lisinopril and Disease-Models--Animal

Angiotensin converting-enzyme (ACE) inhibitors attenuate cardiac hypertrophy and prolong survival in animal models and patients after myocardial infarction (MI). Considering the dual function of the ACE, the therapeutic efficacy of ACE inhibitors after MI implicates the renin-angiotensin system and/or the kallikrein-kinin system in the pathophysiology of postinfarction cardiac remodeling. We evaluated the role of kinins, and their potential contribution to the antiremodeling effects of ACE inhibition in this setting. Rats underwent coronary artery ligation followed by chronic B2 kinin receptor blockade with icatibant (HOE 140). Additional groups of MI rats were treated with the ACE inhibitor lisinopril, alone or in combination with icatibant. B2 kinin receptor blockade enhanced the deposition of collagen (morphometric analysis) in the left ventricular interstitial space after MI, whereas markers of cardiomyocyte hypertrophy (left ventricular weights and prepro-atrial natriuretic factor [ANF] expression) were not affected. Chronic ACE inhibition reduced collagen deposition and cardiomyocyte hypertrophy after MI. The inhibitory action of ACE inhibition on interstitial collagen was partially reversed by B2 kinin receptor blockade. However, B2 kinin receptor blockade did not attenuate the effects of ACE inhibition on cardiomyocyte hypertrophy. In conclusion, kinins inhibit the interstitial accumulation of collagen, but do not modulate cardiomyocyte hypertrophy after MI. Kinins contribute to the reduction of myocardial collagen accumulation by ACE inhibition; however, the effects of ACE inhibition on cardiomyocyte hypertrophy are related to reduced generation of angiotensin II.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Cardiomegaly; Constriction; Disease Models, Animal; Drug Therapy, Combination; Kallikrein-Kinin System; Lisinopril; Myocardial Infarction; Rats

Hypertension and hyperlipidemia are considered risk factors for Alzheimer's disease (AD) and other related dementias. Clinically approved medications typically prescribed to manage these conditions have shown an association with reduced risk of developing AD and could be explored as potential repurposed therapeutics.. We aimed to explore the effects of the pharmacological treatment with angiotensin-converting enzyme inhibitors (ACEI) and statins (STAT) on AD-related neuropathology and the potential benefits of their concurrent use.. We investigated the effect of ACEI, STAT or combination of both by exploring the transcriptomic, proteomic and tau pathology profiles after treatment in both human patients and in P301S transgenic mice (PS19) modeling tauopathies and AD. We performed bioinformatic analysis of enriched pathways after treatment.. Proteomics and transcriptomics analysis revealed proteins and genes whose expression is significantly changed in subjects receiving treatment with ACEI, STAT or combined drugs. In mice, treatment with the ACEI lisinopril significantly decreased brain levels of total tau (Tau) and phosphorylated tau (pTau)-181, while the STAT atorvastatin significantly reduced the levels of pTau-396. The combined therapy with lisinopril and atorvastatin significantly decreased Tau. Moreover, brain levels of lisinopril were negatively correlated with Tau. Among the others, CD200, ADAM22, BCAN and NCAM1 were significantly affected by treatments in both human subjects and transgenic mice.. Our findings provide significant information that may guide future investigation of the potential use of ACEI, STAT, or the combination of the two drug classes as repurposed therapies or preventive strategies for AD and other neurodegenerative diseases.

Topics: Alzheimer Disease; Angiotensin-Converting Enzyme Inhibitors; Animals; Atorvastatin; Disease Models, Animal; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lisinopril; Mice; Mice, Transgenic; Proteomics; tau Proteins

The long-term imposition of pressure overload on the cardiac tissue causes left ventricular hypertrophy (LVH) and cardiac fibrosis. Pinitol has been reported to possess antioxidant potential. The aim was to evaluate the efficacy of pinitol against pressure overload-induced cardiac hypertrophy and fibrosis in the aortic stenosis (AS) rat model. Cardiac hypertrophy was produced in Sprague-Dawley rats by abdominal aortic constriction and treated with lisinopril (15 mg/kg) or pinitol (5, 10, and 20 mg/kg). Pressure overload-induced alterations in hemodynamic and left ventricular function tests, cardiac SOD, GSH, MDA, NO, Na-K-ATPase, and mitochondrial complex enzyme levels were significantly attenuated by pinitol. The upregulated mRNA expressions of cardiac ANP, BNP, cTn-I, TNF-α, IL-1β, IL-6, Bax, Caspase-3, collagen-I, and cardiac apoptosis were markedly downregulated by pinitol. In conclusion, pinitol ameliorated pressure overload-induced LVH and fibrosis via its anti-inflammatory, antioxidant, antifibrotic, and antiapoptotic potential in experimental AS.

Topics: Animals; Cardiomegaly; Disease Models, Animal; Gene Expression Profiling; Heart Function Tests; Inositol; Lisinopril; Mitochondria, Heart; Rats; Rats, Sprague-Dawley; RNA, Messenger; Up-Regulation

Doxorubicin (DOX) is used as an anticancer drug despite its several side effects, especially its irreversible impacts on cardiotoxicity. Coenzyme Q10 (Q10) as a powerful antioxidant and lisinopril (LIS) as an angiotensin-converting enzyme inhibitor seem to provide protection against DOX-induced cardiotoxicity. Therefore, this study aimed to assess the cardioprotective effects of Q10 and LIS against DOX-induced cardiotoxicity in rats. Adult male Sprague-Dawley rats were randomly assigned into the control, LIS, Q10, DOX, DOX + LIS, and DOX + Q10 groups. On day 21, ECG was recorded and the right ventricle was dissected for evaluation of catalase activity and malondialdehyde (MDA) concentration. Additionally, the left ventricle and the sinoatrial (SA) node were dissected to assess the stereological parameters. The results of ECG indicated bradycardia and increase in QRS duration and QT interval in the DOX group compared to the control group. Meanwhile, the total volumes of the left ventricle, myocytes, and microvessels and the number of cardiomyocyte nuclei decreased, whereas the total volume of the connective tissue and the mean volume of cardiomyocytes increased in the DOX group. On the other hand, the SA node and the connective tissue were enlarged, while the volume of the SA node nuclei was reduced in the DOX group. Besides, catalase activity was lower and MDA concentration was higher in the DOX-treated group. Q10 could recover most stereological parameters, catalase activity, and MDA concentration. LIS also prevented some stereological parameters and ECG changes and improved catalase activity and MDA concentration in the DOX group. The findings suggested that Q10 and LIS exerted cardioprotective effects against DOX-induced cardiac toxicity.

Topics: Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Catalase; Disease Models, Animal; Doxorubicin; Electrocardiography; Heart Conduction System; Heart Diseases; Heart Rate; Lisinopril; Male; Malondialdehyde; Myocytes, Cardiac; Rats, Sprague-Dawley; Ubiquinone

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

Targeted overexpression of angiotensin-converting enzyme (ACE), an amyloid-β protein degrading enzyme, to brain resident microglia and peripheral myelomonocytes (ACE10 model) substantially diminished Alzheimer's-like disease in double-transgenic APPSWE/PS1ΔE9 (AD+) mice. In this study, we explored the impact of selective and transient angiotensin-converting enzyme overexpression on macrophage behaviour and the relative contribution of bone marrow-derived ACE10 macrophages, but not microglia, in attenuating disease progression. To this end, two in vivo approaches were applied in AD+ mice: (i) ACE10/GFP+ bone marrow transplantation with head shielding; and (ii) adoptive transfer of CD115+-ACE10/GFP+ monocytes to the peripheral blood. Extensive in vitro studies were further undertaken to establish the unique ACE10-macrophage phenotype(s) in response to amyloid-β1-42 fibrils and oligomers. The combined in vivo approaches showed that increased cerebral infiltration of ACE10 as compared to wild-type monocytes (∼3-fold increase; P < 0.05) led to reductions in cerebral soluble amyloid-β1-42, vascular and parenchymal amyloid-β deposits, and astrocytosis (31%, 47-80%, and 33%, respectively; P < 0.05-0.0001). ACE10 macrophages surrounded brain and retinal amyloid-β plaques and expressed 3.2-fold higher insulin-like growth factor-1 (P < 0.01) and ∼60% lower tumour necrosis factor-α (P < 0.05). Importantly, blood enrichment with CD115+-ACE10 monocytes in symptomatic AD+ mice resulted in pronounced synaptic and cognitive preservation (P < 0.05-0.001). In vitro analysis of macrophage response to well-defined amyloid-β1-42 conformers (fibrils, prion rod-like structures, and stabilized soluble oligomers) revealed extensive resistance to amyloid-β1-42 species by ACE10 macrophages. They exhibited 2-5-fold increased surface binding to amyloid-β conformers as well as substantially more effective amyloid-β1-42 uptake, at least 8-fold higher than those of wild-type macrophages (P < 0.0001), which were associated with enhanced expression of surface scavenger receptors (i.e. CD36, scavenger receptor class A member 1, triggering receptor expressed on myeloid cells 2, CD163; P < 0.05-0.0001), endosomal processing (P < 0.05-0.0001), and ∼80% increased extracellular degradation of amyloid-β1-42 (P < 0.001). Beneficial ACE10 phenotype was reversed by the angiotensin-converting enzyme inhibitor (lisinopril) and thus was dependent on angiotensin-converting enzyme catalytic activity. Fur

Topics: Adoptive Transfer; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Angiotensin-Converting Enzyme Inhibitors; Animals; Bone Marrow Transplantation; Brain; Disease Models, Animal; In Vitro Techniques; Insulin-Like Growth Factor I; Lisinopril; Macrophages; Mice; Mice, Transgenic; Microglia; Monocytes; Nitric Oxide Synthase Type II; Peptide Fragments; Peptidyl-Dipeptidase A; Plaque, Amyloid; Presenilin-1; Tumor Necrosis Factor-alpha

To investigate the prevention of cardiac remodelling and inflammatory immune response after myocardial infarction (MI) via ACEI regulating dendritic cells (DCs), we explored whether the protective effect of ACEI was repressed under hyperlipidemic environment. In vivo, the survival rate and left ventricular function of the mice were recorded on day 7 after MI. Tissue samples of the myocardium, spleen, bone marrow and peripheral blood were assessed for Ang II concentration, inflammatory cytokines and DCs expression. In vitro, DCs were treated with ox-LDL + Ang II, simulating the internal environment of MI in ApoE

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Apolipoproteins E; Dendritic Cells; Disease Models, Animal; Heart; Humans; Hyperlipidemias; Lipoproteins, LDL; Lisinopril; Mice; Mice, Knockout; Myeloid Differentiation Factor 88; Myocardial Infarction; Myocardium; NF-kappa B; Signal Transduction; Toll-Like Receptor 4; Ventricular Remodeling

The Renin-Angiotensin System (RAS) possesses a counter-regulatory axis composed of angiotensin converting enzyme (ACE)2, angiotensin-(1-7) [Ang-(1-7)] and the Mas receptor, which opposes many AT1-receptor-mediated effects of ligand angiotensin II. Ang-(1-7), as a ligand of the Mas receptor, has inhibitory effects on renal inflammation and fibrosis in experimental diabetes. However, Ang-(1-7) has a short half-life in plasma, which may render it unsuitable for use in clinics. Here, we investigated the effects of the lanthionine-stabilized Ang-(1-7), cyclic (c)Ang-(1-7), a lanthipeptide that is more peptidase-resistant than the linear peptide, in BTBR ob/ob mice with type 2 diabetic nephropathy. BTBR ob/ob mice received vehicle, cAng-(1-7), or the ACE inhibitor lisinopril. The treatment started at ten weeks of age, when the animals had already developed albuminuria, and ended at 19-20 weeks of age. cAng-(1-7) limited albuminuria progression, and limited podocyte dysfunction similarly to lisinopril. cAng-(1-7), unlike lisinopril, reduced glomerular fibrosis and inflammation, and counteracted glomerular capillary rarefaction. Furthermore, when cAng-(1-7) was combined with lisinopril, a superior antiproteinuric effect than with lisinopril alone was found, in association with better preservation of podocyte proteins and amelioration of capillary density. Thus, adding cAng-(1-7) to ACE-inhibitor therapy could benefit those diabetic patients who do not respond completely to ACE-inhibitor therapy.

Topics: Alanine; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Drug Therapy, Combination; Half-Life; Humans; Kidney Glomerulus; Lisinopril; Male; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Peptide Fragments; Peptides, Cyclic; Proteinuria; Sulfides

Progress in research and developing therapeutics to prevent diabetic kidney disease (DKD) is limited by a lack of animal models exhibiting progressive kidney disease. Chronic hypertension, a driving factor of disease progression in human patients, is lacking in most available models of diabetes. We hypothesized that superimposition of hypertension on diabetic mouse models would accelerate DKD. To test this possibility, we induced persistent hypertension in three mouse models of type 1 diabetes and two models of type 2 diabetes by adeno-associated virus delivery of renin (ReninAAV). Compared with LacZAAV-treated counterparts, ReninAAV-treated type 1 diabetic Akita/129 mice exhibited a substantial increase in albumin-to-creatinine ratio (ACR) and serum creatinine level and more severe renal lesions. In type 2 models of diabetes (C57BKLS

Topics: Animals; Antihypertensive Agents; Creatinine; Dependovirus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Female; Genetic Vectors; Hypertension; Hypoglycemic Agents; Janus Kinases; Lac Operon; Lisinopril; Male; Mice; Nephrectomy; Nitric Oxide Synthase Type III; Renin; Rosiglitazone; Serum Albumin; Severity of Illness Index; Signal Transduction; STAT Transcription Factors

Patients with chronic kidney disease (CKD) have been reported to benefit from different types of exercises. It has also been shown that the ACE inhibitor lisinopril, and the natural product curcumin are also beneficial in different models of CKD in rats. We assessed the influence of moderate swimming exercise (SE) on rats with adenine-induced CKD, and tested the possible effects of lisinopril and/or curcumin thereon using several physiological, biochemical, histopathological and immunohistochemical parameters. Rats (either sedentary or subjected to SE) were randomly divided into several groups, and given for five weeks either normal food or food mixed with adenine (0.25% w/w) to induce CKD. Some of these groups were also concomitantly treated orally with curcumin (75 mg/kg), or lisinopril (10 mg/kg) and were subjected to moderate SE (45 min/day three days each week). Rats fed adenine showed the typical biochemical, histopathological signs of CKD such as elevations in blood pressure, urinary albumin / creatinine ratio, and plasma urea, creatinine, indoxyl sulfate and phosphorus. SE, curcumin or lisinopril, given singly, significantly ameliorated all the adenine-induced actions. Administering curcumin or lisinopril with SE improved the histopathology of the kidneys, a salutary effect not seen with SE alone. Combining SE to the nephroprotective agents' curcumin or lisinopril might offer additional nephroprotection.

