Initially, four groups of rats were studied: SHAM-operated rats, untreated remnant rats (REM), REM rats treated with losartan and enalapril (REM AIIA), and REM AIIA rats infused with exogenous aldosterone (REM AIIA + ALDO). The last group was maintained with aldosterone levels comparable to those in untreated REM rats by constant infusion of exogenous aldosterone. REM rats had larger adrenal glands and a > 10-fold elevation in plasma aldosterone compared to SHAM. REM AIIA rats demonstrated significant suppression of the hyperaldosteronism as well as marked attenuation of proteinuria, hypertension, and glomerulosclerosis compared to REM. REM AIIA + ALDO rats manifested greater proteinuria, hypertension, and glomerulosclerosis than REM AIIA rats. Indeed, by 4 wk of observation all of these features of the experimental disease were similar in magnitude in REM AIIA + ALDO and untreated REM. In separate REM rats spironolactone administration did not reduce glomerular sclerosis but did transiently reduce proteinuria, lowered arterial pressure, and lessened cardiac hypertrophy. In summary, aldosterone contributes to hypertension and renal injury in the remnant kidney model.

Topics: Adrenal Glands; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Body Weight; Disease Models, Animal; Enalapril; Imidazoles; Kidney; Kidney Diseases; Losartan; Male; Mineralocorticoid Receptor Antagonists; Nephrectomy; Organ Size; Rats; Rats, Sprague-Dawley; Spironolactone; Tetrazoles

The purpose of this experiment was to determine whether use of the angiotensin-converting enzyme (ACE) inhibitor, enalapril, would prevent the occurrence of ovarian hyperstimulation syndrome (OHSS) in the rabbit model. A total of 20 adult female New Zealand white rabbits were studied. All rabbits received 75 IU of human menopausal gonadotrophin s.c. each day for 7 days. On day 8, all rabbits received 2500 IU of human chorionic gonadotrophin (HCG). Ten rabbits were randomly chosen to receive enalapril orally. Five received 1 mg/kg of enalapril and five received 2 mg/kg of enalapril twice daily. The remainder received placebo orally twice daily. On day 10, all rabbits underwent surgical exploration. Total body weight was found to increase significantly in the placebo group (by 293 g, P < 0.001) but not in either group receiving enalapril. Haematocrit also increased significantly in the placebo group (by 3%, P < 0.013) but not in the enalapril groups. Ovarian weights were highest for the 2 mg/kg enalapril group (5.80 +/- 0.52 g), followed by the 1 mg/kg enalapril group (3.64 +/- 0.45), and least for the placebo group (2.69 +/- 0.17). All 10 placebo rabbits met criteria for severe OHSS whereas only six in the enalapril groups did. We concluded that angiotensin II may play a significant role in the development of weight gain, third space fluid accumulation and intravascular fluid depletion in OHSS. ACE inhibition resulted in a 40% decrease in the incidence of OHSS in the rabbit model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Capillary Permeability; Chorionic Gonadotropin; Disease Models, Animal; Enalapril; Female; Ovarian Hyperstimulation Syndrome; Rabbits

Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the obstructed kidney (OBK). In this study we report that a specific angiotensin II (Ang II) receptor antagonists, SC-51316, ameliorates the expansion of the renal cortical interstitium in the OBK of the rat at five days of UUO. This is similar to the effect of an angiotensin converting enzyme (ACE) inhibitor, enalapril. SC-51316 (20 mg/liter in the drinking water) or enalapril (200 mg/liter in the drinking water) was administered beginning 24 hours before UUO and continued through five days after UUO. The relative volume of the tubulointerstitium (Vv) was measured by a point-counting method, and monocyte/macrophage infiltration, alpha smooth muscle actin (alpha SMA), proliferating cell nuclear antigen (PCNA), and collagen type IV (collagen IV) protein deposition were examined histologically using specific antibodies. We also examined the mRNA levels of transforming growth factor beta 1 (TGF-beta 1) and collagen IV by reverse transcription polymerase chain reaction. In untreated rats with UUO, Vv was remarkably expanded; collagen IV and alpha SMA protein deposition in the interstitium and PCNA labeling of nuclei were increased. These changes were significantly ameliorated by administration of an ACE inhibitor or an Ang II receptor antagonist. A monocyte/macrophage infiltration was evident in the OBK of untreated or Ang II receptor antagonist treated rats but was greatly reduced in the OBK of rats given enalapril. Increased expression of TGF-beta 1 mRNA and collagen IV mRNA was blunted (40 to 75%) by the administration of Ang II receptor antagonist or enalapril. The Ang II receptor antagonist or the ACE inhibitor did not affect the contralateral kidney of rats with UUO or the control kidney of normal rats. This study indicates that the renin-angiotensin system has a major role in the pathogenesis of the tubulointerstitial fibrosis of obstructive nephropathy. The tubulointerstitial fibrosis of obstructive nephropathy is most likely mediated by an increased level of Ang II in renal tissue.

Topics: Actins; Angiotensin Receptor Antagonists; Animals; Blood Pressure; Collagen; Disease Models, Animal; Enalapril; Female; Immunohistochemistry; Monocytes; Nephritis, Interstitial; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Triazoles; Ureteral Obstruction

To study the effects of blockade of the renin-angiotensin system on the development of hypertension and end-organ damage in hyporeninaemic deoxycorticosterone acetate (DOCA)-salt hypertensive rats, using an angiotensin II (Ang II) receptor antagonist (TCV-116) or an angiotensin converting enzyme (ACE) inhibitor (enalapril).. DOCA-salt hypertensive rats were produced by uninephrectomy, implantation with DOCA pellets and 1% NaCl loading. TCV-116 (0.1 or 1 mg/kg) or enalapril (10 mg/kg) was given orally once a day from 3 to 6 weeks after the operation. Body weight, blood pressure, plasma renin and creatinine, urinary protein and blood urea nitrogen were measured. After 3 weeks' treatment, oedema and omega 3-subtype benzodiazepine receptor binding in the brain were measured.. Three weeks after the operation the blood pressure in the DOCA-salt hypertensive rats was approximately 200 mmHg, and the plasma renin concentration was lower than in sham-operated rats. However, after a further 3 weeks the renin concentration was slightly above the normal level, and this increase was accompanied by a decrease in body weight and increases in blood urea nitrogen, plasma creatinine, urinary protein and omega 3-subtype benzodiazepine receptor binding in the cerebral cortex, and by brain oedema. Treatment with TCV-116 or enalapril prevented renal damage and decrease in body weight with little effect on blood pressure. Enalapril prevented brain oedema and the increase in benzodiazepine binding in the brain cortex, and 1 mg/kg TCV-116 prevented them markedly.. Although the hypertension in DOCA-salt hypertensive rats is independent of the renin-angiotensin system, the degree of cerebral and renal damage is associated with the activity of the renin-angiotensin system and has little relationship with the blood pressure level.

