ramipril and Disease-Models--Animal

ESRD represents a major health problem. The number of patients who enter kidney replacement programs has increased at an average of 7% per year in the past 10 yr. A large number of experimental and clinical studies have demonstrated that chronic nephropathies share common pathogenic mechanisms that contribute to renal disease progression, even independent of the original cause. Clinical studies found a significant correlation between the extent of urinary protein excretion and the rate of GFR decline in both diabetic and nondiabetic chronic nephropathies. Randomized trials, in particular the Ramipril Efficacy In Nephropathy (REIN) study, also showed that treatments that reduce proteinuria (namely angiotensin-converting enzyme [ACE] inhibitors) are renoprotective and limit progression to ESRD. Meta-analyses of randomized clinical trials also evaluated the role of proteinuria and of ACE inhibition therapy in chronic renal disease progression. Their findings were consistent with those of the REIN study and confirmed in larger series of patients the predictive value of proteinuria and the renoprotective effect of proteinuria reduction by ACE inhibition therapy. Thus, the meta-analyses may confirm and extend previous findings generated by randomized clinical trials. Conceivably, well-designed studies in properly selected and carefully monitored patients who are at increased risk continue to be the best approach to test novel hypotheses. The meta-analyses, however, represent a valuable tool to evaluate the consistency and generalizability of trial results to larger cohorts of patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diet, Protein-Restricted; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Kidney Function Tests; Male; Prognosis; Proteinuria; Ramipril; Risk Assessment; Severity of Illness Index; Treatment Outcome

The goals of rational antihypertensive medication should embrace the alleviation of atherosclerosis, the clinical consequences of which pose a major health problem and hence socio-economic concern for industrialized countries. Angiotensin converting enzyme (ACE) inhibitors are endowed with pharmacodynamic features which may help to attain this aim. Various animal experiments with cholesterol-fed rabbits, pigs and monkeys, as well as with rabbits with inherent disorder of lipid metabolism (WHHL-rabbit), demonstrated endothelial protection against loss of function due to hyperlipidemia and attenuation of lipid deposition in conduit blood vessels with ACE-inhibition. The alleviation of progressive atherosclerosis, which is a common feature of restenosis development following angioplasty, was shown in hypercholesterolemic rabbits and normal rats, but did not occur in clinically more relevant porcine models nor in large clinical trials. Circumstantial evidence from miscellaneous experiments is in line with the view that it is enhancement of bradykinin activity which causes the endothelial protection against the consequences of hypercholesterolemia. Furthermore, loss of relaxation of coronary resistance vessels without overt atherosclerosis despite hypercholesterolemia can be restored by augmentation of the EDRF-pathway as has been demonstrated with ramiprilat in vitro. This is being substantiated in preliminary clinical reports with different ACE-inhibitors. The possible association between improvement in both insulin sensitivity and endothelial function requires further investigation. The critical analysis of present experimental findings on a beneficial influence on both the spontaneous and the progressive development of atherosclerosis indicates ACE-inhibition to be more likely to preserve or restore the function of an intact endothelium than to interfere with the complex reaction occurring after injury of an already affected blood vessel.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Coronary Artery Disease; Coronary Circulation; Disease Models, Animal; Endothelium, Vascular; Haplorhini; Hemodynamics; Rabbits; Ramipril; Rats; Swine; Vascular Resistance

ACE inhibitors induce an increase in kinin levels with subsequent release of nitric oxide (NO) and prostacyclin, as shown in cultured endothelial cells and isolated rat hearts. Isolated perfused working rat hearts continuously release kinins and prostacyclin. During ischemia after ligation of the left coronary artery kinin and prostacyclin concentrations in the venous effluent of the hearts are increased. ACE inhibition with ramiprilat increases kinin concentrations during normoxia, ischemia and reperfusion, whereas deendothelialization markedly reduces kinin and prostacyclin outflow in controls as well as in ACE inhibitor-treated hearts. Rat hearts with postischemic reperfusion arrhythmias are protected by ramiprilat- and bradykinin perfusion, cardiodynamics and metabolism of treated hearts are improved. These effects are observed in concentrations too low to increase coronary flow. The cardioprotective effects of ramiprilat and bradykinin are abolished by the specific B2-kinin receptor antagonist icatibant and by an inhibitor of NO-synthase. Long-term treatment (20 weeks) with ramipril in a blood-pressure-lowering dose (1 mg/kg/day) and a subantihypertensive dose (10 micromg/kg/day) protects spontaneously hypertensive rats (stroke prone) against hypertension and left ventricular hypertrophy in the high dose. In addition, both treatment regimens induce myocardial capillary growth. Isolated hearts of these animals show increased myocardial contractility and coronary flow, reduced release of cytosolic enzymes into the coronary effluent, and improved myocardial metabolism. These changes are observed even at a dose of ramipril which does not affect blood pressure and left ventricular hypertrophy. They are abolished by chronic blockade of kinin receptors with icatibant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bradykinin; Coronary Circulation; Disease Models, Animal; Electrocardiography; Endothelium, Vascular; Hemodynamics; Myocardial Reperfusion Injury; Nitric Oxide; Ramipril; Rats

In this study, the effects of simvastatin on the blood pressure and on the antihypertensive activity of ramipril in hypertensive hypercholesterolemic animals and patients were evaluated. In hypertensive hypercholesterolemic animals, repeated administration of simvastatin slightly but significantly decreased the systolic blood pressure, enhanced its progressive reductions induced by repeated administration of ramipril and corrected the compromised lipid profile. Concomitantly, repeated administration of simvastatin, ramipril or simvastatin in combination with ramipril to these animals, increased nitric oxide (NO) production and decreased the elevated serum malondialdehyde (MDA) and high sensitivity C-reactive protein (hs-CRP) levels. The effects of combined treatment were greater than those of simvastatin or ramipril alone. In hypertensive hypercholesterolemic patients, repeated administration of ramipril decreased systolic and diastolic blood pressure, increased NO production, and decreased the elevated serum MDA and hs-CRP levels. Addition of simvastatin to ramipril therapy enhanced these effects and corrected the compromised lipid profile. Simvastatin but not ramipril inhibited the contractile responses of isolated aortic rings induced by angiotensin 11. l-arginine and acetylcholine enhanced, while l-NAME inhibited effects of simvastatin, and simvastatin in combination with ramipril on these contractile responses. These findings suggest that simvastatin exerts antihypertensive effect and enhances the antihypertensive effect of ramipril in hypertensive hypercholesterolemic animals and patients. In addition to its cholesterol-lowering effect, the ability of simvastatin to ameliorate endothelial dysfunction through increasing NO bioavailability and through suppression of oxidative stress and vascular inflammation and its ability to enhance the effect of ramipril on these parameters may play a pivotal role in these effects.