Topics: Adenine; Animals; Antioxidants; Blood Pressure; Creatinine; Curcumin; Disease Models, Animal; Female; Immunohistochemistry; Indican; Kidney; Lisinopril; Physical Conditioning, Animal; Protective Agents; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Serum Albumin; Swimming; Urea

The aim of this work was to assess the possible beneficial effects of aqueous extracts of Hibiscus sabdariffa L. calyces and anthocyanins isolated therefrom in an adenine-induced chronic kidney disease (CKD) model.. Rats were orally given, for 28 consecutive days, either adenine alone or together with either aqueous extract of H. sabdariffa calyces (5 and 10%) or anthocyanins (50, 100 and 200 mg/kg of anthocyanin concentrate). For comparative purposes, two groups of rats were given lisinopril (10 mg/kg).. When either H. sabdariffa aqueous extract or the anthocyanins isolated from it was administered along with adenine, the adverse effects of adenine-induced CKD were significantly lessened, mostly in a dose-dependent manner. The positive effects were similar to those obtained by administration of lisinopril.. The results obtained show that both H. sabdariffa and its anthocyanins could be considered as possible promising safe dietary agents that could be used to attenuate the progression of human CKD. This could have added significance as H. sabdariffa tea is widely consumed in many parts of Africa and Asia and is thus readily available.

Topics: Adenine; Administration, Oral; Animals; Anthocyanins; Disease Models, Animal; Dose-Response Relationship, Drug; Hibiscus; Lisinopril; Male; Plant Extracts; Rats; Rats, Wistar; Renal Insufficiency, Chronic

The current study sought to clarify the role of bone marrow derived mesenchymal stem cells (BM-MSCs) and adipose tissue derived mesenchymal stem cells (AD-MSCs) in repressing nephropathy in the experimental model. Moreover, the aim of this work was extended to compare between stem cells role and angiotensin converting enzyme inhibitor in kidney repair.. Isolation and preparation of MSCs culture, flow cytometry using CD34, CD44 and CD105 cell surface markers, biochemical analyses for determination of serum creatinine, urea, transforming growth factor β (TGF-β), cystatin C (CYS-C) and urinary N-Acetyl-ß-D-Glucosaminidase (UNAG), and histopathological investigation of kidney tissue sections were performed.. The results of the present study revealed that single intravenous infusion of MSCs either derived from bone marrow or adipose tissue was able to enhance renal reparative processes through significantly decreased serum creatinine, urea, TGF-β and CYS-C levels as well as UNAG level and significantly increase glomerular filtration rate. Additionally, the histopathological investigations of kidney tissues showed that MSCs have significant regenerative effects as evidenced by the decrease in focal inflammatory cells infiltration, focal interstitial nephritis and congested glomeruli as well as degenerated tubules.. The current data provided distinct evidence about the favourable impact of AD-MSCs and BM-MSCs in attenuation of cyclosporine-induced nephropathy in rats through their ability to promote functional and structural kidney repair via transdifferentiation.

Topics: Adipogenesis; Adipose Tissue; Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Bone Marrow Cells; Cell Lineage; Cell Transdifferentiation; Cells, Cultured; Chondrogenesis; Cyclosporine; Disease Models, Animal; Female; Kidney; Kidney Diseases; Lisinopril; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Osteogenesis; Rats, Wistar; Regeneration; Sex-Determining Region Y Protein; Time Factors

The present study investigated the effect of lisinopril on experimental autoimmune myocarditis (EAM) in rats, a histologically similar model to human acute myocarditis.. Twenty four, six week-old male Wistar rats were randomly allocated into 4 groups of 6 rats each. Group I received no treatment. Group II received lisinopril at a dose of 15 mg/kg/day suspended in 1 ml of 2% gum acacia daily, from day 1 to day 21. To induce myocarditis, animals of groups III and IV were injected by 1 mg of porcine cardiac myosin on days 1 and 8. In addition, animals of group IV received lisinopril in gum acacia daily, from day 1 to day 21. All rats were sacrificed on day 21. Serum levels of creatine phosphokinase, troponin-T, tumor necrosis factor-α and interleukin-6 were estimated. Hearts were processed for histopathological, as well as immunohistochemical study for thioredoxin (TRX) immunoreactivity.. The wall of hearts from rats of myocarditis-lisinopril group showed mild focal myocarditis and a significant decrease of the mean percentage of pyknotic nuclei in cardiomyocytes, coincident with a significant decrease in serum biomarkers levels and TRX immunoreactivity, compared to myocarditis group.. The present study suggested a cardio-protective effect of lisinopril on acute EAM in rats, probably through a mechanism related to its suppressive effect on angiotensin II formation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autoimmune Diseases; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Heart; Immunohistochemistry; Lisinopril; Male; Myocarditis; Random Allocation; Rats; Rats, Wistar

Garlic capsule (GAR) and/or selenium- vitamin A, C, E (S-VACE) might be useful in the treatment of lung diseases. The present study evaluated the toxicity of lisinopril (LIS) in the lungs of male rats and the reversal effect of GAR and/or selenium-vitamins A, C, and E (S-VACE).. Group I served as the control, whereas animals in groups II, III, IV, and V received 28 mg of LIS/kg body weight by gavage. Group III was co-treated with GAR at a therapeutic dosage of 250 mg/kg body weight per day. Group IV was co-treated with S-VACE at dosage of 500 mg/kg body weight per day. Lastly, group V was co-treated with GAR and S-VACE at dosages of 250 and 500 mg/kg body weight per day, respectively. The experiment lasted for 8 days (sub-acute exposure).. Administration of therapeutic dose of LIS to male rats depleted enzymatic antioxidants (superoxide dismutase and catalase) and cellular adenosine triphosphate content with concomitant increase in lipid peroxidation. Histopathology examination showed damage to the epithelial cells of the airways. These effects were prevented by both single and combination treatment of GAR and S-VACE in male rats with LIS-induced lung toxicity.. We therefore concluded that the combination of GAR and S-VACE can be a novel therapy for the management of lung diseases in humans.

Topics: Adenosine Triphosphate; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Garlic; Lipid Peroxidation; Lisinopril; Lung Diseases; Male; Rats; Rats, Wistar; Respiratory Mucosa; Selenium; Vitamin A; Vitamin E; Vitamins

Combined treatment with an angiotensin-converting enzyme inhibitor and a mineralocorticoid receptor (MR) antagonist improved cardiac and skeletal muscle function and pathology in a mouse model of Duchenne muscular dystrophy. MR is present in limb and respiratory skeletal muscles and functions as a steroid hormone receptor.. The goals of the current study were to compare the efficacy of the specific MR antagonist eplerenone with the non-specific MR antagonist spironolactone, both in combination with the angiotensin-converting enzyme inhibitor lisinopril.. Three groups of n=18 dystrophin-deficient, utrophin-haploinsufficient male mice were given chow containing: lisinopril plus spironolactone, lisinopril plus eplerenone, or no drug, from four to 20 weeks-of-age. Eighteen C57BL/10 male mice were used as wild-type controls.. Treatment with specific and non-specific MR antagonists did not result in any adverse effects to dystrophic skeletal muscles or heart. Both treatments resulted in similar functional and pathological improvements across a wide array of parameters. MR protein levels were not reduced by treatment.. These data suggest that spironolactone and eplerenone show similar effects in dystrophic mice and support the clinical development of MR antagonists for treating skeletal muscles in Duchenne muscular dystrophy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Eplerenone; Gene Knockdown Techniques; Heart; Lisinopril; Male; Mice; Mice, Inbred mdx; Mineralocorticoid Receptor Antagonists; Muscle, Skeletal; Muscular Dystrophy, Animal; Myocardium; Spironolactone; Treatment Outcome; Utrophin

Hepatic fibrosis results in defective liver regeneration following partial hepatectomy. Angiotensin converting enzyme (ACE) inhibitors can enhance liver regeneration and are also involved in the reduction of hepatic fibrosis. The present study has been conducted to evaluate the potential effect of an ACE inhibitor, lisinopril, on the morphological and biochemical aspects of fibrotic liver regeneration.. Eight-week old female Sprague Dawley rats were made fibrotic by intragastric carbon tetrachloride treatment. Rats were given saline or lisinopril (1 mg/kg) orally for 1 week and were subjected to sham surgery or two-third partial hepatectomy. Liver regenerative and functional capacities were determined 48 hours post surgery.. Lisinopril administration did not affect the regeneration rate, proliferation cell nuclear antigen count, and hepatocellular area of fibrotic livers following partial hepatectomy. No statistically significant difference between treated and control rats regarding mitotic count, hepatocyte nuclear area, and binuclear hepatocyte frequency was observed. Serum biochemical analysis showed that lisinopril non-significantly decreased the partial hepatectomy induced elevated levels of alanine aminotransferase, aspartate transaminase, and alkaline phosphatase whereas lactate dehydrogenase and total bilirubin levels were significantly reduced. No marked reduction in hepatic collagen content and alpha smooth actin positive cells was observed by lisinopril treatment.. ACE inhibitor lisinopril did not produce major histomorphological alterations in regenerating fibrotic liver following partial hepatectomy, however, it may improve its functional capability.

Topics: Alanine Transaminase; Alkaline Phosphatase; Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartate Aminotransferases; Disease Models, Animal; Female; Hepatectomy; Lisinopril; Liver; Liver Cirrhosis; Liver Regeneration; Rats; Rats, Sprague-Dawley

To investigate lisinopril effect on the contribution of nitric oxide (NO) and K(Ca) channels to acetylcholine (ACh)-induced relaxation in isolated mesenteric arteries of spontaneously hypertensive rats (SHRs). Third branch mesenteric arteries isolated from lisinopril treated SHR rats (20 mg/kg/day for ten weeks, SHR-T) or untreated (SHR-UT) or normotensive WKY rats were mounted on tension myograph and ACh concentration-response curves were obtained. Westernblotting of eNOS and K(Ca) channels was performed. ACh-induced relaxations were similar in all groups while L-NMMA and indomethacin caused significant rightward shift only in SHR-T group. Apamin and TRAM-34 (SK(Ca) and IK(Ca) channels blockers, respectively) significantly attenuated ACh-induced maximal relaxation by similar magnitude in vessels from all three groups. In the presence of L-NMMA, indomethacin, apamin and TRAM-34 further attenuated ACh-induced relaxation only in SHR-T. Furthermore, lisinopril treatment increased expression of eNOS, SK(Ca) and BK(Ca) proteins. Lisinopril treatment increased expression of eNOS, SK(Ca), BK(Ca) channel proteins and increased the contribution of NO to ACh-mediated relaxation. This increased role of NO was apparent only when EDHF component was blocked by inhibiting SK(Ca) and IK(Ca) channels. Such may suggest that in mesenteric arteries, non-EDHF component functions act as a reserve system to provide compensatory vasodilatation if (and when) hyperpolarization that is mediated by SK(Ca) and IK(Ca) channels is reduced.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Intermediate-Conductance Calcium-Activated Potassium Channels; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Lisinopril; Male; Mesenteric Arteries; Nitric Oxide; Nitric Oxide Synthase Type III; Potassium Channel Blockers; Potassium Channels, Calcium-Activated; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Small-Conductance Calcium-Activated Potassium Channels; Vasodilation; Vasodilator Agents

Angiotensin converting enzyme (ACE) inhibitors such as lisinopril, represent the front line pharmacological treatment for heart failure, which is characterised by marked left ventricular (LV) dilatation and hypertrophy. This study sought to determine whether initiating treatment with ACE inhibitors at different stages in the remodelling process would alter the efficacy of treatment.. To this end, LV size and function were determined in the aortocaval (AV) fistula model of volume overload-induced heart failure. Sprague-Dawley rats were assigned to sham, untreated AV fistula (21 weeks), AV fistula treated with lisinopril (21 weeks), or AV fistula treated with lisinopril from six to 21 weeks post-fistula groups.. Administration of lisinopril for the entire 21-week period prevented LV dilatation, attenuated myocardial hypertrophy and prevented changes in myocardial compliance and contractility, whereas delaying initiation of treatment until six weeks post-fistula attenuated LV dilatation and hypertrophy, however, the delayed onset of treatment had no beneficial effect on ventricular compliance or systolic function.. The results demonstrate differential effects that can occur with ACE inhibitors depending on the stage during the remodelling process at which treatment is administered.

Topics: Animals; Cardiomegaly; Disease Models, Animal; Heart Failure; Lisinopril; Male; Myocardial Contraction; Rats; Rats, Sprague-Dawley; Ventricular Remodeling

The somatic isozyme of ACE (angiotensin I-converting enzyme) comprises two distinct zinc-dependent catalytic domains with different substrate specificities for angiotensin I (cleaved selectively by the C-domain) and bradykinin (cleaved equally efficiently by both the N- and C-domains). Classical ACEIs (ACE inhibitors) target both domains, with side effects such as cough and angio-oedema being attributed, in part, to N-domain inhibition, probably through bradykinin accumulation. We questioned whether a novel C-domain-selective ACEI (lisW-S) has anti-hypertensive effects without influencing bradykinin status. AngII (angiotensin II)-dependent hypertension was studied in mice that express active human renin in the liver (TtRhRen). Compared with wild-type littermates, TtRhRen mice displayed cardiac hypertrophy and had significantly elevated SBP [systolic BP (blood pressure)] as determined by tail cuff sphygmomanometry (150±3 compared with 112±5 mmHg; P<0.05) and telemetry (163±3 compared with 112±2 mmHg; P<0.01). Treatment with the non-selective ACEI lisinopril (1 mg/kg of body weight per day via an osmotic mini-pump for 2 weeks) reduced SBP (127±3 compared with. 154±6; P<0.05). Similarly, treatment with the C-domain selective ACEI lisW-S (lisinopril-tryptophan; 3.6 mg/kg of body weight per day via an osmotic mini-pump for 2 weeks) reduced BP. Treatment with lisinopril or lisW-S significantly reduced levels of AngII in kidneys (~4-fold; P<0.001). Ang-(2-8) [angiotensin-2-8)] was significantly reduced by lisinopril, but not by lisW-S. Plasma bradykinin levels were significantly increased only in the lisinopril group. These data suggest that C-domain-selective ACEIs reduce BP and AngII levels similarly to classical ACEIs. C-domain-selective ACEIs have the potential to avoid undesirable effects on the bradykinin system common to classic ACEIs and may represent a novel approach to the treatment of hypertension.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Bradykinin; Cardiomegaly; Chronic Disease; Disease Models, Animal; Drug Evaluation, Preclinical; Hypertension; Hypertrophy; Kidney; Lisinopril; Mice; Mice, Transgenic

Duchenne muscular dystrophy (DMD) is an inherited disease that causes striated muscle weakness. Recently, we showed therapeutic effects of the combination of lisinopril (L), an angiotensin converting enzyme (ACE) inhibitor, and spironolactone (S), an aldosterone antagonist, in mice lacking dystrophin and haploinsufficient for utrophin (utrn(+/-);mdx, het mice); both cardiac and skeletal muscle function and histology were improved when these mice were treated early with LS. It was unknown to what extent LS treatment is effective in the most commonly used DMD murine model, the mdx mouse. In addition, current standard-of-care treatment for DMD is limited to corticosteroids. Therefore, potentially useful alternative or additive drugs need to be both compared directly to corticosteroids and tested in presence of corticosteroids. We evaluated the effectiveness of this LS combination in the mdx mouse model both compared with corticosteroid treatment (prednisolone, P) or in combination (LSP). We tested the additional combinatorial treatment containing the angiotensin II receptor blocker losartan (T), which is widely used to halt and treat the developing cardiac dysfunction in DMD patients as an alternative to an ACE inhibitor. Peak myocardial strain rate, assessed by magnetic resonance imaging, showed a negative impact of P, whereas in both diaphragm and extensor digitorum longus (EDL) muscle contractile function was not significantly impaired by P. Histologically, P generally increased cardiac damage, estimated by percentage area infiltrated by IgG as well as by collagen staining. In general, groups that only differed in the presence or absence of P (i.e. mdx vs. P, LS vs. LSP, and TS vs. TSP) demonstrated a significant detrimental impact of P on many assessed parameters, with the most profound impact on cardiac pathology.