Topics: Administration, Oral; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Brain; Desoxycorticosterone; Disease Models, Animal; Enalapril; Hypertension; Kidney; Male; Rats; Rats, Wistar; Receptors, GABA-A; Renin-Angiotensin System; Sodium Chloride; Tetrazoles

In Wistar rats just after weaning, 5/6 of renal parenchyma were removed surgically. Thereafter, the rats were fed either a "high-protein" (21%) or two types of a "low-protein" (6%) diet; in one of the latter the lack of protein was substituted by saccharide, in the other by fat, making the substitution "isocaloric" in either case. In all three diet groups, subgroups were formed drinking either tap water or water containing either the ACE inhibitor enalapril (Ena) or the calcium antagonist diltiazem (Dil), or both (Ena + Dil). In the high-protein diet group, increases in the weight of kidney remnants, in proteinuria and in systolic blood pressure (SBP) were seen. This was prevented by feeding either type of the low-protein diet but also by Ena and Ena + Dil. Ena and Ena + Dil not only prevented the increase in SBP but actually lowered it significantly. Dil alone also had a SBP-lowering action but offered no protection from kidney hypertrophy and proteinuria. No additive protective action of Ena + Dil or Ena + low protein or Ena + Dil + low protein was seen, suggesting that a bottom limit of these protective action was reached by the low-protein diet alone. There was no substantial difference between either type of the low-protein diet except a small and transient decrease in body weight in the first week of fat-rich diet administration.

Topics: Analysis of Variance; Animals; Body Weight; Diet, Protein-Restricted; Diltiazem; Disease Models, Animal; Drug Evaluation, Preclinical; Enalapril; Kidney Diseases; Male; Nephrectomy; Rats; Rats, Wistar; Time Factors

The captopril-inhibited enzyme which forms [Met5]-enkephalin from [Met5]-enkephalin-Arg6,Phe7 in isolated rabbit ear artery was characterized further by using various natural substrate candidates/analogues ([Met5]-enkephalin-Arg6,Phe7 and its amide, [Met5]-enkephalin, angiotensin I and bradykinin), peptidase inhibitors such as captopril, enalaprilate and thiorphan and by endothelial removal. 10(-5) and 10(-4) M but not 10(-6) M captopril reduced the effectiveness of [Met5]-enkephalin-Arg6,Phe7 and potentiated the effect of bradykinin but did not affect markedly the action of the other peptides. Of the inhibitors, enalaprilate was less effective than captopril, and thiorphan had no effect. The [Met5]-enkephalin-Arg6,Phe7-->[Met5]-enkephalin conversion was not affected by endothelial removal. The substrate and inhibitor spectrum of this non-endothelial enzyme activity bears no relationship in other, hitherto characterized dipeptidylcarboxypeptidases/endopeptidases known to be involved in the metabolism of the tested peptides.

Topics: Amino Acid Sequence; Angiotensin I; Animals; Arteries; Bradykinin; Captopril; Disease Models, Animal; Ear, External; Enalapril; Endopeptidases; Endothelium, Vascular; Enkephalin, Methionine; Male; Migraine Disorders; Molecular Sequence Data; Rabbits; Substrate Specificity; Thiorphan

We wished to elucidate the effects of the calcium-sensitizing positive inotropic agent MCI-154 and its combined use with an angiotensin-converting enzyme (ACE) inhibitor enalapril on postischemic contractile dysfunction. Anesthetized dogs underwent a 30-min occlusion of the left anterior descending coronary artery (LAD) followed by 2 h of reperfusion. Regional myocardial segment shortening in the ischemic LAD area was assessed by sonomicrometry. Myocardial segment shortening decreased in response to the LAD occlusion and remained decreased during 2-h reperfusion. The intravenous infusion of MCI-154 (0.1 or 0.3 micrograms/kg/min) initiated 10 min after occlusion and throughout reperfusion significantly improved the recovery of segment shortening. The alleviation of the postischemic contractile dysfunction by MCI-154 was augmented when the animals were treated with a bous injection of enalapril (0.3 mg/kg) 15 min before ischemia followed by an infusion of the drug (0.003 mg/kg/min). The pretreatment with enalapril alone (0.3 mg/kg plus 0.003 mg/kg/min or 1 mg/kg plus 0.01 mg/kg/min) did not alleviate the postichemic dysfunction, however, although it decreased systemic blood pressure (BP). Ischemic bed size, myocardial necrosis (by triphenyltetrazolium chloride staining), and collateral blood flow (by colored microspheres) were similar in all experimental groups. These results indicate that MCI-154 improves the postischemic contractile function of dog heart, whereas enalapril fails to improve it. ACE inhibitors may also augment the efficacy of cardiotonics on postischemic dysfunction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Calcium; Cardiotonic Agents; Coronary Circulation; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Enalapril; Female; Infusions, Intravenous; Male; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Pyridazines

The efficacy of SR 47436 (BMS-186295), 2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)- biphenyl-4-yl)methyl]-1,3-diaza-spiro[4,4]non-1-en-4-one, a non-peptide angiotensin AT1 receptor antagonist, was characterized in various conscious hypertensive rat models. In spontaneously hypertensive rats, single intravenous or oral doses of SR 47436 induced mild to modest antihypertensive effects. No tolerance of the antihypertensive effect was observed when the oral treatment was extended to 15 days. SR 47436 was highly effective to lower blood pressure in high renin-dependent hypertensive models such as two-kidney, one-clip renal hypertensive rats and renal artery-ligated hypertensive rats. In this last model, intravenous or oral administration of the angiotensin II antagonist produced a dose-dependent decrease in blood pressure. When injected after the maximal effective dose, enalapril did not induce any further decrease in blood pressure. Furthermore, the antihypertensive effect elicited after a single oral dose (10 mg/kg) was long-lasting (at least 24 h). The simultaneous blunting effect of the angiotensin II-induced blood pressure increase indicated clearly that the antihypertensive effect was due to the blockade of vascular angiotensin AT1 receptors. As expected, the angiotensin AT1 receptor antagonist did not show any efficacy in deoxycorticosterone acetate hypertensive rats, with a suppressed renin-angiotensin system. In genetic and renal hypertensive rats, the antihypertensive effect induced after acute dosing of SR 47436 was similar to that observed after losartan and enalapril. A reflex tachycardia accompanied the antihypertensive effect only after intravenous treatment with either SR 47436 or losartan. These results show that this angiotensin II antagonist, SR 47436, is an effective and long-lasting antihypertensive agent in rats.