Topics: Adult; Aged; Animals; Antihypertensive Agents; Aorta, Thoracic; Blood Pressure; C-Reactive Protein; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Humans; Hypercholesterolemia; Hypertension; In Vitro Techniques; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Rabbits; Ramipril; Rats; Rats, Wistar; Simvastatin; Treatment Outcome; Vasodilation

Despite the availability of efficacious drugs, the success of treating hypertension is limited by patients' inconsistent drug intake. Immunization against angiotensin II may offer a valuable alternative to conventional drugs for the treatment of hypertension, because vaccines induce relatively long-lasting effects and do not require daily dosing. Here we describe the preclinical development and the phase I clinical trial testing of a virus-like particle (VLP)-based antihypertensive vaccine.. An angiotensin II-derived peptide was conjugated to the VLP Qbeta (AngQb). AngQb was highly immunogenic in mice and rats. To test for efficacy, spontaneously hypertensive rats (SHR) were immunized with 400 microg AngQb or VLP alone. Group mean systolic blood pressure (SBP) was reduced by up to 21 mmHg (159 +/- 2 versus 180 +/- 5 mmHg, P < 0.001), and total angiotensin II levels (antibody-bound and free) were increased ninefold (85 +/- 20 versus 9 +/- 1 pmol/l, P = 0.002) compared with VLP controls. SHR treated with the angiotensin-converting enzyme (ACE) inhibitor ramipril (1 mg/kg per day by mouth) reached an SBP of 155 +/- 2 mmHg. Twelve healthy volunteers of a placebo-controlled randomized phase I trial were injected once with 100 microg AngQb. Angiotensin II-specific antibodies were raised in all subjects (100% responder rate) and AngQb was well tolerated.. AngQb reduces blood pressure in SHR to levels obtained with an ACE inhibitor, and is immunogenic and well tolerated in humans. Therefore, vaccination against angiotensin II has the potential to become a useful antihypertensive treatment providing long-lasting effects and improving patient compliance.

Topics: Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibody Specificity; Antihypertensive Agents; Autoantibodies; Blood Pressure; Disease Models, Animal; Double-Blind Method; Drug Evaluation, Preclinical; Humans; Hypertension; Male; Mice; Mice, Inbred BALB C; Middle Aged; Patient Compliance; Ramipril; Rats; Rats, Inbred SHR; Reference Values; Time Factors; Vaccines; Virion

In renal hypertensive rats with pressure overload left ventricular hypertrophy the angiotensin converting enzyme inhibitor ramipril, given in a high blood pressure lowering dose as well as in a low, non-antihypertensive dose, prevented and regressed left ventricular hypertrophy. These beneficial effects were abolished by coadministration of the specific bradykinin receptor antagonist (HOE 140) in the prevention--but not in the regression studies. Vascular function of rats with pressure overload left ventricular hypertrophy was impaired, whereas treated animals showed a reversal to normal. The angiotensin II subtype AT1 receptor antagonist, losartan, was barely active in the prevention, however markedly active in the regression of left ventricular hypertrophy. From these experimental studies in rats with pressure overload left ventricular hypertrophy and vascular dysfunction we conclude that inhibition of bradykinin degradation induced by ramipril may contribute to the antihypertrophic action during the prevention phase, whereas attenuation of angiotensin II formation may be more important during the regression period. In another model, the spontaneously hypertensive rat (SHR and stroke prone SHR)--a non-renal hypertensive model--cardiac left ventricular hypertrophy could be reduced by chronic high-dose ramipril treatment in prevention and regression studies, whereas the low dose regimen only reduced left ventricular hypertrophy in the regression experiments. In addition, both doses improved the myocardial capillary supply to the heart leading to improved function and metabolism. In comparison, vascular hypertrophy of the mesenteric artery could only be prevented by early-onset high dose treatment with the angiotensin converting enzyme inhibitor but not once hypertrophy has been established.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antihypertensive Agents; Bradykinin; Disease Models, Animal; Drug Evaluation; Hypertension, Renovascular; Hypertrophy, Left Ventricular; Ramipril; Rats; Rats, Inbred SHR

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

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

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

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

Acute kidney injury (AKI) is a malady with a sudden onset resulting in buildup of waste matters in the body, but a specific cure hasn't been found as a lasting solution to AKI. In this study, ramipril was evaluated for its potential therapy in glycerol-induced AKI in rats.. Twenty animals were divided into four groups of five animals each. Group I was the control while group II was given glycerol on day 8 only, groups III and IV were administered with pioglitazone (reference drug) and ramipril for seven days respectively and on day 8 received glycerol. On the ninth day, blood and tissue samples were taken to assay for serum indicators of oxidative damage, enzymatic and nonenzymatic antioxidants, and creatinine and blood urea nitrogen. Animals were sacrificed thereafter; kidney was harvested for histological and immunohistochemical analysis. Expressions of caspase 3, renin receptor, NK-KB, and KIM-1 were carried out.. Ramipril significantly inhibited indicators of oxidative damage while also significantly increasing levels of enzymatic and nonenzymatic antioxidant markers. These drugs also significantly lowered the levels of creatinine and blood urea nitrogen. Histology also indicated that while there were massive infiltration of leucocytes and congestion of the kidney in toxicant group, the ramipril-treated group showed a milder condition. In immunohistochemistry, the two drugs significantly inhibited the expressions of the four proteins, which were highly expressed in the toxicant group.. The study showed that ramipril and pioglitazone have nephroprotective effect and thus have the ability to blunt AKI through their anti-inflammatory, antiapoptosis, antirenin, and antioxidant properties.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Disease Models, Animal; Glycerol; Inflammation Mediators; Oxidative Stress; Ramipril; Rats; Renin