Topics: Animals; Cardiotonic Agents; Disease Models, Animal; Diuretics; Dystrophin; Female; Gene Expression; Glucocorticoids; Humans; Lisinopril; Losartan; Male; Mice; Mice, Inbred mdx; Muscle Contraction; Muscle Weakness; Muscle, Skeletal; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Myocardium; Prednisolone; Spironolactone; Utrophin

The hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) play a critical role in the generation and maintenance of sympathetic nerve activity. The renin-angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. This study was designed to determine whether inhibition of the angiotensin-converting enzyme (ACE) in the PVN modulates cytokines and attenuates oxidative stress (ROS) in the RVLM, and decreases the blood pressure and sympathetic activity in renovascular hypertensive rats. Renovascular hypertension was induced in male Sprague-Dawley rats by the two-kidney one-clip (2K1C) method. Renovascular hypertensive rats received bilateral PVN infusion with ACE inhibitor lisinopril (LSP, 10μg/h) or vehicle via osmotic minipump for 4weeks. Mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma proinflammatory cytokines (PICs) were significantly increased in renovascular hypertensive rats. The renovascular hypertensive rats also had higher levels of ACE in the PVN, and lower level of interleukin-10 (IL-10) in the RVLM. In addition, the levels of PICs, the chemokine MCP-1, the subunit of NAD(P)H oxidase (gp91(phox)) and ROS in the RVLM were increased in hypertensive rats. PVN treatment with LSP attenuated those changes occurring in renovascular hypertensive rats. Our findings suggest that the beneficial effects of ACE inhibition in the PVN in renovascular hypertension are partly due to modulation cytokines and attenuation oxidative stress in the RVLM.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Antioxidants; Arterial Pressure; Chemokine CCL2; Cytokines; Disease Models, Animal; Hypertension, Renovascular; Inflammation Mediators; Infusions, Parenteral; Interleukin-10; Interleukin-1beta; Lisinopril; Male; Medulla Oblongata; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Paraventricular Hypothalamic Nucleus; Peptidyl-Dipeptidase A; Rats; Reactive Oxygen Species; Sympathetic Nervous System; Time Factors

Angiotensin-(1-12) [ANG-(1-12)], a new member of the renin-angiotensin system, is recognized as a renin independent precursor for ANG II. However, the processing of ANG-(1-12) in the circulation in vivo is not fully established. We examined the effect of angiotensin converting enzyme (ACE) and chymase inhibition on angiotensin peptides formation during an intravenous infusion of ANG-(1-12) in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). WKY and SHR were assigned to a short ANG-(1-12) infusion lasting 5, 15, 30, or 60 min (n = 4-10 each group). In another experiment WKY and SHR were assigned to a continuous 15-min ANG-(1-12) infusion with pretreatment of saline, lisinopril (10 mg/kg), or chymostatin (10 mg/kg) (n = 7-13 each group). Saline or lisinopril were infused intravenously 15 min before the administration of ANG-(1-12) (2 nmol·kg(-1)·min(-1)), whereas chymostatin was given by bolus intraperitoneal injection 30 min before ANG-(1-12). Infusion of ANG-(1-12) increased arterial pressure and plasma ANG-(1-12), ANG I, ANG II, and ANG-(1-7) levels in WKY and SHR. Pretreatment with lisinopril caused increase in ANG-(1-12) and ANG I and large decreases in ANG II compared with the other two groups in both strains. Pretreatment of chymostatin had no effect on ANG-(1-12), ANG I, and ANG II levels in both strains, whereas it increased ANG-(1-7) levels in WKY. We conclude that ACE acts as the primary enzyme for the conversion of ANG-(1-12) to smaller angiotensin peptides in the circulation of WKY and SHR and that chymase may be an ANG-(1-7) degrading enzyme.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Chymases; Disease Models, Animal; Hypertension; Infusions, Intravenous; Lisinopril; Male; Oligopeptides; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Diminishing the activity of the renin-angiotensin system (RAS) plays a pivotal role in the treatment of heart failure. In addition to angiotensin converting enzyme (ACE) inhibitors and angiotensin-receptor blockers, direct renin inhibition has emerged as a potential adjunctive treatment to conventional RAS blockade. We sought to determine the effectiveness of this strategy after myocardial infarction (MI) in the setting of preexisting hypertension, a common premorbid condition in patients with ischemic heart disease.. Ten-week-old female heterozygous hypertensive (mRen-2)27 transgenic rats (Ren-2), were randomized to one of five groups (n = 8 per group); sham, MI, MI + aliskiren, MI + lisinopril and MI + combination lisinopril and aliskiren. Cardiac function was assessed by echocardiography and in vivo cardiac catheterization. Untreated MI animals developed heart failure with hypotension, dilation, reduced ejection fraction (EF), and raised left ventricular end-diastolic pressure (LVEDP). Treatment with single agent treatment had only modest effect on cardiac function though combination therapy was associated with significant improvements in EF and LVEDP when compared to untreated MI animals (P < 0.05). Histologic analysis demonstrated increase extracellular matrix deposition and cardiomyocyte hypertrophy in the noninfarct region of all MI groups when compared with sham operated animals (P < 0.05) that was reduced by ACE inhibitor monotherapy and combination treatment but not by aliskiren alone.. In a hypertensive rat model that underwent experimental MI, EF, and LVEDP, key functional indices of heart failure, were improved by treatment with combination ACE and direct renin inhibition when compared with either agent used alone.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Catheterization; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Female; Fumarates; Heart Failure; Hypertension; Lisinopril; Myocardial Infarction; Myocardium; Random Allocation; Rats; Rats, Transgenic; Recovery of Function; Renin; Renin-Angiotensin System; Stroke Volume; Ventricular Function, Left; Ventricular Pressure; Ventricular Remodeling

The present study was undertaken to scientifically evaluate, validate and compare the cardioprotective effects of lisinopril (Lsp), an angiotensin converting enzyme (ACE) inhibitor and vitamin E (Vit E), an antioxidant in the setting of ischemia and reperfusion (I-R) injury. An open chest left anterior descending coronary artery occlusion and reperfusion induced myocardial injury cardiotoxicity model was used in the present study. Hemodynamic, biochemical and histopathological assessment of myocardial injury was undertaken. Pre-treatment (1 month) with Lsp (50 mg/kg) and Vit E (100 mg/kg) to healthy experimental controls did not adversely affect the histopathological architecture of the myocardium as well as the baseline antioxidant parameters. Subsequent to I-R injury, Lsp demonstrated modest antioxidant effects, superior recovery in left ventricular function as compared to the control IR group. Histopathological and biochemical assessment of injury confirmed the myocardial salvaging effect of this intervention. The cardioprotection afforded by Lsp was found to be superior as compared to Vit E treatment.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Arterial Pressure; Blood Pressure; Disease Models, Animal; Heart Rate; Lisinopril; Male; Myocardial Reperfusion Injury; Protective Agents; Rats; Rats, Wistar; Ventricular Function, Left; Vitamin E

Vascular dementia and hypertension are increasing day by day, with a high degree of co-occurrence. Tremendous amount of research work is required so that new pharmacological agents may be identified for their appropriate therapeutic utility to combat different dementing disorders.. This study investigates the effect of natrium diethyldithiocarbamate trihydrate (NDDCT), a nuclear factor kappa-B (NF-κB) inhibitor, as well as lisinopril, an angiotensin converting enzyme (ACE) inhibitor, on deoxycorticosterone acetate (DOCA) hypertension-induced vascular dementia in rats.. DOCA was used to induce hypertension and associated vascular dementia. Morris water maze (MWM) was used for testing learning and memory. Endothelial function was assessed by acetylcholine-induced endothelium-dependent relaxation of aortic strips. Different biochemical estimations were used to assess oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, and brain glutathione), nitric oxide levels (serum nitrite/nitrate), and cholinergic activity (brain acetyl cholinesterase activity).. DOCA treatment significantly raised the mean arterial blood pressure of rats, and these hypertensive rats performed poorly on MWM, reflecting impairment of learning and memory. DOCA treatment also impaired vascular endothelial function and different biochemical parameters. Treatments of NDDCT as well as lisinopril significantly attenuated DOCA hypertension-induced impairment of learning and memory, endothelial dysfunction, and changes in various biochemical levels.. DOCA-salt hypertension induces vascular dementia in rats. NF-κB as well as ACE inhibitors may be considered as potential pharmacological agents for the management of hypertension-induced vascular dementia.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Dementia, Vascular; Desoxycorticosterone; Disease Models, Animal; Ditiocarb; Endothelium, Vascular; Hypertension; Lisinopril; Male; Maze Learning; Memory; NF-kappa B; Oxidative Stress; Rats; Rats, Wistar

Proteinuria is an important cause of progressive tubulo-interstitial damage. Whether proteinuria could trigger a renal lymphangiogenic response has not been established. Moreover, the temporal relationship between development of fibrosis, inflammation and lymphangiogenesis in chronic progressive kidney disease is not clear yet. Therefore, we evaluated the time course of lymph vessel (LV) formation in relation to proteinuria and interstitial damage in a rat model of chronic unilateral adriamycin nephrosis. Proteinuria and kidneys were evaluated up to 30 weeks after induction of nephrosis. LVs were identified by podoplanin/VEGFR3 double staining. After 6 weeks proteinuria was well-established, without influx of interstitial macrophages and myofibroblasts, collagen deposition, osteopontin expression (tubular activation) or LV formation. At 12 weeks, a ∼3-fold increase in cortical LV density was found (p<0.001), gradually increasing over time. This corresponded with a significant increase in tubular osteopontin expression (p<0.01) and interstitial myofibroblast numbers (p<0.05), whereas collagen deposition and macrophage numbers were not yet increased. VEGF-C was mostly expressed by tubular cells rather than interstitial cells. Cultured tubular cells stimulated with FCS showed a dose-dependent increase in mRNA and protein expression of VEGF-C which was not observed by human albumin stimulation. We conclude that chronic proteinuria provoked lymphangiogenesis in temporal conjunction with tubular osteopontin expression and influx of myofibroblasts, that preceded interstitial fibrosis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Line; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Humans; Kidney Diseases; Kidney Tubules; Lisinopril; Lymphangiogenesis; Lymphatic Vessels; Male; Proteinuria; Rats; Vascular Endothelial Growth Factor C

Nearly universal cardiomyopathy in Duchenne muscular dystrophy (DMD) contributes to heart failure and death. Because DMD patients show myocardial fibrosis well before functional impairment, we postulated that earlier treatment using drugs with antifibrotic effect may be beneficial.. Three groups of 10 utrn(+/-);mdx, or "het" mice, deficient for dystrophin and haploinsufficient for utrophin with skeletal myopathy and cardiomyopathy that closely mimics clinical DMD were studied. One het group received spironolactone and lisinopril starting at 8 weeks of life (het-treated-8); a second received the same starting at 4 weeks of life (het-treated-4), and the third het group was untreated. At 20 weeks, all mice had normal ejection fractions though circumferential strain rate was abnormal (-0.21±0.08) in untreated hets. This improved to -0.40±0.07 in het-treated-8 mice (P=0.003) and further improved to -0.56±0.10 in het-treated-4 mice (P=0.014 for het-treated-4 versus het-treated-8). Treated mice showed less cardiomyocyte damage, with a 44% reduction in intracardiomyocyte serum immunoglobulin G localization in het-treated-8 mice (P<0.0001) and a further 53% reduction in het-treated-4 mice (P=0.0003 versus het-treated-8); matrix metalloproteinases were similarly reduced. Cardiac, limb, and diaphragm function by ex vivo muscle testing remained at 80% of normal with early treatment compared to a decline to 40% of normal skeletal muscle function without treatment.. These findings offer clinically available medications with proven antifibrotic effect as a new therapeutic strategy in DMD. Early initiation greatly attenuated myocardial disease and, for the first time with these drugs, improved skeletal myopathy. Thus, early initiation of such agents warrants further clinical evaluation to maintain ambulatory, respiratory, and cardiac function for patients with DMD and related myopathies.