Topics: Administration, Oral; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Blood Pressure; Desoxycorticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Enalapril; Hypertension, Renal; Imidazoles; Injections, Intravenous; Irbesartan; Losartan; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Tachycardia; Tetrazoles

Semotiadil fumarate, a novel benzothiazine calcium antagonist, was given alone or in combination with either enalapril or trichlormethiazide to conscious, spontaneously hypertensive, rats daily for 2 weeks. Systolic blood pressure and heart rate were recorded 24 h before the start of the regimen and then every 2 and 24 h after the 1st, 3rd, 7th, 10th and 14th doses. When given alone, the antihypertensive effects of semotiadil (10 mg/kg, p.o.) and enalapril (5 mg/kg, p.o.) first became apparent after the 3rd dose and thereafter the effects appeared to develop daily although this effect had waned by the time of the next dose. When given in combination, however, these drugs appeared to potentiate each other and after the 7th dose, the antihypertensive effect persisted. Trichlormethiazide (30 mg/kg, p.o.) alone failed to exert any significant antihypertensive effect and in combination was not always additive to that of semotiadil. In contrast to the effect on blood pressure, the heart rate remained resistant to all these drugs. These results indicate that combined daily dosing of semotiadil, especially with enalapril, each at relatively low doses may be able to control hypertension in a continuous manner.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Enalapril; Heart Rate; Hypertension; Male; Rats; Rats, Inbred SHR; Thiazoles; Trichlormethiazide

The Han: SPRD Pkd rat mutant is an autosomal dominant rat model with incomplete penetration of polycystic renal transformation. Progressive renal failure occurs in heterozygous male animals. The mechanisms of progression have not been elucidated. To identify some pathogenetic factors involved we subjected male SPRD Pkd rats (and their non-affected littermates as controls) to uninephrectomy (UNX), castration or enalapril treatment. To assess progression S-urea at age 150 days was chosen as endpoint. (i) In uninephrectomized male Han: SPRD Pkd (n = 12 animals per group) S-urea at age 150 days was consistently above 300 mg/dl, while it was 245 mg/dl (191-290) in control Han: SPRD Pkd. (ii) In castrated male Han: SPRD median S urea at 150 days was 100 mg/dl (69-211) compared to sham-operated male Han: SPRD controls (245; 191-290). Castration did not, however, prevent accelerated progression after uninephrectomy. (iii) Enalapril (50 mg/l) in the drinking fluid did not significantly lower median systolic blood pressure (by plethysmography) in animals on 0.2% sodium diet (at 185 days 160 mmHg; 140-170 versus 170; 140-195 in non-enalapril controls), although circulating ACE was significantly inhibited (17 U; 11-33 versus 89; 52-108 in controls). S-urea at age 185 days was not significantly different in the 2 groups. In conclusion, the Han: SPRD Pkd model differs from human ADPKD to some extent. Uninephrectomy accelerates renal failure in the rat, but not in humans. On the other hand, in contrast to human ADPKD the renin system is suppressed in the rat model and ACE inhibition does not affect the course of renal failure.

Topics: Animals; Castration; Disease Models, Animal; Enalapril; Female; Kidney; Male; Nephrectomy; Polycystic Kidney, Autosomal Dominant; Rats; Renal Insufficiency

Our previous studies showed that imidapril prevented the occurrence of cerebral stroke and ameliorated biochemical parameter changes of renal dysfunction at a dose that did not inhibit the progression of hypertension in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). To confirm these findings, a histopathological investigation was conducted on the kidney of salt-loaded (from 11 to 16 weeks of age) SHRSP, which was the subject of the preceding study. Their brains and hearts were also examined. Histopathologically, renal lesions such as fibrinoid necrosis and proliferative arteritis of small calibration arteries, necrotizing glomerulitis and tubular degeneration, and cerebral hemorrhage and slight cardial hypertrophy were observed in salt-loaded control SHRSP. The occurrence of these lesions were prevented in a dose-dependent manner by the administration of imidapril (1 and 2 mg/kg/day). Especially, the preventive effects on the renal lesions were apparently noted. Enalapril also prevented these renal lesions, but its preventive effects were weaker than those of imidapril at the same dose (2 mg/kg/day). It became evident from the results of the present and previous studies that imidapril reduced renal biochemical and histopathological injuries.

Topics: Animals; Antihypertensive Agents; Autopsy; Basilar Artery; Brain; Cerebrovascular Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Heart; Hypertension, Renal; Imidazoles; Imidazolidines; Kidney; Kidney Function Tests; Kidney Glomerulus; Male; Microscopy, Fluorescence; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Sodium Chloride, Dietary

Puromycin-induced nephrotic syndrome is an animal model of progressive renal disease. Both angiotensin converting enzyme inhibitors and lipid-lowering agents have been used to preserve renal structure and function in this model, although neither completely prevents progression. We tested the hypothesis that the combination of the two agents would be more protective than either alone. Rats were divided into five groups; all were uninephrectomized. Four groups were given puromycin at a dose of 10 mg/100 g body weight (BW) with additional doses of 4 mg/100 g BW given intraperitoneally at 4, 5, and 6 weeks thereafter. One group was given enalapril (EN) 50 mg/l dissolved in the drinking water; the second received lovastatin (L) 15 mg/kg given daily by gavage; the third received both agents; the fourth was left untreated, and the final group received no puromycin and served as the control group. Eight weeks after the initial dose of puromycin, glomerular filtration rate (GFR), as inulin clearance, and protein excretion were determined and blood was collected for cholesterol and triglycerides. Blood pressure was not different between any of the groups. At the end of the study period, serum cholesterol [mean +/- SD, 252 +/- 185 mg/dl (L), 135 +/- 101 mg/dl (L + EN)] and triglycerides (239 +/- 200, 148 +/- 158 mg/dl) were significantly lower (P < 0.001) in the lovastatin-treated groups than in the untreated puromycin group (535 +/- 255 mg/dl and 579 +/- 561 mg/dl, cholesterol and triglyceride, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Enalapril; Glomerular Filtration Rate; Lovastatin; Male; Nephrotic Syndrome; Rats; Rats, Sprague-Dawley