Abdominal aortic aneurysm (AAA) is a common condition that may be life-threatening when it is unrecognized. The aim of this study is to evaluate and compare the efficacy of ramipril and carvedilol on limiting AAA expansion in mouse model.. A total of 36 experimental AAA mouse model was induced with the continuous infusion of angiotensin II (Ang II) in 20-week-old male apolipoprotein E-deficient mice. They were randomly divided into 3 treatment groups and fed orally for 8 weeks; saline alone, ramipril (2.5 mg/30g/d), or carvedilol (3.125 mg/30g/d), respectively. Aortic diameter (AD) was measured by micro-computed tomography, and the level of biomarkers of aortic tissue such as monocyte chemoattractant protein-1 (MCP-1) and tissue inhibitor matrix metalloproteinase-1 (TIMP-1) was evaluated. After treatment, AD of both ramipril and carvedilol group was smaller than in the saline group. The percentage change of AD in both ramipril and carvedilol groups was significantly smaller than that of the saline group. Pathologic examination revealed relatively well-preserved aortic walls in the ramipril group compared to the carvedilol and saline groups. The level of MCP-1 was markedly decreased in both the ramipril and carvedilol groups compared to the saline group. The level of TIMP-1 was higher in the carvedilol group when compared to either the saline or ramipril groups.. Ramipril and carvedilol treatment shows similar efficacy in limiting AAA expansion in mouse model. Future clinical research would be warranted to validate these results.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aortic Aneurysm, Abdominal; Carvedilol; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Ramipril; Random Allocation

We hypothesized that renin-angiotensin system and neprilysin (NEP) inhibition can modulate the nociceptive parameters on hypertensive rats. The aim of this study is to assess the preventive and therapeutic effects of ramipril and sacubitril on the pain hypersensitivities, and their interaction mechanisms with high blood pressure.. Antinociceptive effects of ramipril and sacubitril were compared with those of diclofenac. Threshold of pain assesments were recorded before drugs administration. After a 18 days treatment, normotensive and dexamethasone-induced hypertensive rats were evaluated on thermal hyperalgesia and mechanical allodynia tests. Blood pressure of rats were verified by mean arterial pressure measurement.. Hypertensive rats showed significantly high pain threshold on thermal plantar test compared to that of normotensives. Among hypertensive rats, pain hypersensitivity was lowest in diclofenac group, followed by sacubitril group, while ramipril caused increased thermal and mechanical hypersensitivities.. We found that NEP inhibition may play a role in nociception in hypertensive rats. NEP inhibitors may be suitable choice for the management of hypertension and pain because of their therapeutic and preventive effects on nociception and arterial blood pressure.

Topics: Aminobutyrates; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Dexamethasone; Disease Models, Animal; Drug Combinations; Hypertension; Male; Neprilysin; Pain; Pain Threshold; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Wistar; Renin-Angiotensin System; Tetrazoles; Valsartan

Experimental study.. To evaluate the efficacy of Angiotensin-converting enzyme inhibitor Ramipril, as a mitigator of radiation-induced spinal cord injury.. Stony Brook University, Stony Brook, NY, USA.. Total of 22 rats were irradiated with single doses of 23.6-33 Gy at the C4-T2 spinal levels. After irradiation, the rats were randomized to the radiation only control group and the Ramipril-treated (radiation + Ramipril) experimental group. Ramipril 1.5 mg/kg/day was given in the drinking water starting 1 week after radiation through the study duration.. All the rats irradiated with 28.5-33 Gy became paralyzed at 125 ± 4 days, whereas no rats became paralyzed after 23.6 Gy. The time to develop paralysis was delayed to 135 ± 4 days in Ramipril-treated group (P < 0.001). H&E and LFB showed microscopic structural restoration and remyelination with Ramipril treatment. VEGF expression was increased in the irradiated spinal cord, and the number of VEGF-positive cells was significantly decreased by Ramipril treatment (P < 0.001). Immunohistochemical stain with Iba-1 showed increased microglial infiltration in the irradiated spinal cords. The number of Iba-1-positive microglia was significantly reduced by Ramipril treatment (P < 0.05).. Ramipril reduced the rate of paralysis even at the paralysis-inducing radiation doses. It also significantly delayed the onset of paralysis. Neuroinflammation and endothelial cell damage may be the key mediators of radiation injury. Ramipril can be readily translatable to clinical application as a mitigatory of radiotherapeutic toxicity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium-Binding Proteins; Disease Models, Animal; Dose-Response Relationship, Radiation; Inflammation; Male; Microfilament Proteins; Microglia; Paralysis; Radiation Injuries, Experimental; Ramipril; Random Allocation; Rats, Inbred F344; Remyelination; Spinal Cord Injuries; Spinal Cord Regeneration

Endoplasmic reticulum (ER) stress contributes to progression of diabetic nephropathy, which promotes end-stage renal failure in diabetic patients. This study was undertaken to investigate the actions of tempol and ramipril, pharmacological agents that target the consequences of NADPH oxidase, on diabetic nephropathy in a rat model of type 1 diabetes, with an emphasis on markers of ER stress. Male Sprague-Dawley rats were injected intravenously with a single bolus of streptozotocin (55mg/kg) to induce type 1 diabetes. An additional age-matched group of rats was administered with citrate vehicle as controls. After 4 weeks of untreated diabetes, rats received tempol (1.5mM/kg/day subcutaneously, n=8), ramipril (1mg/kg/day in drinking water, n=8) or remained untreated for an additional 4 weeks (n=7). After 8 weeks of diabetes in total, kidneys were collected for histological analysis, gene expression and protein abundance. Tempol and ramipril blunted diabetes-induced upregulation of NADPH oxidase isoforms (Nox4, Nox2, p47

Topics: Animals; Biomimetic Materials; Cyclic N-Oxides; Diabetic Nephropathies; Disease Models, Animal; Endoplasmic Reticulum Stress; Fibrosis; Kidney Glomerulus; Kidney Tubules; Male; NADPH Oxidases; Nitric Oxide; Oxidative Stress; Ramipril; Rats; Rats, Sprague-Dawley; Spin Labels; Superoxide Dismutase; Up-Regulation