Topics: Animals; Cardiac Imaging Techniques; Cardiomyopathies; Cardiotonic Agents; Disease Models, Animal; Diuretics; Isoproterenol; Lisinopril; Magnetic Resonance Imaging; Mice; Mice, Inbred mdx; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Myocardium; Spironolactone

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

Angiotensin-converting enzyme (ACE) inhibition (ACEi) ameliorates the development of hypertension and the intrarenal ANG II augmentation in ANG II-infused mice. To determine if these effects are associated with changes in the mouse intrarenal renin-angiotensin system, the expression of angiotensinogen (AGT), renin, ACE, angiotensin type 1 receptor (AT(1)R) mRNA (by quanitative RT-PCR) and protein [by Western blot (WB) and/or immunohistochemistry (IHC)] were analyzed. C57BL/6J male mice (9-12 wk old) were distributed as controls (n = 10), ANG II infused (ANG II = 8, 400 ng x kg(-1) x min(-1) for 12 days), ACEi only (ACEi = 10, lisinopril, 100 mg/l), and ANG II infused + ACEi (ANG II + ACEi = 11). When compared with controls (1.00), AGT protein (by WB) was increased by ANG II (1.29 +/- 0.13, P < 0.05), and this was not prevented by ACEi (ACEi + ANG II, 1.31 +/- 0.14, P < 0.05). ACE protein (by WB) was increased by ANG II (1.21 +/- 0.08, P < 0.05), and it was reduced by ACEi alone (0.88 +/- 0.07, P < 0.05) or in combination with ANG II (0.80 +/- 0.07, P < 0.05). AT(1)R protein (by WB) was increased by ANG II (1.27 +/- 0.06, P < 0.05) and ACEi (1.17 +/- 0.06, P < 0.05) but not ANG II + ACEi [1.15 +/- 0.06, not significant (NS)]. Tubular renin protein (semiquantified by IHC) was increased by ANG II (1.49 +/- 0.23, P < 0.05) and ACEi (1.57 +/- 0.15, P < 0.05), but not ANG II + ACEi (1.10 +/- 0.15, NS). No significant changes were observed in AGT, ACE, or AT(1)R mRNA. In summary, reduced responses of intrarenal tubular renin, ACE, and the AT(1)R protein to the stimulatory effects of chronic ANG II infusions, in the presence of ACEi, are associated with the effects of this treatment to ameliorate augmentations in blood pressure and intrarenal ANG II content during ANG II-induced hypertension.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Disease Models, Animal; Hypertension; Kidney; Lisinopril; Male; Mice; Mice, Inbred C57BL; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Vasoconstrictor Agents

Angiotensin converting enzyme (ACE) inhibition is a common therapeutic modality in the treatment of autosomal recessive polycystic kidney disease (ARPKD). This study was designed to investigate whether chronic inhibition of ACE would have a therapeutic effect in attenuating the progression of renal cystogenesis in an orthologous rat model of ARPKD, the polycystic kidney (PCK) rat. Lisinopril (3 mg/kg per day) was administered orally for a period of 12 weeks, beginning at post-natal week 4. Lisinopril treatment resulted in an approximately 30% improvement in the collecting duct cystic indices (CT CI) of PCK animals. Activation of extracellular signal-regulated kinase 1 (ERK1) and 2 (ERK2), proliferative signaling markers, and proliferating cell nuclear antigen (PCNA), an end-point marker for proliferation, was reduced following chronic treatment with lisinopril compared to that in vehicle-treated PCK rats. To assess whether apoptotic pathways were altered due to chronic ACE inhibition, we examined p38 mitogen activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), which are markers of apoptotic signaling cascades. p38 MAPK was significantly reduced (P < 0.0001) following chronic treatment with lisinopril, but no change in the activation of SAPK/JNK could be detected by immunoblot analysis. Lisinopril treatment resulted in a significant reduction (P < 0.01) in cleaved caspase-7 levels, but not caspase-3 activity, in PCK rat kidneys compared to the vehicle-treated PCK rat kidneys. Proteinuria was completely ameliorated in the presence of chronic ACE inhibition in the lisinopril-treated rats compared with the vehicle-treated PCK rats. In all, these findings demonstrated that chronic ACE inhibition can beneficially alter proliferative and apoptotic pathways to promote therapeutic reductions in renal cyst development in ARPKD.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Blotting, Western; Cell Proliferation; Disease Models, Animal; Lisinopril; Male; Polycystic Kidney, Autosomal Recessive; Rats; Rats, Sprague-Dawley; Signal Transduction

The aim of this study was to develop and characterize a rat glomerulonephritis model, which progresses to renal fibrosis and renal failure. A single immunization of female WKY rats with more than 10 microg of recombinant alpha3(IV)NC1 protein caused severe proteinuria followed by progressive increases in plasma creatinine and blood urea nitrogen (BUN) level within 42 days. Sequential histopathological evaluation revealed crescent formation in glomeruli followed by tubular dilation and interstitial fibrosis. Hydroxyproline content and expression of type I collagen and smooth muscle actin genes in the renal cortex increased as renal dysfunction progressed. Furthermore, the TGF-beta1 level in the renal cortex also increased. In the evaluation of antinephritic agents in this model, prednisolone and mycophenolate mofetil (MMF) treatment significantly decreased plasma creatinine and BUN, and suppressed renal fibrosis and histological changes involving crescent formation, compared with the vehicle-treated nephritic rats, whereas lisinopril treatment failed to improve renal function and histology. We demonstrated that immunization of female WKY rats with a sufficient dose of recombinant alpha3(IV)NC1 induces end-stage kidney disease accompanied by renal fibrosis. The relatively short period needed to induce the disease and the high incidence of functional and structural changes were considered a great advantage of this model for clarifying the mechanisms of progressive glomerulonephritis and for evaluating agents used to treat renal failure.

Topics: Actins; Animals; Autoantigens; Collagen Type I; Collagen Type IV; Creatinine; Disease Models, Animal; Female; Gene Expression; Glomerulonephritis; Hydroxyproline; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Lisinopril; Mycophenolic Acid; Prednisolone; Rats; Rats, Inbred WKY; Recombinant Proteins; Transforming Growth Factor beta1

Salvia elegans Vahl. (Lamiaceae), recognized with the popular name of "mirto" is widely used in Mexico for healing purposes, and also them as antihypertensive treatment.. The high prevalence of this illness and the side effects of antihypertensive drugs conducted us to the evaluation of the Salvia elegans extract on angiotensin II action.. The acute response of blood pressure to angiotensin II administration was measured in mice. We also tested in vitro the inhibitory effect on angiotensin convertase enzyme. Additionally, characterization of the pharmacological effect of the extract fraction was obtained.. We obtained dose-response curve for the administration of complete extract and extract fractions. Due to the hydroalcoholic extract (SeHA) treatment blood pressure decreased significantly from systolic dose of 0.75 mg kg(-1) (p<0.05) and even had an antihypertensive effect that was greater than that treatment with losartan. SeHA extract decreased the E(max) of the AG II hypertensive effect by about 20% in both systolic and diastolic pressures, treatment with losartan also decreased the same parameter between 6% and 8% for systolic and diastolic pressures, respectively. Fractions SeF8 and SeF8-8 showed similar levels of AG II ED(50) for both pressures compared with losartan, these fractions showed major compounds with maximum absorbance peaks at 221, 289 and 330 nm typical of flavonoids. In the inhibition assay the activity of angiotensin converting enzyme (ACE), the extract SeHA showed percentage inhibition (%IACE) of 50.27+/-5.09% (n=5). SeBuOH fraction is found to have greater inhibitory capacity of achieving a IACE 78.40+/-2.24% (n=5), which was similar to the values obtained in the presence of the SeF8-22 fraction (82.61+/-1.74%) and lisinopril (87.18+/-1.16%). The changes in the value of K(M) suggest that components of the extracts and fractions were recognized by the enzyme's active site. The main compounds of the fractions SeBuOH, SeF8-22 were by flavonoid and phenyl propanoid types, according to UV absorption spectra of the fractions.. The experimental results demonstrated the antihypertensive effect of Salvia elegans and it was due to the AG II antagonism and inhibition of angiotensin converting enzyme.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Chromatography, Thin Layer; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Injections, Intravenous; Kinetics; Lisinopril; Losartan; Mice; Mice, Inbred ICR; Peptidyl-Dipeptidase A; Plant Components, Aerial; Plant Extracts; Salvia; Spectrophotometry, Ultraviolet

To investigate the effect of ACE inhibitor, lisinopril and AT1 blocker, losartan, on the obstructive pancreatitis in rat.. Acute pancreatitis in rats (n=21) was induced for a common hepatic duct were ligated proximal to its entry into the pancreas and the common bile - pancreatic duct were also ligated near its junction with the duodenum, under ether anesthesia, after which the abdomen were closed. The animals was divided in tree groups, being two treated and control group. The animals was treated with Losartan and Lisinopril at the dose of 10µg/Kg body weight per day, i.p., in a proportional volume, for five days, before and after treatment.. The inflammation, collagen deposition in the pancreas of treated animals were smaller, suggesting that the use of antihypertensive agents interfered positively in the depletion of the injury of the pancreas. Scythe showed a correlation between activity of pancreatic stellate cells (PSCs) lower in treated animals when compared to control.. The pancreatic stellate cells strength are involved in collagen production during acute pancreatitis and why antihypertensive drugs such as lisinopril and losartan may possibly have beneficial effects in reducing pancreatic fibrosis in models of experimental obstructive pancreatitis.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Collagen; Disease Models, Animal; Lisinopril; Losartan; Male; Pancreatic Stellate Cells; Pancreatitis; Random Allocation; Rats; Rats, Wistar

The extent to which endogenous angiotensin (Ang) II formation is responsible for increasing kidney Ang II content and blood pressure during Ang II-induced hypertension is unknown. To address this, mice were treated with an Ang-converting enzyme (ACE) inhibitor (ACEi) to block endogenous Ang II formation during chronic Ang II infusions. C57BL/6J male mice (8 to 12 weeks) were subjected to Ang II infusions (400 ng/kg per minute) with or without an ACEi (lisinopril, 100 mg/L in the drinking water) for 12 days. Blood pressure was monitored by tail-cuff method and telemetry. Ang II content was determined by radioimmunoanalysis. Ang II infusions increased 24-hour mean arterial pressure significantly (141.0+/-3.7 mm Hg) versus controls (110.0+/-1.0 mm Hg). ACEi prevented the increase in concentration in Ang II-infused mice (Ang II+ACEi; 114.0+/-7.4 mm Hg; P value not significant). Plasma Ang II content was significantly increased by Ang II (367+/-60 fmol/mL) versus controls (128+/-22 fmol/mL; P<0.05); plasma Ang II was not altered by ACEi alone (90+/-31) or in combination with Ang II infusions (76+/-27). Intrarenal Ang II content was significantly increased by Ang II (998+/-143 fmol/g) versus controls (524+/-60 fmol/g; P<0.05), and this was prevented by ACEi (Ang II+ACEi; 484+/-102 fmol/g; P value not significant). Thus, ACEi ameliorates the increases in blood pressure and intrarenal Ang II content caused by Ang II infusions, indicating that endogenous ACE-mediated Ang II formation plays a significant role in the increases of blood pressure and intrarenal Ang II during Ang II-induced hypertension.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Hypertension; Kidney; Lisinopril; Male; Mice; Mice, Inbred C57BL; Peptidyl-Dipeptidase A

Clinical and experimental studies suggest cross-talk between lipid metabolism and the renin-angiotensin system (RAS) in atherogenesis. The aim of this study was to explore interactions between these two systems in mediating cancer risk in type 2 diabetes.. A prospective cohort of 4,160 Chinese patients with type 2 diabetes, free of cancer at enrollment, were analyzed using Cox models. Interaction of RAS inhibitors (angiotensin I-converting enzyme inhibitors or angiotensin II receptor blockers) and statins was estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S). RERI > 0, AP > 0, or S > 1 indicates additive interaction between the two classes of drugs. Molecular mechanisms underlying these interactions were explored using a uninephrectomy (UNX) rat model with renal carcinogenesis.. During 21,992 person-years of follow-up, 190 patients developed cancer. Use of RAS inhibitors and statins in isolation or combination during follow-up was associated with reduced risk of cancer after adjustment for covariates. The multivariable RERI and AP for the additive interaction between these drug classes for cancer were significant (0.53 [95% CI 0.20-0.87] and 2.65 [0.38-4.91], respectively). In the UNX rat model, inhibition of the RAS prevented renal cell carcinoma by normalizing hydroxymethylglutaryl-CoA reductase (HMGCR) expression and the insulin-like growth factor-1 (IGF-1) signaling pathway.. Combined use of RAS inhibitors and statins may act synergistically to reduce cancer risk, possibly via HMGCR and IGF-1 signaling pathways in high-risk conditions such as type 2 diabetes.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Carcinoma, Renal Cell; Cohort Studies; Diabetes Mellitus, Type 2; Disease Models, Animal; Hong Kong; Humans; Inpatients; Insulin-Like Growth Factor I; Kidney Function Tests; Kidney Neoplasms; Lipids; Lisinopril; Neoplasms; Outpatients; Rats; Rats, Sprague-Dawley; Registries; Renin-Angiotensin System; Risk Factors

Hypertension and left ventricular (LV) hypertrophy often precede diastolic dysfunction and are risk factors for diastolic heart failure. Although pharmacologic inhibition of the renin-angiotensin system (RAS) improves diastolic function and functional capacity in hypertensive patients with LV hypertrophy, the effects of combination therapy with an angiotensin converting enzyme inhibitor (ACEi) and an angiotensin receptor blocker (ARB) are unclear.. We assessed the effects of the combined 10-week administration of lisinopril (10 mg/kg/ day, p.o.) and losartan (10 mg/kg/day, p.o.) (LIS/LOS) on diastolic function and LV structure in seven young (5 weeks), prehypertensive congenic mRen2.Lewis male rat, a model of tissue renin overexpression and angiotensin II (Ang II)-dependent hypertension compared to vehicle (VEH) treated (n = 7), age-matched rats.. Systolic blood pressures were 64% lower with the combination therapy (p < 0.001), but there were no differences in heart rate or systolic function between groups. RAS inhibition increased myocardial relaxation, defined by tissue Doppler mitral annular descent (e') by 2.2 fold (p < 0.001). The preserved lusitropy in the LIS/LOS-treated rats was accompanied by a reduction in phospholamban-to-SERCA2 ratio (p < 0.001). Despite lower relative wall thicknesses (VEH: 1.56+/-0.17 versus LIS/LOS: 0.78+/-0.05) and filling pressures, defined by the transmitral Doppler-to-mitral annular descent ratio (E/e', VEH: 28.7+/-1.9 versus LIS/LOS: 17.96+/-1.5), no differences in cardiac collagen were observed.. We conclude that the lusitropic benefit of early dual RAS blockade may be due to improved vascular hemodynamics and/or cardiac calcium handling rather than effects on extracellular matrix reduction.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Congenic; Blood Pressure; Calcium-Binding Proteins; Collagen; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Echocardiography, Doppler; Fibrosis; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; Lisinopril; Losartan; Male; Myocardial Contraction; Myocardium; Rats; Rats, Inbred Lew; Rats, Transgenic; Renin; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Ventricular Function, Left