Little is known about the effects of common antihypertensive drugs in obese, insulin-resistant females. Nine-month-old obese female SHHF/Mcc-fa(cp) rats that received either nifedipine, a calcium channel antagonist, or enalapril, an angiotensin-converting-enzyme inhibitor, for three months were compared with untreated SHHF/Mcc-fa(cp) rats (controls). After one month, nifedipine significantly decreased body weight in obese females compared to either enalapril or controls. After three months of treatment, total, abdominal, and subcutaneous fat masses were decreased in obese females given nifedipine compared to either enalapril or controls. Enalapril treatment was associated with a redistribution of fat mass from abdominal to subcutaneous depots. Nifedipine reduced plasma triglyceride and fasting glucose levels and improved insulin response to an oral glucose load in obese females, whereas enalapril did not appear to affect glycemic control. Systolic pressure was not significantly decreased until after two months of treatment with nifedipine or three months of treatment with enalapril in obese females and may have coincided with improvement in insulin-resistance. Similarly, plasma atrial natriuretic peptide concentrations were significantly lower in obese females given nifedipine. To determine how obese males responded to a calcium channel antagonist, six-month-old obese male SHHF/Mcc-fa(cp) rats were treated for three months with either nifedipine or placebo (controls). Nifedipine-treated obese males showed a mild but significant decrease in weight gain that was due to a decrease in fat deposition in both subcutaneous and abdominal depots and systolic blood pressure was significantly reduced after one month of treatment. Nifedipine did not affect other plasma biochemical parameters in obese males. In conclusion, nifedipine improved systolic pressure and glycemic control in obese female SHHF/Mcc-fa(cp) rats, effects that may be associated with a marked loss in body weight and fat mass and improved lipid metabolism. Nifedipine-treated obese males exhibited only a diminished weight gain that was not associated with changes in diabetic characteristics.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Composition; Body Constitution; Body Weight; Disease Models, Animal; Enalapril; Female; Insulin; Insulin Resistance; Lipid Metabolism; Lipids; Male; Nifedipine; Obesity; Placebos; Rats; Sex Factors; Systole; Time Factors; Vasodilator Agents

Spiraprilat, a new angiotensin-converting enzyme (ACE) inhibitor, was compared with enalaprilat for its ability to improve left ventricular (LV) function and metabolism in anesthetized open-chest dogs with a new model of acute LV failure (ALVF) induced by embolization of the left coronary artery with 50 microns plastic microspheres followed by intravenous (i.v.) infusion of methoxamine. With this procedure, LV end-diastolic pressure (LVEDP) increased from 4.2 +/- 0.7 to 12.8 +/- 1.3 mm Hg and remained at approximately 12 mm Hg throughout the experiment. Cardiac output (CO) decreased from 1.25 +/- 0.12 to 0.79 +/- 0.06 and 0.55 +/- 0.02 L/min at 30 and 90 min after methoxamine infusion, respectively. LVdP/dtmax and dP/dt/P decreased, while total peripheral resistance (TPR) increased. These hemodynamic changes indicated establishment of stable ALVF of a moderate degree. Moreover, decreases in myocardial lactate consumption and contents of creatine phosphate in the myocardium indicated the existence of moderate ischemia. The new ACE inhibitor, spiraprilat, as well as enalaprilat (30 micrograms/kg i.v.) effectively decreased mean aortic pressure (30%), LVEDP (20%), and TPR (30%) and increased stroke volume (SV) CO, and dP/dt/P. Both agents decreased myocardial oxygen consumption (20%) and caused a significant increase in myocardial creatine phosphate contents. These data indicate that the beneficial effects of both inhibitors extended not only to LV function but also to myocardial energy metabolism in ALVF.

Topics: Adenosine Triphosphate; Anesthesia; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Coronary Vessels; Disease Models, Animal; Dogs; Enalapril; Heart Failure; Lactates; Lactic Acid; Methoxamine; Microspheres; Myocardium; Oxygen Consumption; Phosphocreatine; Vascular Resistance; Ventricular Function, Left

Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Enalapril; Hypertension; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Rats; Rats, Inbred SHR

This study was undertaken to determine the role of angiotensin II (AII) in the development of glomerulosclerosis, using an AII receptor antagonist in an animal model of hyperlipidemia. Hyperlipidemic Imai rats were employed because they spontaneously develop glomerulosclerosis; this is especially true in males. Group 1 (n = 5) received no specific therapy. Group 2 (n = 5) was treated with enalapril at a dosage of 50 mg/l in drinking water starting at 6 weeks of age. Group 3 (n = 5) and group 4 (n = 6) were treated with the AII receptor antagonist DuP 753 at a respective dosage of 15 mg/l (low-dose DuP) and 150 mg/l (high-dose DuP) in drinking water. Body weight, blood pressure, urinary protein, serum albumin, cholesterol, BUN and serum creatinine were measured and compared among the groups from 12 to 24 weeks of age. Enalapril and high-dose DuP were almost equally effective in controlling systemic hypertension. Each treatment significantly reduced proteinuria (172 +/- 112 and 152 +/- 72 mg/kg/day at 24 weeks) as compared with that in the controls (421 +/- 147 mg/kg/day; p < 0.05 and p < 0.01, respectively). Hypercholesterolemia also decreased (82 +/- 4 and 89 +/- 6 mg/dl) as compared with that of the controls (141 +/- 48 mg/dl; both p < 0.05). Glomerulosclerosis index (SI) was significantly higher in the untreated control rats (55 +/- 26) than in the enalapril-treated rats (2 +/- 3; p < 0.005) and the high-dose-DuP-treated rats (6 +/- 6, p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Blood Pressure; Blood Urea Nitrogen; Cholesterol; Disease Models, Animal; Enalapril; Glomerulonephritis; Hyperlipidemias; Imidazoles; Kidney; Kidney Failure, Chronic; Losartan; Male; Organ Size; Proteinuria; Rats; Renin-Angiotensin System; Serum Albumin; Tetrazoles

The antihypertensive activity of quinapril was examined in normotensive and various hypertensive animal models. In 2-kidney, 1-clip renal hypertensive rats (2K-RHR), quinapril (0.1 to 1.0 mg/kg, p.o.) had a dose-related and sustained antihypertensive action, which was as potent as that of enalapril and approximately 40 times stronger than that of captopril. Heart rate was not changed by these doses of quinapril. In spontaneously hypertensive rats (SHR) and 1-kidney, 1-clip renal hypertensive rats, quinapril as well as enalapril dose-dependently produced a significant fall in blood pressure. The relative potency and duration of the effect of quinapril was the same as that of enalapril in these models. Quinapril at 30 mg/kg, p.o. lowered blood pressure and increased heart rate in normotensive rats. In contrast, quinapril and enalapril failed to reduce blood pressure in DOCA/salt hypertensive rats. In the repeated dose study, no development of tolerance was observed during the administration period in 2K RHR and SHR. The antihypertensive effects in 2K RHR was greater than those in SHR. Quinapril was more potent and long-lasting than enalapril in 2K RHR and SHR. From these results, quinapril is expected to be useful for the clinical treatment of hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Captopril; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Heart Rate; Hypertension; Hypertension, Renal; Isoquinolines; Male; Quinapril; Rats; Rats, Inbred SHR; Rats, Wistar; Tetrahydroisoquinolines

Cardiac hypertrophy in rats was produced by aortic banding for 6 weeks and regression of hypertrophy in these experimental animals was induced by administration of angiotensin converting enzyme inhibitor, enalapril (10 mg/kg/day) for 6 weeks. The left ventricular muscle mass and systolic pressure were decrease upon treating the hypertrophied rats with enalapril. This drug also decreased the number of alpha 1-adrenoceptors in hypertrophied myocardium without any changes in beta-adrenoceptors. The regression of cardiac hypertrophy in spontaneously hypertensive rats by enalapril for 10 weeks was not associated with any alterations in alpha 1-adrenoceptors in hypertrophied myocardium, but was decreased in beta-adrenoceptors. Effects of enalapril on extracellular matrix in the myocardium was also observed in regression of hypertrophy in which the type III collagen mRNA expression and collagen contents were reduced in comparison with those of hypertrophied myocardium. These results indicate that regression of cardiac hypertrophy is not always associated with a decrease in the number of alpha 1-adrenergic receptors and that the beneficial effects of enalapril in the hypertrophied heart in aortic banding animals may be of some specific nature.