Mitochondrial dysfunction is a pathological mediator of diabetic kidney disease (DKD). Our objective was to test the mitochondrially targeted agent, MitoQ, alone and in combination with first line therapy for DKD. Intervention therapies (i) vehicle (D); (ii) MitoQ (DMitoQ;0.6 mg/kg/day); (iii) Ramipril (DRam;3 mg/kg/day) or (iv) combination (DCoAd) were administered to male diabetic db/db mice for 12 weeks (n = 11-13/group). Non-diabetic (C) db/m mice were followed concurrently. No therapy altered glycaemic control or body weight. By the study end, both monotherapies improved renal function, decreasing glomerular hyperfiltration and albuminuria. All therapies prevented tubulointerstitial collagen deposition, but glomerular mesangial expansion was unaffected. Renal cortical concentrations of ATP, ADP, AMP, cAMP, creatinine phosphate and ATP:AMP ratio were increased by diabetes and mostly decreased with therapy. A higher creatine phosphate:ATP ratio in diabetic kidney cortices, suggested a decrease in ATP consumption. Diabetes elevated glucose 6-phosphate, fructose 6-phosphate and oxidised (NAD+ and NADP+) and reduced (NADH) nicotinamide dinucleotides, which therapy decreased generally. Diabetes increased mitochondrial oxygen consumption (OCR) at complex II-IV. MitoQ further increased OCR but decreased ATP, suggesting mitochondrial uncoupling as its mechanism of action. MitoQ showed renoprotection equivalent to ramipril but no synergistic benefits of combining these agents were shown.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetic Nephropathies; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Mice; Molecular Targeted Therapy; Organophosphorus Compounds; Ramipril; Treatment Outcome; Ubiquinone

Acute kidney injury (AKI) and progressive chronic kidney disease (CKD) are intrinsically tied syndromes. In this regard, the acutely injured kidney often does not achieve its full regenerative capacity and AKI directly transitions into progressive CKD associated with tubulointerstitial fibrosis. Underlying mechanisms of such AKI-to-CKD progression are still incompletely understood and specific therapeutic interventions are still elusive. Because epigenetic modifications play a role in maintaining tissue fibrosis, we used a murine model of ischemia-reperfusion injury to determine whether aberrant promoter methylation of RASAL1 contributes causally to the switch between physiological regeneration and tubulointerstitial fibrogenesis, a hallmark of AKI-to-CKD progression. It is known that the antihypertensive drug hydralazine has demethylating activity, and that its optimum demethylating activity occurs at concentrations below blood pressure-lowering doses. Administration of low-dose hydralazine effectively induced expression of hydroxylase TET3, which catalyzed RASAL1 hydroxymethylation and subsequent RASAL1 promoter demethylation. Hydralazine-induced CpG promoter demethylation subsequently attenuated renal fibrosis and preserved excretory renal function independent of its blood pressure-lowering effects. In comparison, RASAL1 demethylation and inhibition of tubulointerstitial fibrosis was not detected upon administration of the angiotensin-converting enzyme inhibitor Ramipril in this model. Thus, RASAL1 promoter methylation and subsequent transcriptional RASAL1 suppression plays a causal role in AKI-to-CKD progression.

Topics: Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Animals; CpG Islands; Dioxygenases; Disease Models, Animal; Disease Progression; DNA Methylation; DNA-Binding Proteins; Epigenesis, Genetic; Fibroblasts; Fibrosis; GTPase-Activating Proteins; Humans; Hydralazine; Kidney; Mice; Mice, Inbred C57BL; Mice, Transgenic; Primary Cell Culture; Promoter Regions, Genetic; Proto-Oncogene Proteins; Ramipril; Renal Elimination; Renal Insufficiency, Chronic; Reperfusion Injury; Vasodilator Agents

Interruption of blood supply to the heart results in acute myocardial infarction (AMI), and further damages the heart muscles. Available drugs for the treatment MI have one or other side effects, and there is a need for development of better alternative drugs from herbal sources. Here, we evaluated cardioprotective effect of Cyperus rotundus on isoprenaline- induced myocardial infarction. Thirty five Wistar rats, aged 60-100 days with body wt. 150-200 g, pretreated with ethanolic extract of Cyperus rotundus L. (@ 250 and 500 mg/kg body wt.) orally before induction of myocardial necrosis by administrating isoprenaline (85 mg/kg, s.c.) on 19th and 20th day of the pretreatment period. The treated rats were examined for gross functioning of heart, heart weight/body wt. Ratio, and also observed histopathologically. Further, activities of various cardiac enzymes such as aspartate transaminase, alanine transaminase, creatinine kinase-myoglobulin, lactate dehydrogenase, and the gold marker troponin-I were also determined. The levels altered by isoproterenol were found to be restored significantly by the test extracts especially at higher dose. Biochemical observations viz., serum ALT (P <0.0001), AST (P <0.0001), creatine kinase-myoglobulin (CK-MB) (P <0.0001), LDH (P <0.0001) demonstrated significant cardioprotective activity of the ethanolic extract of C. rotundus (500 mg/kg body wt.), against isoprenaline induced myocardial infarction. These results were also substantiated by physical parameters and histopathological observations. All these results were comparable with that of two standard drugs metoprolol (10 mg/kg/day), ramipril (3 mg/kg/day) as well as polyherbal formulation Abana (50 mg/kg/day).

Topics: Adrenergic beta-1 Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Cardiotoxicity; Cardiovascular Agents; Cyperus; Cytoprotection; Disease Models, Animal; Ethanol; Isoproterenol; Male; Metoprolol; Myocardial Infarction; Myocardium; Necrosis; Phytotherapy; Plant Extracts; Plants, Medicinal; Ramipril; Rats, Wistar; Rhizome; Solvents