Activation of the renin-angiotensin system (RAS) plays a critical role in the pathogenesis of heart failure (HF). We studied the effect of lisinopril (LP) and fosinopril (FP), the inhibitors of angiotensin-converting enzyme, and of losartan (LT), the antagonist of Angiotensin II receptors, on the behavior of multifunctional mast cells (MCs) under experimental HF. The inhibitors of RAS were daily injected during 4 weeks in 4 weeks after two (at 24-h interval) isoproterenol injections. MCs of different degrees of maturity were identified on paraffin sections stained with Alcian blue and Safranin. Expressiveness of HF was estimated by functional parameters with the help of echocardiogram and by morphological markers. The MC density in the myocardium of the intact rats as well as of the rats with HF, both treated and untreated with the preparations, was relatively low: from 3 to 4 cells/mm2. The MC density in the pericardium of the intact rats was several times higher than in the myocardium: 35 +/- 7 cells/mm2. The density ofpericardial MC under HF was 1.7 higher than that in the intact rats at the expense of the increase in the density of Alcian-positive immature cells (P < 0.05). The injections of LP increased the MC density still in 1.4 times at the expense of the density of Safranin-positive mature cells (P < 0.01). The injections of FP and LT had no influence on the MC density and the balance of cells of different degrees of maturity in the pericardium. 96-99% of MCs in lung were Alcian-positive cells. The density of such cells in the intact rats, in the rats with HF, and in the rats with HF treated with FP was 30 cells/mm2. The injections of LP and LT decreased the density of pulmonary MCs up to 7 cells/mm2 (P < 0.01) and 19 cells/mm2 (P < 0.05), respectively. Functional parameters of the hearts were consistent with the data of morphological analyses. Myocardium function improvement was noted only in the rats with HF treated with FP and LT. The reaction of MCs (as cell elements of "tissue" RAS) to injections of inhibitors of RAS was various in the myocardium, pericardium and lung of the rats with HF. The injections of LP stimulated maturation of the resident MCs in the pericardium and the replenishment of the population through immature cells migrating from the outside. It allows us to suppose an intensification of secretory activity of the cells. In contrast, the injections of LP and LT reduced the pulmonary MC population.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Count; Disease Models, Animal; Heart Failure; Lisinopril; Losartan; Lung; Male; Mast Cells; Myocardium; Pericardium; Rats; Rats, Wistar

The number of patients with chronic kidney disease (CKD) has continuously grown worldwide. Treatment with antihypertensive agents reduces the rate of progression of CKD, however, there is still a large unmet need to develop strategies for the treatment of CKD. Although we have previously reported that the antifibrotic agent, SMP-534 inhibits the progression of CKD, it is unknown whether combination therapy with SMP-534 and antihypertensive agent shows additive effects on CKD. In present study, we examined whether combination therapy with SMP-534 and the antihypertensive agent, lisinopril is more effective than single therapy with SMP-534 or lisinopril on five-sixths nephrectomized (5/6Nx) rat model. Combination therapy with SMP-534 (50 mg/kg) and lisinopril (5 mg/kg) significantly decreased urinary albumin excretion, blood urea nitrogen (BUN) and serum creatinine and increased creatinine clearance in 5/6Nx rats. On the other hands, single treatment with SMP-534 or lisinopril did not improve renal function at this dose. In addition, combination therapy with SMP-534 and lisinopril significantly decreased extracellular matrix (ECM) accumulation in renal glomeruli and tubulointerstitial injury. These data suggest that combination therapy with an antifibrotic agent and an antihypertensive agent may offer a new therapeutic option for suppressing the progression of CKD.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzamides; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Drug Therapy, Combination; Extracellular Matrix; Kidney; Kidney Failure, Chronic; Lisinopril; Male; Nephrectomy; Protective Agents; Rats; Rats, Sprague-Dawley

Zhao et al. demonstrated that chronic renal failure was associated with lipid redistribution in the kidney and other organs. We discuss three types of lipid redistribution in the context of inflammatory stress, which might help to explain many conflicting clinical observations in relation to lipid-mediated renal and vascular injury. An assessment of lipid redistribution may provide a new target for therapeutic intervention.

Topics: Adipocytes; Animals; Disease Models, Animal; Intra-Abdominal Fat; Kidney; Kidney Failure, Chronic; Lipid Metabolism; Lisinopril; Nephrectomy; Rats; Rats, Sprague-Dawley; Subcutaneous Fat; Time Factors

1. The present study was designed to investigate the potential antifibrotic and anti-oxidant effects of lisinopril, fosinopril and losartan in an experimental rat model of liver injury using carbon tetrachloride (CCl(4)). 2. First, the potential hepatoprotective dose of each drug was screened against CCl(4)-induced acute hepatotoxicity. Then, we chose the minimum hepatoprotective dose of each drug to further investigate the mechanisms involved in the hepatoprotection using a chronic model of hepatotoxicity induced by CCl(4). 3. Liver function was assessed in addition to histopathological examination. Furthermore, oxidative stress markers (reduced glutathione (GSH) and lipid peroxides levels) and markers of fibrosis (hydroxyproline content and liver fibrosis area) were assessed. 4. It was found that treatment of animals with different drugs concomitantly with CCl(4) significantly counteracted the changes in liver function induced by CCl(4) (except fosinopril). In addition, the drugs ameliorated the histopathological changes induced by CCl(4). All drugs significantly counteracted lipid peroxidation and GSH depletion (except fosinopril) compared with the CCl(4)-intoxicated group. Moreover, the drugs studied significantly reduced liver hydroxyproline levels and the area of fibrosis compared with the CCl(4)-intoxicated group. 5. In conclusion, the present study provides evidence for the hepatoprotective effect of lisinopril, fosinopril and losartan. Both lisinopril and losartan was found to have better hepatoprotective potential than fosinopril against CCl(4)-induced hepatotoxicity. These hepatoprotective effects can be explained on the basis of anti-oxidant and antifibrotic mechanisms, mainly enhancement of GSH and reduction of lipid peroxidation and fibrosis.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Carbon Tetrachloride; Disease Models, Animal; Dose-Response Relationship, Drug; Fosinopril; Glutathione; Hydroxyproline; Lipid Peroxidation; Lisinopril; Liver; Liver Cirrhosis; Liver Function Tests; Losartan; Male; Oxidative Stress; Rats; Renin-Angiotensin System

Proteinuria plays a pathogenic role in the development of end stage renal disease. Angiotensin converting enzyme (ACE) inhibitors lower proteinuria and are renoprotective. However, large inter-individual variation in antiproteinuric response to ACE inhibitors exists. In this study, we explored the mechanism of therapeutic resistance to an ACE inhibitor in the rat 5/6 nephrectomy model. At week 6 after 5/6 nephrectomy, treatment with lisinopril was initiated for 6 weeks. Proteinuria and blood pressure were evaluated weekly. At the end of the experiment, rats were divided into tertiles according to their antiproteinuric response: (1) responders (n=9), (2) intermediate responders (n=8) and (3) non-responders to ACE inhibitor therapy (n=9). At the start of treatment, proteinuria had progressively increased to 154 (95% confidence interval [CI]: 123-185) mg/24 h in the entire cohort, with comparable proteinuria and blood pressure in all groups. Following treatment with ACE inhibitor, proteinuria was significantly lower in the responders (68, CI: 46-89 mg/24 h) compared to the non-responders (251, CI: 83-420) mg/24 h). Similarly, blood pressure was reduced in the responders, but unaffected in the non-responders. At autopsy, renal ACE activity and renal ACE expression were significantly lower in the responders compared to the non-responders. Although lisinopril intake was comparable in all animals, urinary drug excretion was increased in the non-responders, demonstrating increased drug clearance. Average urinary lisinopril excretion was correlated with antiproteinuric response (R(2)=0.32, P=0.003). In conclusion, both pharmacodynamic and -kinetic factors account for the non-response to lisinopril. Whether these can be overcome simply by increasing drug dosage in non-responders should be investigated.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Drug Resistance; Lisinopril; Male; Nephrectomy; Peptidyl-Dipeptidase A; Proteinuria; Rats; Rats, Wistar

Angiotensin-converting enzyme (ACE) inhibitors represent the front-line pharmacological treatment of heart failure, which is characterized by left ventricular (LV) dilatation and inappropriate hypertrophy. The mechanism of action of ACE inhibitors is still unclear, but evidence suggests that they may act by influencing matrix metalloproteinase (MMP) activity. This study sought to determine whether ACE inhibitors can directly regulate MMP activity and whether this results in positive structural and functional adaptations to the heart. To this end, MMP-2 activity in LV tissue extracted from rats with an aortocaval (AV) fistula was assessed by in vitro incubation as well as in vivo treatment with captopril, lisinopril, or quinapril. Furthermore, LV size and function were determined in untreated AV fistula rats, AV fistula rats treated with lisinopril (3, 5, and 8 wk), and age-matched sham-operated controls. In vitro incubation with captopril, lisinopril, or quinapril significantly reduced MMP-2 activity, as did in vivo treatment. This occurred without a reduction in the available pool of MMP-2 protein. Long-term in vivo administration of lisinopril also prevented LV dilatation, attenuated myocardial hypertrophy, and prevented changes in myocardial compliance and contractility. The results herein demonstrate that ACE inhibitors prevent MMP-2 activity and, in so doing, represent a mechanism responsible for preventing the negative structural and functional changes that occur in the rat AV fistula model of heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Arteriovenous Shunt, Surgical; Captopril; Compliance; Disease Models, Animal; Heart Failure; Hypertrophy, Left Ventricular; Lisinopril; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Myocardial Contraction; Myocardium; Quinapril; Rats; Rats, Sprague-Dawley; Tetrahydroisoquinolines; Time Factors; Venae Cavae; Ventricular Function, Left; Ventricular Pressure; Ventricular Remodeling

Today angiotensin II inhibition is primarily used to slow the rate of progression of kidney diseases. There is evidence that these therapies can induce a partial regression of glomerular lesions. However, we do not know yet the extent of sclerotic lesion regression and whether new glomerular tissue is formed to help support the renal function. We used male Munich Wistar Fromter (MWF) rats, an experimental model for progressive kidney disease, to quantify kidney structural lesions upon angiotensin-converting enzyme (ACE) inhibition therapy. Animals were studied at 50 weeks of age, when renal function and structure are severely altered, and after a 10-week observation period, without or with treatment with lisinopril (80 mg/l in drinking water). A group of untreated Wistar rats was used as controls. With age, proteinuria, and serum creatinine worsen, but lisinopril almost normalized proteinuria and stabilized serum creatinine. Serial section analysis of whole glomerular tufts showed that at baseline, glomerulosclerosis affected the entire glomerular population, and that these changes further increased with age. Lisinopril significantly reduced incidence and extent of glomerulosclerosis, with the presence of glomerular tufts not affected by sclerosis (23% of glomeruli). Glomerular volume was not significantly affected by treatment, and glomerular mass spared from sclerosis increased from 46.9 to 65.5% upon treatment, indicating consistent regeneration of glomerular tissue. Lisinopril normalized baseline glomerular transforming growth factor-beta and alpha-smooth muscle actin overexpression, and prevented worsening of interstitial changes. Hence, ACE inhibition, which is widely used in human kidney disease, may not only halt the progression of renal failure, but also actually induce the regeneration of new renal tissue.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Capillaries; Disease Models, Animal; Disease Progression; Glomerulosclerosis, Focal Segmental; Immunohistochemistry; Kidney Glomerulus; Lisinopril; Male; Rats; Rats, Inbred Strains; Regeneration; Renal Circulation; Transforming Growth Factor beta

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Hypertrophy, Left Ventricular; Lisinopril; Losartan; Male; Myocardial Infarction; Rats; Rats, Wistar; Ventricular Remodeling

The present study was aimed to investigate the effect of ACE inhibition on trinitrobenzene sulphonic acid (TNBS)-induced colonic inflammation in rats by using captopril and lisinopril. In treatment groups, the rats were treated with ACE inhibitors, captopril or lisinopril (0.1 and 1 mg/kg/day; intraperitoneally). The drugs were given 5 min after induction of colitis and the treatment was continued for 3 days. Three days after the induction of colitis, all rats were decapitated. The distal colon was weighed and the mucosal lesions were scored at both macroscopical at microscopic levels. Malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content were assessed in tissue samples. Formation of reactive oxygen species in colonic samples was monitored by using chemiluminescence technique. Serum TNF-alphalevel was assessed in trunk blood. Captopril treatment was found to be beneficial in all parameters, except colonic glutathione content. On the other hand, although stimulation of lipid peroxidation and increase in serum TNF-alpha level were successfully prevented by lisinopril, the morphology of the lesions remained unchanged. In conclusion, sulphydryl and non-sulphydryl ACE inhibitors, captopril and lisinopril do not seem to be similarly effective in TNBS-induced colitis model at least at the doses tested in our study.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Colitis; Collagen; Colon; Disease Models, Animal; Enzyme Inhibitors; Female; Glutathione; Lisinopril; Male; Malondialdehyde; Organ Size; Peroxidase; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Time Factors; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Hypertension and arthritis are frequent comorbidities. Nonsteroidal anti-inflammatory drugs (NSAIDs) are well known to produce hypertension or attenuate the effects of antihypertensive agents in a few patients. The influence of selective NSAIDs on blood pressure and the cardiovascular and renal effects of coxibs have still to be investigated. The purpose of this study was to test the hypothesis that rofecoxib interferes with antihypertensive activity and cardiorenal protective effects of lisinopril in spontaneously hypertensive rats (SHRs).. Twenty-one unanaesthetised, male spontaneously hypertensive rats (SHRs), 16 weeks old, were randomized to receive lisinopril (LS) 15 mg/kg/d or rofecoxib (RF) 20 mg/kg/d or combination of lisinopril (LS) and rofecoxib (RF) for 2 weeks. The arterial blood pressure changes were recorded each week. The Sodium Hydrogen Exchange (NHE) activity of erythrocytes was determined 2 weeks after the study. The surviving animals were sacrificed 24 h after the last dose, and the sections of their hearts and kidneys were assessed histologically for injury by a pathologist masked to the treatment.. RF completely prevented the hypotensive effects of LS during the first week of treatment but the antihypertensive efficacy of LS was restored during the second week of treatment. The NHE in erythrocytes of 18-week-old SHRs was found to be significantly lower than the age-matched Wistar rats (P < 0.05), and LS treatment reversed these values to Wistar control in SHRs. RF was devoid of any effect on NHE of erythrocytes. The histological examination revealed that the myocardial and renal protection induced by LS was attenuated by concomitant RF therapy.. These results indicate that COX-2 inhibitors should be used judiciously in patients with history of hypertension, ischemic heart disease, or chronic renal failure.