Topics: Animals; Cardiomyopathy, Hypertrophic; Collagen; Disease Models, Animal; Down-Regulation; Enalapril; Extracellular Matrix; Gene Expression Regulation; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta

Left ventricular myocardial blood flow and metabolic parameters were studied in dogs with severe heart failure induced by rapid ventricular pacing. The impact of early administration of enalapril was also evaluated. Seventeen dogs were randomly assigned in a blinded fashion to receive enalapril at a dose of 10 mg orally per day or a matching placebo commencing 1 week after initiation of pacing. Six dogs underwent sham operations and served as a control for the myocardial blood flow and metabolic studies. In general, there was no significant difference in myocardial blood flow among the control dogs, the placebo-treated, and the enalapril-treated, paced dogs. However, tissue adenosine triphosphate was markedly reduced in both the enalapril-treated, paced dogs (2.43 +/- 0.55 mumol/gm wet weight, mean +/- SD) and the placebo-treated, paced dogs (2.79 +/- 0.39 mumol/gm) compared with the level in control dogs (4.77 +/- 0.88 mumol/gm, both p < 0.01). Tissue glycogen and lactate levels were similar in the three groups. The time to development of severe heart failure tended to be longer in the enalapril-treated dogs (33 +/- 12 days) than in the placebo-treated dogs (24 +/- 10 days, p = 0.07). In pacing-induced heart failure, therefore, an imbalance between energy supply and demand may contribute to the left ventricular dysfunction, myocardial ischemia does not play a major role, and early treatment with enalapril may prolong the time to development of severe heart failure.

Topics: Animals; Coronary Circulation; Disease Models, Animal; Dogs; Echocardiography; Enalapril; Heart Failure; Heart Rate; Hemodynamics; Male; Myocardium; Norepinephrine; Renin

To investigate the mechanism by which angiotensin-converting enzyme (ACE) inhibition attenuates atherogenesis, we have studied the effects of a non-sulfhydryl ACE inhibitor, enalapril, and an angiotensin receptor antagonist, SC-51316, in cholesterol-fed rabbits. After 3 mo of enalapril treatment (10 mg/kg per d, p.o.) the percent plaque areas in the thoracic aortas of treated animals were significantly reduced (controls: 86.8 +/- 3.5%; treated: 31.1 +/- 8%, P < 0.001). Aortic cholesterol content was also reduced (controls: 31.4 +/- 3.2 mg/g tissue; treated: 7.4 +/- 1.8 mg/g, P < 0.001). Enalapril had no significant effect on plasma lipid levels or conscious blood pressure. In a second study, the angiotensin II receptor antagonist SC-51316 was administered at a dose equivalent to enalapril at blocking angiotensin pressor effects in vivo (30 mg/kg per d, p.o.). Evaluation after 3 mo indicated no significant attenuation of aortic atherosclerosis. These results demonstrate that: (a) enalapril attenuates atherogenesis without affecting either blood pressure or plasma lipid levels; (b) antioxidant activity, found with sulfhydryl-containing ACE inhibitors, is not necessary for reducing plaque formation; and (c) the attenuation of atherogenesis by ACE inhibition may not be due to blockade of the renin-angiotensin system. Alternatively, one must consider the multiple effects of ACE inhibition on other hormone systems, such as bradykinin, or the possibility that alternate angiotensin II receptors may be involved in atherosclerosis.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Feed; Animals; Arteriosclerosis; Cholesterol, Dietary; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Male; Rabbits; Renin-Angiotensin System; Tetrazoles; Time Factors; Triazoles

In vitro coronary artery responsiveness to angiotensin I, angiotensin II, noradrenaline, phenylephrine, BHT 920, and potassium chloride together with functional relaxation to acetylcholine was investigated in dogs with pacing-induced heart failure treated with enalapril (oral administration of 10 mg.day-1) for a mean duration of 26 days. Although maximal responses generated to both angiotensin I and angiotensin II were unaltered in the enalapril-treated group, angiotensin II became more potent following enalapril treatment: the EC50 for angiotensin II following placebo treatment was 2.4 (0.6-5.8; 95% confidence limits) nM and following enalapril treatment was 0.03 (0.007-0.1; 95% confidence limits) nM. In addition to the above changes, coronary artery rings from dogs treated with enalapril developed significantly less tension to noradrenaline, phenylephrine, and BHT 920. In contrast, responses to potassium chloride were unaltered following enalapril treatment. However, the relaxation to acetylcholine was enhanced from 38.9 +/- 3.0 to 50.4 +/- 3.5% (placebo versus enalapril, p < 0.05). These findings indicate that enalapril may possess alpha-blocking properties and enhance the relaxation response to acetylcholine through an endothelial-dependent mechanism in addition to inhibiting converting enzyme.

Topics: Acetylcholine; Adrenergic alpha-Agonists; Angiotensin I; Angiotensin II; Animals; Cardiac Pacing, Artificial; Coronary Vessels; Disease Models, Animal; Dogs; Enalapril; Endothelium, Vascular; Heart Failure; In Vitro Techniques; Male; Vasoconstriction

Blunted cardiac responses to sympathetic and vagal activation are key features of heart failure. Since the modulation of drug effects by a selective autonomic dysfunction is little known, we developed an acute rabbit model imitating these defects. Anesthetized rabbits were subject to cervical vagotomy and propranolol (1 mg/kg i.v.) pretreatment, thus eliminating vagally and sympathetically mediated cardiac responses, while maintaining the responsiveness of the peripheral circulation to these reflexes ("V-B" animals). Responses to drugs were altered in V-B compared with normal animals: Ouabain (5-50 micrograms/kg) increased myocardial contractile force more and milrinone (30-300 micrograms/kg) less, yet it increased the heart rate more; the reflex tachycardia to nitroprusside (1-10 micrograms/kg/min) was blunted and spirapril (0.1 and 1 mg/kg, all i.v.) decreased the central venous pressure only in V-B animals. Several drug effects were thus strongly modulated by autonomic dysfunction and responses of V-B animals were closer to those of heart failure patients than the responses of the normal animals, especially for milrinone.