Angiotensin-converting enzyme inhibitors are associated with deleterious hypotension during anesthesia and shock. Because the pharmacologic effects of angiotensin-converting enzyme inhibitors are partly mediated by increased bradykinin B2 receptor activation, this study aimed to determine the impact of acute B2 receptor blockade during hemorrhagic shock in angiotensin-converting enzyme inhibitor-treated mice.. In vivo study.. University research unit.. C57/Bl6 mice.. The hemodynamic effect of B2 receptor blockade using icatibant (B2 receptor antagonist) was studied using a pressure-targeted hemorrhagic shock and a volume-targeted hemorrhagic shock. Animals were anesthetized with ketamine and xylazine (250 mg/kg and 10 mg/kg, respectively), intubated using intratracheal cannula, and ventilated (9 mL/kg, 150 min). Five groups were studied: 1) sham-operated animals, 2) control shocked mice, 3) shocked mice treated with ramipril for 7 days (angiotensin-converting enzyme inhibitors) before hemorrhagic shock, 4) shocked mice treated with angiotensin-converting enzyme inhibitors and a single bolus of icatibant (HOE-140) immediately before anesthesia (angiotensin-converting enzyme inhibitors + icatibant), and 5) shocked mice treated with a single bolus of icatibant. One hour after volume-targeted hemorrhagic shock, blood lactate was measured to evaluate organ failure.. During pressure-targeted hemorrhagic shock, the mean blood volume withdrawn was significantly lower in the angiotensin-converting enzyme inhibitor group than in the other groups (p < 0.001). During volume-targeted hemorrhagic shock, icatibant prevented blood pressure lowering in the angiotensin-converting enzyme inhibitor group (p < 0.001). Blood lactate was significantly higher in the angiotensin-converting enzyme inhibitor group than in the other groups, particularly the HOE groups.. During hemorrhagic shock, acute B2 receptor blockade significantly attenuates the deleterious hemodynamic effect of angiotensin-converting enzyme inhibitor treatment in mice. This beneficial effect of B2 receptor blockade is rapidly reached and sustained with a single bolus of icatibant. This benefit could be of interest in angiotensin-converting enzyme inhibitor-treated patients during both emergency anesthesia and resuscitation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Disease Models, Animal; Hypotension; Mice; Mice, Inbred C57BL; Ramipril; Shock, Hemorrhagic

Prior studies have shown that overexpression of ACT A can lead to ventricular remodeling in rat models of heart failure. Furthermore, recently work studying demonstrated that stimulation of activin An expression in rat aortic smooth muscle (RASM) cells by angiotensin II (Ang II). Ramipril is a recently developed angiotensin converting enzyme (ACE) inhibitor. To investigate the effects of Ramipril on expression of ACT A-FS, we established the rat model of heart failure after myocardial infarction (MI), and divided into either a sham operation (SO), MI, or MI-Ramipril group. We found that Ramipril significantly attenuates collagen-I and III deposition (col-I and III). Notably, we determined that expression of ACT A and II activin receptor (ActRII) were significantly down-regulated in the non-infarcted area of the left ventricle in the Ramipril group, whereas the mRNA and protein levels of FS were markedly up-regulated. Our data suggested that Ramipril benefited left ventricular remodeling by reducing fibrosis and collagen accumulation in the left ventricle of rats after myocardial infarction. This observation was also associated with down-regulation of ACT A expression. This study elucidated a new protective mechanism of Ramipril and suggests a novel strategy for treatment of post-infarct remodeling and subsequent heart failure.

Topics: Activins; Animals; Biomarkers; Biopsy; Disease Models, Animal; Female; Fibrosis; Follistatin; Gene Expression Regulation; Heart Failure; Heart Function Tests; Heart Ventricles; Hemodynamics; Immunohistochemistry; Myocardial Infarction; Ramipril; Rats; Ventricular Remodeling

Cardiovascular disease, including cardiac hypertrophy, is common in patients with kidney disease and can be partially attenuated using blockers of the renin-angiotensin system (RAS). It is unknown whether cardiac microRNAs contribute to the pathogenesis of cardiac hypertrophy or to the protective effect of RAS blockade in kidney disease. Using a subtotal nephrectomy rat model of kidney injury, we investigated changes in cardiac microRNAs that are known to have direct target genes involved in the regulation of apoptosis, fibrosis, and hypertrophy. The effect of treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril on cardiac microRNAs was also investigated. Kidney injury led to a significant increase in cardiac microRNA-212 and microRNA-132 expression. Ramipril reduced cardiac hypertrophy, attenuated the increase in microRNA-212 and microRNA-132, and significantly increased microRNA-133 and microRNA-1 expression. There was altered expression of caspase-9, B cell lymphoma-2, transforming growth factor-β, fibronectin 1, collagen type 1A1, and forkhead box protein O3, which are all known to be involved in the regulation of apoptosis, fibrosis, and hypertrophy in cardiac cells while being targets for the above microRNAs. ACE inhibitor treatment increased expression of microRNA-133 and microRNA-1. The inhibitory action of ACE inhibitor treatment on increased cardiac NADPH oxidase isoform 1 expression after subtotal nephrectomy surgery suggests that inhibition of oxidative stress is also one of mechanism of ACE inhibitor-mediated cardioprotection. These finding suggests the involvement of microRNAs in the cardioprotective action of ACE inhibition in acute renal injury, which is mediated through an inhibitory action on profibrotic and proapoptotic target genes and stimulatory action on antihypertrophic and antiapoptotic target genes.

Topics: Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Apoptosis Regulatory Proteins; Cardiomegaly; Cell Line; Collagen; Cytoprotection; Disease Models, Animal; Fibrosis; Kidney; MicroRNAs; Myocytes, Cardiac; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; Oxidative Stress; Ramipril; Rats, Sprague-Dawley; Signal Transduction; Superoxide Dismutase; Transforming Growth Factor beta1

The present study was carried out to study the effect of spironolactone, atenolol, metoprolol, ramipril and perindopril on cardiovascular complications in neonatal model of diabetes in rats, induced by administering 90 mg/kg streptozotocin (STZ), i.p. in 2-day-old rats. Our data suggest that spironolactone, metoprolol and perindopril prevent not only the STZ-induced metabolic abnormalities but also cardiovascular complications as evident from the reduction in cholesterol, triglyceride and decrease in cardiac hypertrophy which are the initial symptoms of congestive heart failure. Metoprolol and perindopril appears to be beneficial agents as compared to atenolol and ramipril.