Topics: Age Factors; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Cell Nucleus; Cyclooxygenase Inhibitors; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Erythrocytes; Heart Rate; Kidney; Lactones; Lisinopril; Men; Myocytes, Cardiac; Rats; Rats, Inbred SHR; Rats, Wistar; Sodium; Sodium-Hydrogen Exchangers; Sulfones; Toxicity Tests

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

We recently reported an involvement of peripheral angiotensin II (ANG II) in the development of both the fever and the peripheral interleukin (IL)-1beta production induced in rats by a systemic injection of lipopolysaccharide (LPS). The present study was performed to investigate whether brain ANG II contributes to the fever and IL-1beta production in the rat brain induced by i.c.v. injection of LPS. LPS (0.2 and 2 microg i.c.v.) induced dose-related fevers and increases in the brain (hypothalamus, hippocampus, and cerebellum) concentrations of IL-1beta. These effects were significantly inhibited by i.c.v. administration of either an angiotensin-converting-enzyme (ACE) inhibitor or an angiotensin type 1 (AT(1)) receptor antagonist. By contrast, the ACE inhibitor had no effect on the IL-1beta (i.c.v.)-induced fever, whereas the AT(1) receptor antagonist enhanced (rather than reduced) it. The AT(1) receptor antagonist had no effect on the brain levels of prostaglandin E(2) in rats given an i.c.v. injection of IL-1beta. These results suggest that in rats, brain ANG II and AT(1) receptors are involved in the LPS-induced production of brain IL-1beta, thus contributing to the fever induced by the presence of LPS within the brain.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Antihypertensive Agents; Brain; Disease Models, Animal; Fever; Injections; Interleukin-1; Lipopolysaccharides; Lisinopril; Losartan; Male; Rats; Rats, Wistar

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

Neovascularization in the retina and iris of diabetic patients is a major cause of severe visual loss. However, study of these lesions is compromised by the lack of a comparable diabetic rodent model. Because the vasoactive and angiogenic agent, angiotensin II, is involved in diabetic microvascular disease, we aimed to determine whether endothelial cell proliferation could be induced in the retinae and irides of hypertensive transgenic (mRen-2)27 rats that display an enhanced extra-renal renin-angiotensin system (RAS), including the eye. Six-week-old Ren-2, spontaneously hypertensive, and Sprague-Dawley rats received either streptozotocin or control vehicle and were studied for 36 weeks. Additional nondiabetic and diabetic Ren-2 rats were treated throughout with the angiotensin-converting enzyme inhibitor lisinopril (LIS) (10 mg/kg/day in drinking water). Endothelial cell proliferation was only observed in retinae and irides of diabetic Ren-2 rats and was reduced with LIS. In diabetic Ren-2, vascular endothelial growth factor (VEGF) and VEGFR-2 mRNA were increased in retinae and irides and reduced with LIS. Diabetes activated ocular renin in Ren-2 but not Sprague-Dawley rats. The diabetic Ren-2 rat is a model of intraocular endothelial cell proliferation that can be attenuated by RAS blockade via VEGF-dependent pathways. RAS blockade is a potential treatment for vision-threatening diabetic microvascular complications.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Chronic Disease; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Disease Models, Animal; Endothelial Growth Factors; Endothelium, Vascular; Eye; Female; Heterozygote; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Iris; Lisinopril; Lymphokines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Retina; RNA, Messenger; Streptozocin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors

Several factors such as proteinuria and renal fibrosis may be important in the progression of many forms of chronic renal diseases. The purposes of the current study were to investigate the progressive renal failure of the rats with surgical renal mass reduction (RMR) and the effect of the angiotensin-converting enzyme (ACE) inhibitor, lisinopril, and to document correlation of several factors associated with progressive renal failure. Rats were subtotal (5/6) nephrectomized by resection of the renal poles and sham-operated. The functional, histological and haematological changes of the rats were studied for up to 10 weeks. After 2 weeks of RMR, oral administration of lisinopril (10 mg kg(-1) per day) was performed for 8 weeks. RMR resulted in progressive renal failure with proteinuria, monocyte/macrophage (ED1+) infiltration, anaemia as assessed by haemoglobin and haematocrit (Htc), renal hypertrophy as assessed by left kidney to body weight ratio (BKW/BW), and renal fibrosis as assessed by glomerular lesions and tubulointerstitial changes. Lisinopril exhibited renoprotection with antiproteinuric effect and inhibition of monocyte/macrophage (ED1+) infiltration. However, beneficial effect of lisinopril on anaemia was not observed. At 10 weeks after surgery, severity of proteinuria positively correlated with plasma creatinine (Pcr), BKW/BW, histological damage, and systolic blood pressure, and negatively correlated with haemoglobin. Severity of tubulointerstitial changes positively correlated with Pcr and blood urea nitrogen, and negatively correlated with haemoglobin and Htc. Moreover, monocyte/macrophage (ED1+) infiltration positively correlated with severity of proteinuria and tubulointerstitial changes. These findings strongly support that proteinuria, monocyte/macrophage infiltration and renal fibrosis appear to play principal roles in the progressive renal failure with anaemia and renoprotection of ACE inhibition may be mediated by multiple actions of ACE inhibitor. The present study confirms that rats with RMR is useful to explore target molecules for renoprotective drugs and evaluate renoprotective effect of new molecular entities.

Topics: Analysis of Variance; Anemia; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Disease Models, Animal; Disease Progression; Kidney; Lisinopril; Male; Proteinuria; Rats; Rats, Wistar; Renal Insufficiency

(1) Increased vascular resistance in chronic heart failure (CHF) has been attributed to stimulated neurohumoral systems. However, local mechanisms may also importantly contribute to set arterial tone. Our aim, therefore, was to test whether pressure-induced myogenic constriction of resistance arteries in vitro--devoid of acute effects of circulating factors--is increased in CHF and to explore underlying mechanisms. (2) At 12 weeks after coronary ligation-induced myocardial infarction or SHAM-operations in rats, we studied isolated mesenteric arteries for myogenic constriction, determined as the active constriction (% of passive diameter) in response to stepwise increase in intraluminal pressure (20 - 160 mmHg), in the absence and presence of inhibitors of potentially involved modulators of myogenic constriction. (3) We found that myogenic constriction in mesenteric arteries from CHF rats was markedly increased compared to SHAM over the whole pressure range, the difference being most pronounced at 60 mmHg (24+/-2 versus 4+/-3%, respectively, P<0.001). (4) Both removal of the endothelium as well as inhibition of NO production (L-N(G)-monomethylarginine, 100 micro M) significantly increased myogenic constriction (+16 and +25%, respectively), the increase being similar in CHF- and SHAM-arteries (P=NS). Neither endothelin type A (ET(A))-receptor blockade (BQ123, 1 micro M) nor inhibition of perivascular (sympathetic) nerve conduction (tetrodotoxin, 100 nM) affected the myogenic response in either group. (5) Interestingly, increased myogenic constriction in CHF was fully reversed after angiotensin II type I (AT(1))-receptor blockade (candesartan, 100 nM; losartan, 10 micro M), which was without effect in SHAM. In contrast, neither angiotensin-converting enzyme (ACE) inhibition (lisinopril, 1 micro M; captopril, 10 micro M) or AT(2)-receptor blockade (PD123319, 1 micro M), nor inhibition of superoxide production (superoxide dismutase, 50 U ml(-1)), TXA(2)-receptor blockade (SQ29,548, 1 micro M) or inhibition of cyclooxygenase-derived prostaglandins (indomethacin, 10 micro M) affected myogenic constriction. (6) Sensitivity of mesenteric arteries to angiotensin II (10 nM - 100 micro M) was increased (P<0.05) in CHF (pD(2) 7.1+/-0.4) compared to SHAM (pD(2) 6.2+/-0.3), while the sensitivity to KCl and phenylephrine was not different. (7) Our results demonstrate increased myogenic constriction in small mesenteric arteries of rats with CHF, potentially making it an i

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Captopril; Chronic Disease; Coronary Vessels; Disease Models, Animal; Endothelium-Dependent Relaxing Factors; Endothelium, Vascular; Fatty Acids, Unsaturated; Heart; Heart Failure; Hydrazines; Imidazoles; Indomethacin; Lisinopril; Losartan; Male; Mesenteric Arteries; Nitric Oxide; omega-N-Methylarginine; Pyridines; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Superoxide Dismutase; Sympathetic Nervous System; Tetrazoles; Tetrodotoxin; Vascular Resistance

In this study, a murine model of granulomatous experimental autoimmune thyroiditis (G-EAT) was used to determine the role of TGFbeta1 in fibrosis initiated by an autoimmune inflammatory response. The fibrotic process was evaluated by staining thyroid tissue for collagen, alpha-smooth muscle actin, TGFbeta1, and angiotensin-converting enzyme (ACE), and measuring serum thyroxine in mice given anti-TGFbeta1 or the ACE inhibitor lisinopril. The role of particular inflammatory cells in fibrosis was tested by depletion experiments, and the cytokine profile in thyroids was examined by RT-PCR. Neutralization of TGFbeta1 by anti-TGFbeta1 or lisinopril resulted in less collagen deposition and less accumulation of myofibroblasts, and levels of active TGFbeta1 and ACE were reduced in thyroids of treated mice compared with those of untreated controls. Other profibrotic molecules, such as platelet-derived growth factor, monocyte chemotactic protein-1, and IL-13, were also reduced in thyroids of anti-TGFbeta1- and lisinopril-treated mice compared with those of controls. Confocal microscopy showed that CD4(+) T cells and macrophages expressed TGFbeta1. Fibrosis was reduced by injection of anti-CD4 mAb on day 12, when G-EAT was very severe (4-5+). Together, these results suggest a critical role for TGFbeta1 in fibrosis initiated by autoimmune-induced inflammation. Autoreactive CD4(+) T cells may contribute to thyroid fibrosis through production of TGFbeta1. This G-EAT model provides a new model to study how fibrosis associated with autoimmune damage can be inhibited.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antibodies, Monoclonal; Autoimmunity; CD4-Positive T-Lymphocytes; Cytokines; Disease Models, Animal; Female; Fibrosis; Gene Expression; Lisinopril; Male; Mice; Mice, Inbred DBA; RNA, Messenger; Thyroid Gland; Thyroiditis, Autoimmune; Transforming Growth Factor beta; Transforming Growth Factor beta1

Chronic diseases of the kidney have a progressive course toward organ failure. Common pathway mechanisms of progressive injury, irrespectively of the etiology of the underlying diseases, include glomerular capillary hypertension and enhanced passage of plasma proteins across the glomerular capillary barrier because of impaired permselective function. These changes are associated with podocyte injury and glomerular sclerosis. Direct evidence for causal roles is lacking, particularly for the link between intraglomerular protein deposition and sclerosing reaction. Because transforming growth factor-beta1 (TGF-beta1) is the putative central mediator of scarring, we hypothesized that TGF-beta1 can be up-regulated by protein overload of podocytes thereby contributing to sclerosis. In rats with renal mass reduction, protein accumulation in podocytes as a consequence of enhanced transcapillary passage preceded podocyte dedifferentiation and injury, increase in TGF-beta1 expression in podocytes, and TGF-beta1-dependent activation of mesangial cells. Angiotensin-converting enzyme inhibitor prevented both accumulation of plasma proteins and TGF-beta1 overexpression in podocytes and sclerosis. Albumin load on podocytes in vitro caused loss of the synaptopodin differentiation marker and enhanced TGF-beta1 mRNA and protein. Conditioned medium of albumin-stimulated podocytes induced a sclerosing phenotype in mesangial cells, an effect mimicked by TGF-beta1 and blocked by anti-TGF-beta1 antibodies. Thus, the passage of excess plasma proteins across the glomerular capillary wall is the trigger of podocyte dysfunction and of a TGF-beta1-mediated mechanism underlying sclerosis. Agents to reduce TGF-beta1, possibly combined with angiotensin blockade, should have priority in novel approaches to treatment of progressive nephropathies.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Proteins; Cell Line; Desmin; Disease Models, Animal; Disease Progression; Epithelial Cells; Humans; Immunohistochemistry; In Situ Hybridization; Kidney; Kidney Glomerulus; Lisinopril; Macrophages; Male; Mice; Microfilament Proteins; Rats; Rats, Sprague-Dawley; Sclerosis; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

Angiotensin-converting enzyme (ACE) inhibitors provide renoprotection, but there is considerable interindividual variability in therapeutic efficacy, with residual proteinuria and progressive renal function loss in many individuals. This requires additional strategies to optimize therapy response, particularly for individuals with a poor response to ACE inhibition. We studied whether co-treatment with an angiotensin II subtype 1 (AT1) receptor antagonist (AII-A) improves the individual antiproteinuric response of maximal ACE inhibition in established adriamycin nephrosis.. Rats were instituted on lisinopril (75 mg/L) six weeks after disease induction. After two weeks rats were re-stratified for residual proteinuria to continue this regimen, to a higher dose of lisinopril (150 mg/L) or to co-treatment with the AII-A L 158,809 for another four weeks. Groups on monotherapy AII-A and vehicle served as controls (all groups N=15).. Lisinopril lowered proteinuria by 63% from 741 to 246 g/day (range of percentage change -90 to +2%). Neither increasing the dose of the ACE inhibitor nor addition of AII-A to ACE inhibition improved the antiproteinuric efficacy on a group or individual level: non-responders remained non-responders. All drug categories reduced hard end-points of focal glomerulosclerosis to a similar degree.. ACE inhibition has variable renal protective efficacy in the adriamycin model. Neither increasing the dose of the ACE inhibitor beyond the optimal level nor co-treatment with AII-A overcome the individual therapy resistance. Thus, in established adriamycin nephrosis, blockade of the renin-angiotensin system at two different levels offers no additional benefit over ACE inhibition alone, either on the group or individual level.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Antineoplastic Agents; Blood Pressure; Body Weight; Disease Models, Animal; Doxorubicin; Drug Resistance; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Imidazoles; Lisinopril; Male; Nephrosis; Proteinuria; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Tetrazoles

Angiotensin-converting enzyme (ACE) inhibitor therapy given soon after disease induction uniformly prevents proteinuria in virtually all models of disease progression. This does not necessarily apply to patients with proteinuric nephropathies, who might be referred late in the course of their disease. Here we used a severe rat model of passive Heymann nephritis (PHN), which may mimic advanced phases of human membranous nephropathy, to study the response to ACE inhibitor alone or in combination with a HMG CoA reductase inhibitor (statin) that independently of the cholesterol-lowering effect influences pathways involved in inflammatory and fibrogenic processes. Therapies started when animals had massive proteinuria and renal lesions.. PHN was accelerated by uninephrectomy seven days after IV injection of rabbit anti-FX1A antibody. Four months later, when massive proteinuria and renal lesions were present, the rats were divided into five groups and daily given orally: vehicle; lisinopril 40 mg/L; lisinopril 400 mg/L; simvastatin 2 mg/kg b.i.d; or lisinopril 40 mg/L plus simvastatin. Six normal rats served as controls. Animals were sacrificed at 10 months.. By the end of the study three PHN rats died in the vehicle group, four in the group given lisinopril at 40 mg/L and two in the group at 400 mg/L, whereas all rats on simvastatin or combined therapy were alive. Blood pressure increased during time in PHN and was normalized by treatment with ACE inhibitor and combined therapy. Even at the high dose lisinopril failed to reduce proteinuria. Simvastatin only partially affected proteinuria. However, combining lisinopril with simvastatin had a remarkable antiproteinuric effect, such that at 10 months the urinary proteins were comparable to pre-treatment values and significantly lower than either the vehicle or lisinopril groups. Hypercholesterolemia of PHN rats was limited by combined therapy, and a positive correlation was found between serum cholesterol and proteinuria. Renal function was only partially ameliorated by simvastatin but significantly improved by combined therapy. Drug combination significantly limited glomerulosclerosis, tubular damage and interstitial inflammation, compared to vehicle or drugs alone. Up-regulation of monocyte chemoattractant protein-1 (MCP-1) mRNA in PHN kidneys was not affected by lisinopril, it was inhibited by 30% after simvastatin, and almost completely normalized by lisinopril plus simvastatin.. These data suggest that a combined ACE inhibitor and statin approach could represent a therapeutic option for patients with advanced renal disease in whom ACE inhibitors alone fail to lower proteinuria and injury to any substantial extent.