Topics: Animals; Autonomic Nervous System; Cardiovascular Agents; Disease Models, Animal; Enalapril; Heart Failure; Heart Rate; Milrinone; Myocardial Contraction; Nitroprusside; Ouabain; Propranolol; Pyridones; Rabbits; Vagotomy; Vasodilator Agents

Angiotensin converting enzyme inhibitors (ACEI) are believed to protect remnant kidney, but all previous studies used the ligation model which causes severe hypertension, and very few have compared drugs in rats having similar control of blood pressure (BP). We compared rats with uremia obtained by 70% excision of total renal mass, a model which causes mild, late hypertension. Study I compared the effects of enalapril (E), cicletanine (C) and placebo (P) in uremic (U) rats fed a 0.50% (normal-high) Na diet. Study II compared the effects of E, C, P, and guanfacine (G) in U rats fed a diet restricted to 0.25% Na (normal-low). In study I, UP rats developed progressive hypertension (140, 146, 160 and 166 mm Hg at 3, 6, 9 and 12 weeks), proteinuria (240 mg/day at 9 and 12 weeks) which were not affected by E or C. The occurrence of end-stage renal disease (ESRD) led to the sacrifice of all rats after three months. All three groups had similar severe renal lesions (over 25% sclerosed glomeruli in 5 of 10 UP, 9 of 14 UE, 7 of 14 UC rats, with huge cystic tubular dilatations). In study II, rats could be sacrificed later (6 months) and had evidence of less severe renal disease. All the drugs tested prevented hypertension throughout the study (P less than 0.001), with lowest values in UE rats. E and G, but not C, reduced proteinuria. Renal damage was reduced with E and G, but not with C, despite similar BP in C and G rats. Thus, in contrast with what was obtained in the ligation model, ACEI affected neither the BP nor the renal lesions of rats made uremic by renal excision and fed a 0.50% Na diet. Moderate Na restriction improved the consequences of nephron loss and restored the anti-hypertensive effect of drugs. However, these drugs had a different effect on renal preservation: it was dramatic with E, good with G, and undetectable with C.

Topics: Animals; Antihypertensive Agents; Disease Models, Animal; Diuretics; Enalapril; Hypertension, Renal; Kidney; Male; Nephrectomy; Pyridines; Rats; Rats, Wistar; Sodium, Dietary; Uremia

Adriamycin induces proteinuria and glomerular changes in rats similar to those found in human focal segmental glomerulosclerosis (FSGS). Progression of this lesion may be slowed by use of angiotensin converting enzyme inhibition. To evaluate this we injected two groups of Sprague-Dawley rats with Adriamycin (2 intravenous doses of 2 mg/kg given at an interval of 3 weeks). One group of rats received enalapril (50 mg/l) in their drinking water. Control rats were injected with saline. After 28 weeks, the mean whole kidney glomerular filtration rate was significantly less and proteinuria and sclerotic index were significantly greater in rats receiving adriamycin compared with controls (P < 0.05). Administration of enalapril did not decrease proteinuria (545 +/- 398 mg/day vs 494 +/- 325 mg/day, P >0.05) or improve the glomerular filtration rate (0.31 +/- 0.18 ml/min per g kidney weight vs 0.41 +/- 0.21 ml/min per g, P = 0.27). However, treatment with enalapril significantly reduced the mean glomerular sclerotic index compared with untreated rats (1.62 +/- 0.88 vs 0.82 +/- 0.49, P = 0.05). Enalapril may be beneficial in preserving glomerular structure in this experimental model of FSGS.

Topics: Administration, Oral; Animals; Disease Models, Animal; Doxorubicin; Enalapril; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Hemodynamics; Injections, Intravenous; Kidney; Male; Nephrosis; Organ Size; Rats; Rats, Sprague-Dawley

The aim was to compare the effects of two novel angiotensin converting enzyme (ACE) inhibitors, spirapril and zofenopril, on cardiac remodelling in rats with congestive heart failure after myocardial infarction. Spirapril contains no sulphydryl group, whereas zofenopril is a sulphydryl containing ACE inhibitor.. Experimental myocardial infarction was induced by ligation of the left coronary artery. Sham operated animals served as controls. Treatment with spirapril (2-2.5 mg.kg-1.d-1) or zofenopril (12-15 mg.kg-1.d-1) added to the drinking water was started immediately after myocardial infarction or sham operation and continued for six weeks. After the treatment period, all rats were killed. The heart was rapidly removed and perfused as described by Langendorff. Heart rate and left ventricular pressure were measured both at baseline and during stimulation with isoprenaline (6 nM). Heart and lung weights were determined.. Normotensive male Wistar rats (220-240 g) were used.. Experimental myocardial infarction considerably increased left ventricular cavity volume. Chronic treatment with either spirapril or zofenopril significantly attenuated this increase in volume. In infarcted rats, the increase in total heart and lung weight was also significantly reduced by chronic treatment with spirapril and zofenopril, indicating that these compounds reduce cardiac mass and pulmonary congestion in congestive heart failure due to myocardial infarction. There were no significant differences between treatment with spirapril and zofenopril. In the isolated and perfused rat heart, myocardial infarction significantly decreased both heart rate and left ventricular pressure. Converting enzyme inhibition only affected heart rate. Heart rate was significantly higher in infarcted animals treated with spirapril and zofenopril than in untreated infarcted animals.. Both spirapril and zofenopril attenuated ventricular enlargement and cardiac hypertrophy in rats with congestive heart failure after myocardial infarction when treatment was started in the acute phase of myocardial infarction. No additional role could be attributed to the sulphydryl moiety of zofenopril. It is also suggested that these two ACE inhibitors modify cardiac sympathetic activity in rats with congestive heart failure, but more studies are needed to confirm these findings.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Disease Models, Animal; Enalapril; Heart; Heart Rate; Isoproterenol; Male; Myocardial Infarction; Myocardium; Rats; Rats, Inbred Strains

The relationship between tubulointerstitial nephritis and proteinuria was characterized in experimental nephrosis in rats. In one group, proteinuria induced by aminonucleoside of puromycin (PAN) was reduced by using an 8% protein diet and adding the angiotensin I-converting enzyme (ACE) inhibitor enalapril to the drinking water. Two control groups were injected with saline and PAN, respectively, and fed a 27% protein diet. The first group had significantly reduced albuminuria and a definite attenuation of tubular cell injury. There was a strong positive correlation between the number of interstitial macrophages and albuminuria. The beneficial effect was reproduced by dietary-protein restriction alone, whereas ACE inhibition alone had an insignificant effect on the degree of proteinuria. Depletion of circulating T lymphocytes in one group of nephrotic rats eliminated interstitial lymphocytes but did not affect interstitial macrophage influx. Inhibition of the in situ proliferation of resident interstitial macrophages by unilateral kidney irradiation failed to change the intensity of the macrophage infiltration. Treatment of rats with sodium maleate produced proximal tubular cell toxicity but interstitial inflammation did not develop, suggesting that the latter is not a nonspecific response to tubular injury. These studies demonstrate a strong relationship between tubulointerstitial nephritis and the severity of proteinuria in experimental nephrosis.