Topics: Animals; Animals, Newborn; Antihypertensive Agents; Atenolol; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Metoprolol; Perindopril; Ramipril; Rats, Wistar; Spironolactone

The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of chronic kidney disease (CKD) progression. Aliskiren, a direct renin inhibitor, inhibits the rate-limiting step of the RAAS without any alternative pathway. It is proven to reduce albuminuria in CKD patients treated with angiotensin blockade. However, there are few reports which evaluate the advantage of aliskiren as the first-line drug against CKD progression in RAAS-activated hypertensive patients.. Tsukuba hypertensive mice (THM), double transgenic mice carrying both the human renin and human angiotensinogen genes, were fed a high-salt diet and treated with hydraladine, ramipril and aliskiren for 10 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks during the experimental period. We evaluated renal histological changes and gene expression. Plasma angiotensin concentration was measured to evaluate the RAAS inhibitory effect.. High-salt-loaded THM showed severe hypertension and renal injury. All antihypertensive drugs suppressed blood pressure and prevented renal disease progression. RAAS blockade showed a higher renoprotective effect than hydraladine despite an equivalent blood pressure lowering effect. Aliskiren exhibited even stronger renoprotection than ramipril. Plasma angiotensin concentration was increased in THM fed both normal salt and high salt. Hydraladine did not alter the plasma angiotensin concentration. Ramipril significantly decreased angiotensin II concentration. Aliskiren treatment almost completely suppressed angiotensin I and resulted in lower angiotensin II concentration than ramipril treatment.. Aliskiren prevents renal disease progression by suppressing both angiotensin I and II in RAAS-activated pathology. Our data suggest the application of a renin inhibitor for preventing kidney disease progression in CKD patients.

Topics: Albuminuria; Amides; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Cytoprotection; Disease Models, Animal; Disease Progression; Down-Regulation; Fumarates; Humans; Hydralazine; Hypertension; Kidney; Kidney Diseases; Mice; Mice, Transgenic; Ramipril; Renin; Renin-Angiotensin System; Sodium Chloride, Dietary; Time Factors

The COL4A3-/- mouse serves as animal model for progressive renal fibrosis. Using this animal model, the present study investigates the nephroprotective effects of Paricalcitol versus Calcitriol alone and on top of ACE-inhibitor therapy.. Eighty six mice were divided into six groups: (PC) with Paricalcitol 0.1 mcg/kg, (CA) Calcitriol 0.03 mcg/kg (dose equipotent), (PLAC) vehicle 0.1 mL i.p. five times per week, (ACE + PC) Paricalcitol plus Ramipril, (ACE + CA) Calcitriol plus Ramipril and (ACE + PLAC) vehicle plus Ramipril 10 mg/kg/day p.o. ACE therapy started pre-emptively in Week 4, PC/CA therapy was initiated in 6-week-old animals with ongoing renal fibrosis and lasted for 8 weeks. Four to six animals were sacrificed after 9.5 weeks and kidneys were further investigated using histological, immunohistological and Western-blot techniques. Survival until end-stage renal failure was determined in the remaining animals.. PC, but not CA, prolonged lifespan until renal failure by 13% compared with untreated controls (P = 0.069). ACE-inhibition prolonged lifespan by >50%. Added on top of ACE inhibition, ACE + PC (but not ACE + CA) even further prolonged lifespan by additional 18.0% (P < 0.01 versus ACE + PLAC) and improved renal function (blood urea nitrogen; P < 0.05 versus ACE + CA). Accumulation of extracellular matrix and renal scarring was decreased in PC and ACE + PC-treated mice.. The present study demonstrated a substantial nephroprotective and antifibrotic effect of the vitamin D-receptor activator Paricalcitol on top of early ACE inhibition in the COL4A3-/- model of progressive kidney fibrosis. The synergistic effect of Paricalcitol on top of RAAS-blockade might as well be valuable in other chronic kidney diseases.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autoantigens; Bone Density Conservation Agents; Calcitriol; Collagen Type IV; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Ergocalciferols; Extracellular Matrix; Female; Fibrosis; Immunoblotting; Immunoenzyme Techniques; Kidney Diseases; Male; Mice; Mice, Knockout; Ramipril; Receptors, Calcitriol

Impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signaling is involved in the pathogenesis of ischemic heart diseases, yet the impact of long-term sGC activation on progressive cardiac remodeling and heart failure after myocardial infarction (MI) has not been explored. Moreover, it is unknown whether stimulating the NO/heme-independent sGC provides additional benefits to ACE inhibition in chronic ischemic heart failure. Starting 10 days after MI, rats were treated with placebo, the sGC activator ataciguat (10 mg/kg/twice daily), ramipril (1 mg/kg/day), or a combination of both for 9 weeks. Long-term ataciguat therapy reduced left ventricular (LV) diastolic filling pressure and pulmonary edema, improved the rightward shift of the pressure-volume curve, LV contractile function and diastolic stiffness, without lowering blood pressure. NO/heme-independent sGC activation provided protection over ACE inhibition against mitochondrial superoxide production and progressive fibrotic remodeling, ultimately leading to a further improvement of cardiac performance, hypertrophic growth and heart failure. We found that ataciguat stimulating sGC activity was potentiated in (myo)fibroblasts during hypoxia-induced oxidative stress and that NO/heme-independent sGC activation modulated fibroblast-cardiomyocyte crosstalk in the context of heart failure and hypoxia. In addition, ataciguat inhibited human cardiac fibroblast differentiation and extracellular matrix protein production in response to TGF-β1. Overall, long-term sGC activation targeting extracellular matrix homeostasis conferred cardioprotection against progressive cardiac dysfunction, pathological remodeling and heart failure after myocardial infarction. NO/heme-independent sGC activation may prove to be a useful therapeutic target in patients with chronic heart failure and ongoing fibrotic remodeling.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiotonic Agents; Cell Communication; Cells, Cultured; Disease Models, Animal; Drug Therapy, Combination; Enzyme Activation; Enzyme Activators; Extracellular Matrix; Fibrosis; Guanylate Cyclase; Heart Failure; Hemodynamics; Humans; Male; Mice; Mitochondria, Heart; Myocardial Contraction; Myocardial Infarction; Myocytes, Cardiac; Myofibroblasts; Nitric Oxide; Nitric Oxide Synthase Type III; ortho-Aminobenzoates; Oxidative Stress; Ramipril; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Sulfonamides; Superoxides; Time Factors; Ventricular Function, Left; Ventricular Remodeling

While it is known that non-steroidal anti-inflammatory drugs including selective cyclooxygenase-2 (COX-2) inhibitors influence BP, the exact relationship and underlying mechanisms are still unclear. We investigated the effect of etoricoxib, a selective COX-2 inhibitor on the antihypertensive efficacy of atenolol; beta-blocker, ramipril; angiotensin converting enzyme inhibitor and telmisartan; angiotensin receptor blocker in deoxycorticosterone acetate (DOCA)-salt hypertensive rats, a mineralocorticoid volume expansion model. Etoricoxib attenuated the antihypertensive-induced reduction of systolic (atenolol; P < .001, ramipril; P = .011, telmisartan; P = .003) and mean arterial pressure (atenolol; P < .001, ramipril; P = .032, telmisartan; P = .023). These results demonstrate that COX-2 dependent mechanisms play a significant role in blood pressure regulation, and etoricoxib-induced COX-2 inhibition blunts the therapeutic effect of different classes of antihypertensives in this mineralocorticoid volume expansion model of hypertension.