Topics: Alanine Transaminase; Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartate Aminotransferases; Blood Pressure; Body Weight; CD4-Positive T-Lymphocytes; Chemokine CCL2; Cholesterol; Disease Models, Animal; Drug Therapy, Combination; Eating; Glomerulonephritis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney; Lisinopril; Male; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger; Simvastatin; Triglycerides

Changes in tissue protein synthesis in hypertension have usually been measured in vitro in heart from acutely hypertensive rats without consideration of changes in atrial or pulmonary tissue or changes occurring in long-standing hypertension. The objective of the study was to investigate the in vivo changes in cardiopulmonary protein synthesis in three different rat models of chronic hypertension. Hypertension in aortic constriction, the Goldblatt model, and the bromoethylamine model were induced in rats for 30 days. At the end of the experimental period, in vivo rates of protein synthesis were measured with a flooding dose of [3H]phenylalanine (a method which effectively considers precursor pools). Concomitant measurements included quantification of contractile protein and RNA and DNA contents. Indices of protein breakdown were also assessed by selective measurement of protease activities. At the end of 30 days, aortic constriction induced marked increases in protein contents of the left ventricle, septum, left atria, and lungs. Accompanying changes included concomitant increases in RNA and DNA contents. Left ventricular myofibrillary, sarcoplasmic, and stromal protein contents increased in the aortic constriction model. Less marked changes occurred in the Goldblatt model, though the left atria were not significantly affected. In contrast, the bromoethylamine model had no effect on the protein or RNA contents of any region. In all cardiac regions of all three models, fractional rates of protein synthesis were not significantly affected. However, protein synthesis increased in the lungs of both the Goldblatt and bromoethylamine models at 30 days. Protease activities were decreased in the left ventricles of all three models at 30 days, with lysosomal protease activities declining in the aortic constriction model and cytoplasmic protease activities declining in the other two models. The failure of chronic hypertension to increase ventricular synthesis rates may represent inherent limitations in the time frame for measuring protein synthesis in vivo. However, at earlier time points (i.e., 10 days), the aortic constriction model was characterized by marked increases in left ventricular and atrial protein contents, RNA contents, and fractional rates of protein synthesis. This was consistent with the supposition that, in acute phases of hypertrophy, rates of protein synthesis increase, whereas in established hypertrophy, synthesis rates remain unchanged or decr

Topics: Animals; Aorta, Abdominal; Blood Pressure; Constriction, Pathologic; Disease Models, Animal; DNA; Endopeptidases; Ethylamines; Heart Atria; Heart Ventricles; Hypertension, Renovascular; Hypertrophy, Left Ventricular; Kidney Medulla; Lisinopril; Lung; Male; Organ Size; Protein Biosynthesis; Rats; Rats, Wistar; RNA

We have previously demonstrated that antihypertensive treatment with doxazosin (DZN), an alpha-adrenergic blocker, and lisinopril (LIS), an ACE inhibitor, reverse glomerular sclerosis in corpulent spontaneously hypertensive rats with type 2 diabetes. In this study, we examined the effects of the above-mentioned antihypertensive drugs alone and in combination on the structure of interlobular and arcuate arteries in these rats. Both male and female rats aged 6 months were treated with antihypertensive drugs for 16 weeks. Various structural parameters were evaluated by light microscopy, with the use of digital image analysis, in kidney sections stained with periodic acid-SCHIFF: Systolic blood pressure was significantly lower in treated than in untreated rats. Untreated diabetic rats had a significantly higher media/lumen ratio (smaller luminal diameter) of both arteries compared with the ratio in treated rats (for interlobular artery, 0.72+/-0.06 [no treatment], 0.49+/-0.03 [DZN treatment], 0.54+/-0.06 [LIS treatment], and 0.52+/-0.04 [combination therapy], P<0.05 to <0.001 for no treatment versus treatment; for arcuate artery, 0.66+/-0.11 [no treatment], 0.40+/-0.02 [DZN treatment], 0.39+/-0.04 [LIS treatment], and 0.40+/-0.03 [combination therapy], P<0.05 for no treatment versus treatment). Antihypertensive treatment caused significant increases in total arterial cross-sectional area, internal and external diameters, luminal and medial cross-sectional area, and medial thickness in both interlobular and arcuate arteries. The improvement in arterial structure after antihypertensive treatment was due to remodeling and growth of the vessels. Both DZN and LIS were equally efficacious, and combination therapy had no additive or synergistic effect.

Topics: Adrenergic alpha-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Diabetes Mellitus, Type 2; Disease Models, Animal; Doxazosin; Female; Hypertension; Lisinopril; Male; Rats; Rats, Inbred SHR; Renal Artery

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

Both angiotensin II and vascular endothelial growth factor are angiogenic agents that have recently been implicated in the pathogenesis of proliferative diabetic retinopathy. In this study, retinal neovascularization was examined in a model of retinopathy of prematurity with the use of neonatal transgenic (mRen-2)27 rats, which overexpress renin in tissues, and Sprague-Dawley rats. Blockers of the renin-angiotensin system were administered during the neovascularization period. The ACE inhibitor lisinopril and the angiotensin type 1 receptor antagonist losartan both increased retinal renin levels and prevented inner retinal blood vessel growth. Quantitative in situ hybridization revealed that the expression of vascular endothelial growth factor and its type 2 receptor in the inner retina and proliferating blood vessels were increased in rats with retinopathy of prematurity. Lisinopril reduced both retinal vascular endothelial growth factor and its type 2 receptor mRNA in retinopathy of prematurity rats, whereas losartan had no effect. It is predicted that agents that interrupt the renin-angiotensin system may play an important role as retinoprotective agents in various forms of proliferative retinopathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Animals, Newborn; Disease Models, Animal; Endothelial Growth Factors; Humans; In Situ Hybridization; Infant, Newborn; Lisinopril; Lymphokines; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Retina; Retinal Neovascularization; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

In proteinuric glomerulopathies, the excess traffic of proteins into the renal tubule is a candidate trigger of interstitial inflammatory and immune events leading to progressive injury, and a key target for the renoprotective action of antiproteinuric drugs. Among proteins trafficked to the proximal tubule, the third component of complement (C3) can be activated locally and contribute to inflammation at sites of protein reabsorption. Experiments were performed in rats with renal mass reduction (RMR, 5/6 nephrectomy) with the following aims: (1) to study Ig (IgG) and complement deposition in proximal tubules, and interstitial macrophage infiltration and MHC class II expression at intervals after surgery by double immunofluorescence analysis; (2) to assess whether lisinopril (angiotensin-converting enzyme inhibitor [ACEi], 25 mg/L in the drinking water, from either day 1 or day 7) limited IgG and C3 accumulation and interstitial inflammation at day 30. In 7-d remnant kidneys, intracellular staining for both IgG and C3 was detectable in proximal tubules in focal areas; C3 was restricted to IgG-positive tubular cells, and there were no interstitial ED-1 macrophage and MHC II-positive cellular infiltrates. In 14-d and 30-d remnant kidneys, proximal tubular IgG and C3 staining was associated with the appearance of interstitial infiltrates that preferentially localized to areas of tubules positive for both proteins. RMR rats given ACEi had no or limited increases in levels of urinary protein excretion, tubular IgG, and C3 reactivity, and interstitial cellular infiltrates in kidneys at 30 d, even when ACEi was started from day 7 after surgery. These findings document that (1) in RMR, IgG and C3 accumulation in proximal tubular cells is followed by leukocyte infiltration and MHC II overexpression in the adjacent interstitium; (2) ACEi while preventing proteinuria limits both tubular accumulation of IgG and C3 and interstitial inflammation. The data suggest that ACE inhibition can be renoprotective by limiting the early abnormal protein traffic in proximal tubule and consequent deleterious effects of excess protein reabsorption, including the accumulation and local activation of complement as well as the induction of chemokines and endothelin genes known to promote interstitial inflammation and fibrosis.

Topics: Analysis of Variance; Animals; Complement C3 Nephritic Factor; Culture Techniques; Disease Models, Animal; Genes, MHC Class II; Immunoglobulin G; Immunohistochemistry; Inflammation; Kidney Tubules, Proximal; Lisinopril; Macrophages; Male; Nephrectomy; Nephritis, Interstitial; Proteinuria; Rats; Rats, Sprague-Dawley; Reference Values

Chronic renal diseases progress to organ insufficiency, which may require replacement therapy within one to three decades even independently of the type of initial insults. In the majority of cases, the degrees of proteinuria and interstitial leukocyte infiltration and scarring are strictly correlated with the rate of disease progression. This study tests the hypothesis that excess intrarenal protein traffic may cause lymphocyte-dependent interstitial injury that, while not fully controlled by antiproteinuric therapy, can be further inhibited by concomitant immunosuppression. A primarily nonimmune model was used to reproduce progressive renal disease due to a critical loss of nephron mass. Angiotensin-converting enzyme (ACE) inhibitor limited proteinuria, interstitial inflammation, MHC class II antigen expression, and severe lesions. Combined treatment with ACE inhibitor and a specific antilymphocyte agent, mycophenolate mofetil, dramatically attenuated macrophage and T cell infiltration, MHC-class II overexpression, dendritic cells, and all manifestations of the disease. Evidence of lymphocyte-mediated renal injury in the setting of excess protein traffic provides the basis for combining ACE inhibition and immunosuppression to halt progression of proteinuric kidney disease and minimize the need for dialysis or transplantation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Lisinopril; Lymphocytes; Male; Mycophenolic Acid; Proteinuria; Rats; Rats, Sprague-Dawley

In this study, the vascular responses of diabetic rat femoral arteries to epinephrine were investigated. The effects of lisinopril (ACE inhibitor) on vascular epinephrine sensitivity were also tested in a different group. This study was carried out in sodium pentobarbital-anesthetized rats 8 weeks after induction of diabetes with streptozotocin. After extensive dissection of the femoral arteries with adventitial stripping, epinephrine and chlorpromazine were applied to the vascular wall, and their vascular effects were compared in streptozotocin-diabetic (STZ-D), lisinopril-administered streptozotocin-diabetic (LASTZ-D), lisinopril-administered nondiabetic (LAND), and non-diabetic (ND) groups. Vasoconstriction was induced by epinephrine in all groups in a dose-response fashion. There were statistically significant differences in maximum percent constriction between STZ-D and LASTZ-D groups. There was also a significant increase in sensitivity to epinephrine in the STZ-D group. The vasoconstriction induced by epinephrine was relieved by chlorpromazine in all groups. Results suggest that there are important functional abnormalities in the responses of vessels to epinephrine in diabetics, and that the attenuation of vasoconstriction by ACE inhibitors may have beneficial effects in microsurgical procedures performed on diabetic patients. Topically-applied chlorpromazine appears to be effective in relieving vasospasm due to epinephrine, and may be a useful tool to resolve perioperative vascular spasm in microsurgical procedures for diabetic and non-diabetic patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Chlorpromazine; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Epinephrine; Femoral Artery; Lisinopril; Male; Random Allocation; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Streptozocin; Vasoconstriction; Vasoconstrictor Agents

Experimental data consistently indicate that renal disease progression is fully prevented in proteinuric glomerulopathies by long-enough angiotensin-converting enzyme (ACE) inhibition therapy. Whether regression of established proteinuria to normal can be achieved is, however, ill defined. The current study was designed with the aim to clarify whether ACE inhibition may induce regression of established proteinuria and renal structural damage in MWF rats, a genetic model of progressive proteinuria and renal injury. Animals treated with the ACE inhibitor lisinopril from 20 weeks of age (time when proteinuria is already important) and age-matched untreated rats were followed for 10 weeks. ACE inhibition normalized systolic blood pressure and progressively reduced proteinuria (from 172 +/- 79 to 81 +/- 23 mg/24 hours). In these animals, a highly significant correlation was obtained between baseline proteinuria and antiproteinuric response. At variance in untreated rats, proteinuria showed a marked increase in the 10-week follow-up period (from 165 +/- 57 to 325 +/- 86 mg/24 hours). Lisinopril prevented the progression of renal damage, as documented by a significantly lower incidence of glomeruli affected by sclerotic lesions (P < 0.01) than in untreated animals after the 10-week study period. Kidney tissue damage was comparable in lisinopril-treated rats and in untreated animals at 20 weeks of age, indicating that structural changes were arrested by the treatment. Thus, in proteinuric MWF rats, late-onset ACE inhibition normalized blood pressure, effectively and progressively restored high protein excretion rate toward normal values, and arrested progression of tissue damage.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Gene Expression; Humans; Kidney Function Tests; Kidney Glomerulus; Lisinopril; Male; Models, Genetic; Nephritis, Hereditary; Proteinuria; Rats; Rats, Inbred Strains; Treatment Outcome