Topics: Acute Disease; Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Division; Dietary Proteins; Disease Models, Animal; Enalapril; Female; Kidney; Lymphocyte Depletion; Macrophages; Maleates; Nephritis, Interstitial; Nephrotic Syndrome; Proteinuria; Puromycin; Rats; Rats, Inbred Lew

Increased activity of the renin-angiotensin system is thought to play a major role in the pathogenesis of salt retention and edema formation in congestive heart failure. The present study evaluates the effects of chronic inhibition of angiotensin-converting enzyme on the response to infusion of exogenous atrial natriuretic factor (ANF) in salt-retaining rats with chronic arteriovenous (a-v) fistula, an experimental model of high-output congestive heart failure. Administration of ANF in incremental doses (5-50 micrograms.kg-1.h-1) to Inactin-anesthetized, sham-operated control rats resulted in dose-dependent increases in urine flow, sodium excretion, and glomerular filtration rate, and significant decreases in mean arterial blood pressure. These effects of atrial peptide were markedly attenuated in salt-retaining rats with a-v fistula. However, chronic oral treatment with the angiotensin-converting-enzyme inhibitor enalapril restored the natriuretic response of sodium-retaining rats with a-v fistula to high doses of ANF. At a dose of 50 micrograms.kg-1.h-1, fractional excretion of Na (FENa) in a-v fistula rats given enalapril was 4.0 +/- 0.5%, which was significantly greater than that in a-v fistula rats without enalapril (0.5 +/- 0.4%, P less than 0.05) and not different from the response in sham-control rats (4.9 +/- 0.7%). The improvement in the natriuretic response after enalapril was not associated with a significant increase in GFR and occurred despite a decrease in mean arterial pressure. Moreover, chronic enalapril treatment did not significantly alter the plasma levels of immunoreactive ANF in either the sham controls or in the rats with a-v fistula.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Disease Models, Animal; Enalapril; Kidney; Rats; Rats, Inbred Strains; Renin-Angiotensin System

We compared the effects of the angiotensin-converting enzyme inhibitor enalapril and a conventional antihypertensive regimen (hydralazine and metoprolol) on kidney function, albuminuria, and glomerular ultrastructure in hypertensive diabetic and nondiabetic rats. Diabetes was induced with streptozocin at 8 wk of age in spontaneously hypertensive (SHR) rats. Antihypertensive drugs were administered in drinking water from the time of induction of diabetes in all groups. Blood pressure reduction was equal in the diabetic and nondiabetic SHR rats receiving either enalapril or hydralazine plus metoprolol. In diabetic SHR rats, there was a rise in serum creatinine after 32 wk, which did not occur in diabetic rats treated with either antihypertensive regimen or in nondiabetic rats. Both drug regimens reduced albuminuria in diabetic and nondiabetic SHR rats to a similar degree. Enalapril and the combination of hydralazine and metoprolol were associated with decreased glomerular basement membrane thickness and glomerular volume in diabetic and nondiabetic SHR rats without significant effect on fractional mesangial volume. Thus, antihypertensive therapy retards the development of albuminuria, glomerular basement membrane thickening, and glomerular hypertrophy in the rat in the presence or absence of diabetes. No specific benefit of angiotensin-converting enzyme inhibition was observed in these hypertensive models of nephropathy. Human studies comparing the effects of different classes of antihypertensive drugs on kidney function, proteinuria, and glomerular morphology are warranted.

Topics: Administration, Oral; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Drug Therapy, Combination; Enalapril; Hydralazine; Hypertension; Kidney; Kidney Glomerulus; Male; Metoprolol; Rats; Rats, Inbred SHR

We have developed marmoset models for the in vivo evaluation of primate-specific inhibitors of human renin. After acute intravenous administration to normotensive sodium-depleted marmosets, renin inhibitors of different structural types induced a maximum hypotensive response of a magnitude similar to that induced after angiotensin converting enzyme (ACE) inhibition. The response was prevented by pretreatment with an ACE inhibitor. A close relationship between the inhibition of plasma renin activity (PRA) and the fall in blood pressure was observed with most of the inhibitors. CGP 29,287, a synthetic renin inhibitor, and R-3-36-16, a monoclonal antibody, both induced a selective increase in renal blood flow similar to that induced by an ACE inhibitor. A sustained reduction in blood pressure was observed during continuous administration of CGP 29,287 or R-3-36-16 over 14 days, despite an increase in immunoreactive renin and an apparent recovery of PRA. A similar blood pressure fall and an increase in plasma renin was observed during continuous administration of an ACE inhibitor. The renin inhibitor CGP 29,287 also lowered blood pressure after acute administration to hypertensive marmosets with normal PRA. Our studies demonstrate that renin inhibitors have similar haemodynamic effects to ACE inhibitors, and indicate that they may have a similar antihypertensive efficacy.

Topics: Animals; Antibodies, Monoclonal; Blood Pressure; Callithrix; Disease Models, Animal; Enalapril; Female; Hypertension, Renal; Kidney; Male; Oligopeptides; Regional Blood Flow; Renin; Sodium

Glomerular hemodynamics measurements in rats with experimental membranous nephropathy [passive Heymann nephritis (PHN)] have demonstrated that the appearance of proteinuria 5 days after administration of anti-Fx1A antibody is temporally related to changes in the glomerular ultrafiltration coefficient (LpA). Previous studies in other models of glomerular injury have suggested a significant role for angiotensin II (ANG II) in the glomerular hemodynamic abnormalities. To evaluate the possible role of ANG II in the LpA decrease, converting enzyme inhibitor (CEI) was administered acutely or chronically (5 days before and after induction of PHN) to rats with PHN. Acute ANG II blockade produced a fall in mean arterial pressure (MAP), single-nephron glomerular filtration rate (SNGFR), absolute proximal reabsorption (APR), single-nephron plasma flow, single-nephron blood flow, and glomerular capillary hydrostatic pressure (PG); however, no changes in LpA were detected. Chronic administration of CEI (MK421, 5 mg.kg-1.day-1) in the drinking water was associated with a fall in MAP; however, both SNGFR and APR increased. PG and the transcapillary hydrostatic pressure gradient were unchanged, and LpA remained depressed. These results suggest that reduction of LpA in rats with PHN is ANG II independent and that other mechanisms are required to explain these changes in glomerular hemodynamics.