Topics: Animals; Antihypertensive Agents; Atenolol; Benzimidazoles; Benzoates; Blood Pressure; Cyclooxygenase 2 Inhibitors; Desoxycorticosterone Acetate; Disease Models, Animal; Etoricoxib; Hypertension; Mineralocorticoids; Pyridines; Ramipril; Rats; Rats, Sprague-Dawley; Sodium Chloride; Sulfones; Telmisartan

Bardoxolone methyl is an antioxidant inflammation modulator acting through induction of Keap1-Nrf2 pathway. Results from a recent phase IIb clinical trial reported that bardoxolone methyl was associated with improvement in the estimated glomerular filtration rate in patients with advanced chronic kidney disease and Type 2 diabetes. However, increases in albuminuria, serum transaminase, and frequency of adverse events were noted. We studied the effect of 3-mo treatment with RTA 405, a synthetic triterpenoid analog of bardoxolone methyl in Zucker diabetic fatty rats with overt Type 2 diabetes. Rats were treated from 3 mo of age with vehicle, RTA 405, ramipril, or RTA 405 plus ramipril. RTA 405 caused severe changes in food intake and diuresis with decline in body weight, worsening of dyslipidemia, and increase in blood pressure. Early elevation in serum transaminase was followed by liver injury. RTA 405 worsened proteinuria, glomerulosclerosis, and tubular damage. Ramipril was renoprotective, but when given with RTA 405 it was not able to limit its worsening effects. These data could be due to degradation products in the drug substance used, as disclosed by the company once the study was concluded. To overcome such a drawback, the company offered to test dh404, a variant of RTA 405, in Zucker diabetic fatty rats. The dh404 did not display beneficial effects on proteinuria, glomerulosclerosis, and interstitial inflammation. Rather, kidneys from three rats receiving dh404 showed the presence of a granulomatous and inflammatory process reminiscent of a pseudotumor. Altogether these data raise serious concerns on the use of bardoxolone analogs in Type 2 diabetic nephropathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Chromatography, Liquid; Diabetic Nephropathies; Disease Models, Animal; Diuresis; Drinking; Hemodynamics; Kidney; Liver; Male; Mass Spectrometry; Oleanolic Acid; Ramipril; Rats; Rats, Zucker; Renal Circulation; Triterpenes

Angiotensin converting enzyme inhibitors have been used clinically to prevent myocardial infarction (MI). The angiotensin converting enzyme inhibitors attenuated ventricular remodeling and improved cardiac function by inhibition of matrix metalloproteinases after MI. Although the effect is thought to be a class effect, there are significant differences among the drugs. The aim of this study was to compare the effects of imidapril and ramipril on ventricular remodeling after MI.. The middle portion of left anterior descending artery was ligated to induce a moderate size MI in rats (moderate MI group). The proximal portion of the artery was ligated to induce a large size MI (large MI group). The animals were assigned to subgroups in moderate MI group and large MI group: (1) nontreated group, (2) ramipril group (1 mg/kg daily), and (3) imidapril group (1 mg/kg daily). All rats were killed on day 28 after the MI operation.. Although the nontreated MI group showed impaired ventricular contraction and severe fibrosis, imidapril significantly negated ischemia-induced changes. Imidapril had a superior effect for preventing ventricular remodeling characterized by fibrosis and collagen accumulation in left ventricle compared with ramipril in the moderate and large MI groups, even though the dosage used in this study was too small to reduce systemic blood pressure.. Imidapril can be used as a substitute for ramipril to prevent ventricular remodeling after MI.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Collagen; Disease Models, Animal; Fibrosis; Imidazolidines; Male; Myocardial Contraction; Myocardial Infarction; Ramipril; Rats; Rats, Sprague-Dawley; Ventricular Remodeling

An increase in the production of reactive oxygen species is commonly thought to contribute to the development of diabetic cardiomyopathy. This study aimed to assess whether administration of the antioxidant coenzyme Q(10) would protect the diabetic heart against dysfunction and remodelling, using the db/db mouse model of type 2 diabetes. Furthermore, we aimed to compare the efficacy of coenzyme Q(10) to that of the ACE inhibitor ramipril.. Six-week-old non-diabetic db/+ mice and diabetic db/db mice received either normal drinking water or water supplemented with coenzyme Q(10) for 10 weeks. Endpoint cardiac function was assessed by echocardiography and catheterisation. Ventricular tissue was collected for histology, gene expression and protein analysis.. Untreated db/db diabetic mice exhibited hyperglycaemia, accompanied by diastolic dysfunction and adverse structural remodelling, including cardiomyocyte hypertrophy, myocardial fibrosis and increased apoptosis. Systemic lipid peroxidation and myocardial superoxide generation were also elevated in db/db mice. Coenzyme Q(10) and ramipril treatment reduced superoxide generation, ameliorated diastolic dysfunction and reduced cardiomyocyte hypertrophy and fibrosis in db/db mice. Phosphorylation of Akt, although depressed in untreated db/db mice, was restored with coenzyme Q(10) administration. We postulate that preservation of cardioprotective Akt signalling may be a mechanism by which coenzyme Q(10)-treated db/db mice are protected from pathological cardiac hypertrophy.. These data demonstrate that coenzyme Q(10) attenuates oxidative stress and left ventricular diastolic dysfunction and remodelling in the diabetic heart. Addition of coenzyme Q(10) to the current therapy used in diabetic patients with diastolic dysfunction warrants further investigation.