Unilateral ureteral obstruction (UUO) is a well established experimental model of renal injury leading to interstitial fibrosis. The molecular and cellular mechanism(s) of interstitial fibrosis in UUO are beginning to be elucidated. In the progression of interstitial fibrosis in UUO, up-regulation of collagen synthesis is commonly observed. HSP47 is a collagen-binding stress protein and is thought to be a collagen-specific molecular chaperone, which plays a pivotal role during the biosynthesis and secretion of collagen molecules in the endoplasmic reticulum. The synthesis of HSP47 has been demonstrated to always parallel that of collagen in physiological and pathophysiological conditions. It is well recognized that renin-angiotensin system (RAS) is enhanced in the setting of UUO and that enhanced RAS has been implicated in the pathogenesis of interstitial fibrosis in the obstructed kidneys.. To investigate the role of HSP47 in the progression of interstitial fibrosis in mouse UUO, the expression of HSP47 was examined by Northern blotting, immunohistochemistry and in situ hybridization in the obstructed kidneys. To test the possible involvement of enhanced RAS on the HSP47 expression, we examined the effects of lisinopril, an angiotensin converting enzyme inhibitor, on interstitial fibrosis. HSP47 and type I collagen mRNA expression.. By Northern blot analysis, HSP47 mRNA was significantly up-regulated at 12 hours (about twice that of sham operated kidneys) after the onset of ureteral obstruction, further increased and stayed at the increased level until seven days (about 8 times that of sham operated kidneys). HSP47 mRNA and protein expression were observed in the periglomerular and peritubular interstitial regions of the obstructed kidneys. Distribution of smooth muscle alpha actin and type I collagen immunoreactivity were similar to the HSP47 distribution pattern, suggesting that HSP47 was up-regulated in the myofibroblasts. Lisinopril ameliorated the expansion of cortical interstitium in the obstructed kidneys at four and seven days after ureteral obstruction. HSP47 mRNA expression was suppressed at four and seven days, whereas type I collagen mRNA was suppressed only at seven days after the onset of ureteral obstruction.. These results demonstrate the early and persistent up-regulation of HSP47 during the progression of interstitial fibrosis in mouse UUO kidneys, and further suggest the potential role of HSP47 in the pathogenesis of interstitial fibrosis in the obstructed kidneys. Partial suppression of HSP47 mRNA expression by lisinopril at day 4 and day 7 after ureteral obstruction suggests that there are other immediate trigger(s) that induce the HSP47 mRNA expression. Identification of the molecular mechanism of HSP47 induction during UUO may give an insight into the novel aspects of the molecular pathophysiology of interstitial fibrosis in obstructive nephropathy.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Collagen; Disease Models, Animal; Fibrosis; Gene Expression; Heat-Shock Proteins; HSP47 Heat-Shock Proteins; Immunoenzyme Techniques; In Situ Hybridization; Kidney; Lisinopril; Male; Mice; Mice, Inbred C3H; Renin; Renin-Angiotensin System; RNA, Messenger; Ureteral Obstruction

To investigate the effects of angiotensin II on discharge rates of somatosensory thalamic neurons and whether these effects are altered in hypertensive transgenic rats [TGR(mREN-2)27] and by long-term treatment with the angiotensin converting enzyme inhibitor lisinopril.. Three strains of rats anesthetized with urethane were used (normotensive Wistar and Sprague-Dawley rats (SDR), and [TGR(mREN-2)27]). In addition, the effects of lisinopril treatment on SDR and transgenic animals were tested. The neuronal discharge frequency and the pattern were recorded extracellularly, and their behaviors in response to angiotensin and angiotensin antagonists administered iontophoretically were analyzed.. Angiotensin-sensitive neurons located in the ventral posteromedial and ventral posterolateral thalamic nuclei, and in the zona incerta were excited mainly by angiotensin II. The increase in the firing rates induced by administration of angiotensin II often coincided with an increase in the number of bursts of discharges. Effects induced by angiotensin II could be blocked by administration of specific antagonists (losartan, PD 123319). Long-term treatment with lisinopril reduced the neuronal responsiveness to angiotensin II in SDR significantly in comparison with that of untreated SDR controls. Lisinopril-treated SDR had a significantly lower responsiveness to angiotensin II than did hypertensive transgenic rats that had been treated with lisinopril.. The results show for the first time that administration of angiotensin II induced changes in discharge rates of somatosensory neurons, and that long-term administration of lisinopril caused a significant difference between the neuronal responsiveness to angiotensin of normotensive SDR and that of hypertensive transgenic rats.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Antihypertensive Agents; Disease Models, Animal; Electroencephalography; Hypertension; Imidazoles; Lisinopril; Losartan; Male; Neurons, Afferent; Pyridines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Thalamus; Vasoconstrictor Agents

Two substrains of the fawn-hooded (FH) rat have been developed, one of which develops progressive hypertension and proteinuria, the FHH, and one which shows little increase in blood pressure and no renal damage, the FHL. Other hypertensive rodent models show primary metabolic disturbances before the development of renal damage, notably hypertriglyceridemia, which may also contribute to progression of renal disease. In this study we evaluated whether hyperlipidemia is a primary disturbance in FHH, or only occurs secondary to proteinuria. Lipid levels were determined before and after development of proteinuria, and compared to those found in age-matched FHL. We also determined whether reducing proteinuria with lisinopril would normalize lipid levels in aging FHH. At 4 weeks of age, proteinuria was very low (2-3 mg/day) in both FHH and FHL. While proteinuria increased steadily in aging FHH, reaching 350 +/- 62 mg/day at 40 weeks, much less increase was observed in FHL over the same period (32 +/- 5 mg/day at 40 weeks). Blood pressure was markedly higher in adult FHH than in FHL (158 +/- 2 vs. 129 +/- 2 mm Hg, p < 0.01). In 4-week-old FHL and FHH, plasma cholesterol levels were similar. Subsequently, cholesterol increased in FHH, reaching 3.4 +/- 0.9 mmol/l at 40 weeks, whereas cholesterol was barely affected by aging in FHL (2.1 +/- 0.2 mmol/l at 40 weeks). At 4 weeks, triglyceride levels were lowest in FHH. Subsequently, triglycerides increased in FHH, reaching 3.5 +/- 1.5 mmol/l at 40 weeks, as compared to 1.3 +/- 0.2 mmol/l in FHL. Besides a transient increase in triglyerides in lisinopril-treated FHH at 11 weeks, increments in blood pressure, proteinuria, cholesterol, triglycerides and apolipoproteins A-I, B and E aging FHH were effectively prevented by lisinopril. These data strongly suggest that there is no primary difference in lipid metabolism between FHH and FHL and that changes in plasma lipids in FHH as compared to FHL are all secondary to proteinuria.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Apolipoproteins; Blood Pressure; Body Weight; Cholesterol; Creatinine; Disease Models, Animal; Hyperlipidemias; Hypertension; Lisinopril; Male; Osmotic Pressure; Proteinuria; Rats; Rats, Inbred Strains; Statistics as Topic; Triglycerides

This study was undertaken to assess whether the converting enzyme inhibitor lisinopril, and the long-acting nitrate, isosorbide-5-mononitrate, affect left ventricle dysfunction and anatomical remodelling in rats with myocardial infarction. Lisinopril, isosorbide-5-mononitrate or vehicle were given to rats (n = 10-14 per group) immediately after coronary artery occlusion (by an intravenous bolus) and then for nine weeks (in drinking water). At the end of the study, left ventricular pressures were measured, the heart arrested in diastole, and infarct size, left ventricular chamber volume and wall thicknesses measured. Lisinopril significantly lowered systemic blood pressure and left ventricular systolic pressure in rats with small (< 15% scarred tissue of the left ventricle) and large (> 15%) infarcts; the weight of the left ventricle (including the septum) was reduced by 24% and 28% in animals with small and large infarcts, respectively. Lisinopril lowered left ventricular end-diastolic pressure (by 33% and 39%) and chamber volume (by 4% and 34%) in rats with small and large infarcts, respectively, compared with controls (NS). The combined anatomical and hemodynamic changes led to a reduction of the circumferential wall stress by 20% and 44% in lisinopril-treated rats with small and large infarcts, respectively (NS). No significant changes were seen in the nitrate-treated hearts compared with controls. Lisinopril, given early after myocardial infarction and continued for nine weeks, significantly affected cardiac hemodynamics and ventricular weights in rats with infarcts of different sizes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Follow-Up Studies; Hemodynamics; Isosorbide Dinitrate; Lisinopril; Male; Myocardial Infarction; Organ Size; Rats; Vasodilator Agents; Ventricular Dysfunction, Left

To assess in conscious two-kidney, one clip renal hypertensive rats whether angiotensin converting enzyme (ACE) inhibition with lisinopril, angiotensin II receptor blockade with losartan or vasodilation with sodium nitroprusside have similar effects on intra-arterial mean blood pressure, heart rate and splanchnic nerve activity.. A bolus dose of lisinopril or losartan (both 10 mg/kg, intravenously) induced within 2 h an equal reduction in mean blood pressure, whereas sodium nitroprusside infused during the same period (at 10 micrograms/min) lowered mean blood pressure, but less strongly. The heart rate was accelerated significantly more during sodium nitroprusside infusion than during lisinopril or losartan treatment. Splanchnic nerve activity increased significantly only in those rats given sodium nitroprusside. No change in the parameters studied was observed in vehicle-treated rats. The doses of lisinopril and losartan were repeated after 12 and 24 h. Before administration of the last dose, the mean blood pressure was still low. Administration of lisinopril or losartan again 24 h after the initial dose had no further effect on the mean blood pressure, heart rate or splanchnic nerve activity.. These results obtained in rats with a renin-dependent form of hypertension show that blockade of the renin-angiotensin system for 24 h produces an equivalent blood pressure reduction irrespective of whether it is due to ACE inhibition or angiotensin II antagonism. The results also indicate that there is less reflex activation of sympathetic nerve activity when blood pressure is lowered with a blocker of the renin-angiotensin system rather than with a direct vasodilator such as sodium nitroprusside.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Blood Pressure; Disease Models, Animal; Heart Rate; Hypertension, Renal; Imidazoles; Lisinopril; Losartan; Male; Nitroprusside; Rats; Rats, Wistar; Renin-Angiotensin System; Splanchnic Nerves; Sympathetic Nervous System; Tetrazoles

Many studies have consistently documented that angiotensin converting enzyme (ACE) inhibitors prevent proteinuria and glomerulosclerosis in progressive renal disease, but very few data are available on whether they also prevent renal failure and death. The mechanisms of the beneficial effect of ACE inhibition are only partially understood. Recent data suggest that angiotensin II modulates renal synthesis of endothelin-1, a vasoactive peptide implicated in the process of renal injury. Here we investigated in a long-term study whether ACE inhibition ameliorated renal function in uninephrectomized (UNx) male MWF/Ztm rats. Three groups of rats at nine weeks of age underwent UNx or sham-operation. Nephrectomized animals were left untreated or treated with the ACE inhibitor lisinopril in drinking water. In untreated UNx animals systolic blood pressure, serum creatinine, urinary protein and renal synthesis of endothelin-1, evaluated by its urinary excretion, were significantly increased, as compared with control animals with two kidneys. End-stage renal failure developed in all untreated UNx rats that died within 9 to 14 months from UNx. ACE inhibitor significantly reduced systolic blood pressure, completely prevented proteinuria and renal function deterioration, and reduced endothelin-1 excretion. All UNx rats treated with lisinopril were alive 14 months after UNx. These results show that ACE inhibition prevents end-stage renal failure induced by UNx in male MWF/Ztm, and that the beneficial effects of angiotensin II inhibition in this model are related to modulation of renal synthesis of endothelin-1.

Topics: Aging; Animals; Blood Pressure; Creatinine; Disease Models, Animal; Endothelins; Kidney Failure, Chronic; Lisinopril; Male; Nephrectomy; Proteinuria; Rats

To clarify whether angiotensin converting enzyme (ACE) inhibitors prevent progressive renal injury directly by their antihypertensive effect we administered the ACE inhibitor lisinopril to male MWF/Ztm rats as a single daily dose that lowered blood pressure for only 9 of 24 h. We investigated the effects of this treatment in short- and long-term studies and compared them with another antihypertensive drug, the calcium channel blocker nitrendipine, given to partially control blood pressure as done with the ACE inhibitor. In untreated animals systemic hypertension, proteinuria, and glomerulosclerosis developed spontaneously with age, and lisinopril reduced systemic hypertension and prevented proteinuria and glomerular lesions. Nitrendipine, despite similar blood pressure control, was ineffective in preventing both proteinuria and glomerulosclerosis. After 2 mo of treatment glomerular capillary pressure was significantly reduced by lisinopril and slightly but significantly increased by nitrendipine, compared with untreated controls. The ultrafiltration coefficient was significantly higher in lisinopril than in controls and not significantly changed by nitrendipine. With both drugs, however, glomerular hemodynamic effects were observed only at a few hours after administration and were abolished before the next administration. No significant changes in glomerular tuft volume were observed in treated and untreated animals after 2 and 6 mo of observation. Thus ACE inhibitor, despite only partial control of systemic blood pressure, effectively prevented proteinuria and glomerular injury. Comparable blood pressure control obtained with a calcium channel blocker was not associated with renal protection. These results suggest that ACE inhibitors could protect glomerular microcirculation by a mechanism that is not directly related to their antihypertensive action.

Topics: Alpha-Globulins; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Glomerulonephritis; Hemodynamics; Hypertension; Kidney; Kidney Diseases; Kinetics; Lisinopril; Male; Nitrendipine; Proteinuria; Rats

Topics: Animals; Carrier Proteins; Disease Models, Animal; Humans; Hypertension; Hypertrophy, Left Ventricular; Lisinopril; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Somatomedins

Topics: Animals; Blood Pressure; Collagen; Creatinine; Disease Models, Animal; Heart; Heart Ventricles; Hypertension, Renal; Kidney; Lisinopril; Male; Nephrectomy; Rats; Rats, Wistar; Uremia

We evaluated the effects of lisinopril (1 mg/kg per day) on hemodynamics, cardiac hypertrophy, and neurohumoral factors in Wistar rats with an abdominal aortocaval fistula. After 4 weeks of treatment, the results were compared with values obtained for untreated rats with a fistula and for sham-operated rats. Volume loading induced biventricular hypertrophy, hemodynamic signs of high-output heart failure (increased cardiac output, left ventricular end-diastolic pressure, and pulse pressure), and impaired renal function (decreased renal blood flow and kidney weight; increased blood urea nitrogen). Lisinopril did not affect these cardiorenal hemodynamics, but decreased left ventricular mass and mortality rate (both P < 0.05). Lisinopril attenuated the increase in plasma norepinephrine, and increased plasma renin activity (both P < 0.05). Thus, lisinopril reduced left ventricular mass and mortality in rats with high-output heart failure without changing the cardiorenal hemodynamics. Neurohumoral inhibition may play a role in the beneficial effects of lisinopril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Abdominal; Arteriovenous Fistula; Body Weight; Cardiomegaly; Dipeptides; Disease Models, Animal; Heart; Hemodynamics; Kidney; Lisinopril; Male; Organ Size; Rats; Rats, Wistar; Vena Cava, Inferior

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