Topics: Angiotensin II; Animals; Antibodies, Monoclonal; Blood Pressure; Disease Models, Animal; Enalapril; Glomerular Filtration Rate; Kidney Tubules, Proximal; Nephritis; Nephrons; Rats; Rats, Inbred Strains; Reference Values; Renin-Angiotensin System

To evaluate whether hypertension is a cause or just an association with diabetic renal disease, diabetes was induced in both normotensive Wistar-Kyoto and spontaneously hypertensive rats (WKY and SHR). Animals were assessed monthly for 8 months before sacrifice. When compared to normotensive diabetic rats (WKY-STZ), hypertensive diabetic rats (SHR-STZ) had an earlier and more rapid rise in urinary albumin excretion. In addition, SHR-STZ had increased glomerular basement membrane thickness when compared to WKY-STZ or SHR. In a separate experiment, Enalapril therapy (35 mg/L) was administered in drinking water to WKY-STZ and SHR-STZ. Enalapril significantly reduced blood pressure in both animal groups, and this was associated with a decrease in urinary albumin excretion. The SHR-STZ model has accelerated nephropathy as determined by both functional and structural parameters. Angiotensin-converting enzyme inhibition is associated with a reduction in albuminuria in both hypertensive and normotensive models of diabetic nephropathy.

Topics: Albuminuria; Analysis of Variance; Animals; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Enalapril; Glomerular Filtration Rate; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Streptozocin; Time Factors

Functional and morphologic measurements were performed in Munich-Wistar rats after a single central venous injection of puromycin aminonucleoside (PA) or saline vehicle (sham). During phase I, PA rats exhibited overt nephrotic syndrome and impaired glomerular filtration, primarily due to a reduction in the glomerular capillary ultrafiltration coefficient. The morphologic counterpart of the latter consisted of effacement of glomerular epithelial cell foot processes and decrease in the number of filtration slit diaphragms. Administration of the angiotensin I converting enzyme inhibitor (CEI) enalapril to PA rats did not ameliorate glomerular dysfunction. During phase II, PA rats exhibited spontaneous resolution of proteinuria, impaired function, and morphologic abnormalities. However, PA rats now demonstrated marked glomerular capillary hypertension and continued, albeit lesser, reductions in the ultrafiltration coefficient. Concurrent CEI administration modestly lowered systemic arterial pressure, and normalized the glomerular capillary hydraulic pressure and ultrafiltration coefficient. Additional rats were studied during phase III, 70 wk after injection. In PA rats, prior glomerular hypertension was associated with development of recurrent proteinuria and extensive glomerular sclerosis, whereas concurrent CEI administration limited these parameters to values comparable to those in sham rats. Glomerular hypertension thus may explain the development of glomerular sclerosis and renal failure long after an episode of acute glomerular injury.

Topics: Animals; Blood Pressure; Disease Models, Animal; Enalapril; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Kidney Glomerulus; Male; Microcirculation; Nephrotic Syndrome; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Enalapril; Kidney Failure, Chronic; Kidney Glomerulus; Male; Nephrectomy; Proteinuria; Rats; Rats, Inbred Strains; Reference Values; Thromboxane-A Synthase

The angiotensin converting enzyme inhibitor, lisinopril, was studied in a cryo-injury model of chronic heart failure. This model is characterized by a progressive decrease in cardiac output starting six weeks after cryo-injury to a 30% decrease in cardiac output 10 weeks after injury. Although histological damage to the myocardial tissue, particularly in the epicardial area, was observed, no significant changes occurred in body weight, mean arterial blood pressure, heart rate or central venous pressure. Daily intraperitoneal injection of 3 mg/kg lisinopril was instituted starting four weeks after injury for a duration of six weeks. Lisinopril completely restored the cardiac output to normal values at the end of this six week period. Thus, converting enzyme inhibition appears to be an effective therapeutic agent in this model of chronic cardiac failure.

Topics: Animals; Cardiac Output; Cryosurgery; Disease Models, Animal; Enalapril; Heart Diseases; Heart Ventricles; Hemodynamics; Lisinopril; Male; Rats; Rats, Inbred Strains

To evaluate the role of angiotensin II (ANG II) in renal vasoconstriction due to ipsilateral CPUO, guinea pigs were subjected to incomplete left ureteral stenosis within the first 48 hr of life, and were given enalapril from the 14th day of life until study at 23 +/- 3 days or 8 weeks of age. Renal blood flow (RBF) was measured using radioactive microspheres, and glomerular filtration rate (GFR) was derived from inulin extraction. The number of perfused glomeruli per kidney was determined following in vivo India ink perfusion. Enalapril treatment resulted in an 83% rise in RBF of the obstructed kidney, from 2.58 +/- 0.26 to 4.73 +/- 0.48 ml/min (P less than 0.001), which was associated with a 26% increase in number of perfused glomeruli (P less than 0.01). Mean GFR of the hydronephrotic kidney increased from 0.13 +/- 0.02 to 0.37 +/- 0.10 ml/min (P less than 0.05). Enalapril had no effect on intraureteral pressure of the obstructed left kidney after 7 to 13 days of administration, and did not affect renal mass or ureteral diameter after 6 weeks of treatment. It is concluded that hemodynamic consequences of CPUO in the neonate may be attenuated by ANG converting enzyme inhibition. The primary effect of enalapril is most likely inhibition of intrarenal ANG II formation.

Topics: Angiotensin II; Animals; Animals, Newborn; Disease Models, Animal; Enalapril; Glomerular Filtration Rate; Guinea Pigs; Hemodynamics; Hydronephrosis; Kidney Glomerulus; Time Factors; Ureteral Obstruction; Vascular Resistance

CI-906 and CI-907, new orally active nonsulfhydryl angiotensin-converting enzyme inhibitors, were examined for antihypertensive effects in unanesthetized hypertensive rats and dogs. In two-kidney, one-clip Goldblatt hypertensive rats, single oral daily doses (0.03-30 mg/kg) produced dose-dependent decreases in blood pressure; a single 3 mg/kg oral dose lowered blood pressure to normotensive levels. In spontaneously hypertensive rats, 30 mg/(kg X day) orally administered for 5 consecutive days achieved the same blood pressure decrease as that obtained on the first day in the renal hypertensive rats. In diuretic-pretreated renal hypertensive dogs, a 10 mg/kg oral dose decreased blood pressure by 25%. No adverse side effects were observed with CI-906 and CI-907 in any of the conscious animals. These studies indicate that CI-906 and CI-907 are potent, orally active antihypertensive agents without any apparent limiting side effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Captopril; Dipeptides; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Enalapril; Female; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Indoles; Isoquinolines; Kinetics; Male; Quinapril; Rats; Rats, Inbred Strains; Renin-Angiotensin System; Tetrahydroisoquinolines

Topics: Administration, Oral; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Dipeptides; Disease Models, Animal; Dogs; Drug Therapy, Combination; Enalapril; Female; Hydrochlorothiazide; Hypertension; Hypertension, Renal; Male; Nephrectomy; Rats; Renin