Topics: Animals; Antihypertensive Agents; Apoptosis; Cardiomegaly; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Endomyocardial Fibrosis; Female; Hyperglycemia; Lipid Peroxidation; Mice; Mice, Inbred C57BL; Oxidative Stress; Proto-Oncogene Proteins c-akt; Ramipril; Superoxides; Ubiquinone; Ultrasonography; Ventricular Remodeling; Vitamins

The current study aims to explore the effect of ramipril on the occurrence of ventricular arrhythmias and its possible mechanism after myocardial infarction (MI) in rabbits.. A total of 24 rabbits were divided into three groups: the sham operation group (SHAM), the MI group, and the ramipril group (RAM). All groups were subjected to thoracotomy under sterile conditions; the MI and RAM groups underwent ligation of the left anterior descending coronary artery. On the second day after surgery, the RAM group was given ramipril (1 mg/kg per day). The rabbits in each group were fed for 12 weeks. The monophasic action potentials of the epicardium, mid-myocardium and endocardium in each group were, respectively, recorded before the MI and at 12 weeks after the MI. Meanwhile, the episodes of ventricular tachycardia or fibrillation (VT/VF) induced by procedure stimulations were counted, and the changes in L-type Ca flux (Ica-L) were recorded by means of the whole-cell patch-clamp technique.. The episodes of VT/VF were decreased in the RAM group after MI. At 12 weeks after MI, the transmural dispersion of repolarization (TDR) in the MI group was prolonged significantly compared with the SHAM and RAM groups. The density of Ica-L in the MI group was significantly lower than that any other group.. Ramipril manifestly decreases the incidence of VT/VF after MI in rabbits, and the mechanism may be associated with its inhibitory effect on electrical remodeling after MI.

Topics: Action Potentials; Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channels, L-Type; Calcium Signaling; Cardiac Pacing, Artificial; Disease Models, Animal; Electrocardiography; Heart Ventricles; Myocardial Infarction; Myocardium; Patch-Clamp Techniques; Rabbits; Ramipril; Tachycardia, Ventricular; Time Factors; Ventricular Fibrillation

Gap junctions (GJs) between the cells play a pivotal role in the transformation and proliferation processes of vascular smooth muscle cells (VSMCs). However, the expression of the component proteins of GJs, connexins 40 and 43 (Cx40 and Cx43), are inconsistent in numerous cases. The aim of this study was to determine whether Cx40 and Cx43 play different roles in the renin-angiotensin system (RAS) involved in the remodeling of GJs in VSMCs under pathological conditions. A total of 28 male New Zealand white rabbits were divided medially into four groups: control, sham injury, injury and injury plus ramipril (0.5 mg/kg/day in the diet for two weeks). The animals were used to set up the rabbit model of arterial balloon injury. Transmission electron microscopy, western blotting, immunohistochemistry and reverse transcription‑polymerase chain reaction (RT-PCR) were performed on four samples of ballooned iliac arteries. Larger and more abundant GJs appeared in neointimal VSMCs and there were smaller and fewer GJs following ramipril treatment. mRNA and protein expression levels and level of immunostaining of Cx40 and Cx43 were consistently increased following injury. Although ramipril reduced the change in the levels of Cx43, no significant changes in Cx40 immunostaining, protein or mRNA levels were observed in the ramipril treatments. Ramipril may inhibit neointimal formation and downregulate the expression of Cx43 protein and mRNA, but the drug had no significant effect on the Cx40 protein and mRNA levels, suggesting that it was not Cx40 but Cx43 in GJs that contributes to the process of angiotensin II (Ang II)-converting enzyme inhibitors inhibiting the prolife-ration of VSMCs in balloon injury.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Catheterization; Cell Proliferation; Connexin 43; Connexins; Disease Models, Animal; Down-Regulation; Gap Junction alpha-5 Protein; Gap Junctions; Iliac Artery; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Rabbits; Ramipril; Renin-Angiotensin System

Recent studies revealed that co-morbidity and mortality due to cardiovascular disease are increased in patients with rheumatoid arthritis (RA) but little is known about factors involved in these manifestations. This study aimed at characterizing the impact of arthritis on oxidative stress status and tissue fibrosis in the heart of rats with adjuvant-induced arthritis (AIA).. AIA was induced with complete Freund's adjuvant in female Lewis rats. Animals were treated by oral administration of vehicle or angiotensin-converting enzyme inhibitor ramipril (10 mg/kg/day) for 28 days, beginning 1 day after arthritis induction. Isolated adult cardiomyocytes were exposed to 10 μM 4-hydroxynonenal (HNE) for 24 hours in the presence or absence of 10 μM ramipril.. Compared to controls, AIA rats showed significant 55 and 30% increase of 4-HNE/protein adducts in serum and left ventricular (LV) tissues, respectively. Cardiac mitochondrial NADP+-isocitrate dehydrogenase (mNADP-ICDH) activity decreased by 25% in AIA rats without any changes in its protein and mRNA expression. The loss of mNADP-ICDH activity was correlated with enhanced accumulation of HNE/mNADP-ICDH adducts as well as with decrease of glutathione and NADPH. Angiotensin II type 1 receptor (AT1R) expression and tissue fibrosis were induced in LV tissues from AIA rats. In isolated cardiomyocytes, HNE significantly decreased mNADP-ICDH activity and enhanced type I collagen and connective tissue growth factor expression. The oral administration of ramipril significantly reduced HNE and AT1R levels and restored mNADP-ICDH activity and redox status in LV tissues of AIA rats. The protective effects of this drug were also evident from the decrease in arthritis scoring and inflammatory markers.. Collectively, our findings disclosed that AIA induced oxidative stress and fibrosis in the heart. The fact that ramipril attenuates inflammation, oxidative stress and tissue fibrosis may provide a novel strategy to prevent heart diseases in RA.

Topics: Aldehydes; Angiotensin-Converting Enzyme Inhibitors; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Cells, Cultured; Dinoprostone; Disease Models, Animal; Female; Fibrosis; Lipid Peroxidation; Mitochondria, Heart; Myocardium; Myocytes, Cardiac; Oxidative Stress; Ramipril; Rats; Rats, Inbred Lew; Tumor Necrosis Factor-alpha

Aortic valve stenosis (AVS) is associated with significant cardiovascular morbidity and mortality. To date, no therapeutic modality has been shown to be effective in retarding AVS progression. We evaluated the effect of angiotensin-converting enzyme inhibition with ramipril on disease progression in a recently developed rabbit model of AVS.. The effects of 8 weeks of treatment with either vitamin D₂ at 25,000 IU for 4 days a week alone or in combination with ramipril (0.5 mg·kg⁻¹) on aortic valve structure and function were examined in New Zealand white rabbits. Echocardiographic aortic valve backscatter (AV(BS)) and aortic valve:outflow tract flow velocity ratio were utilized to quantify changes in valve structure and function.. Treatment with ramipril significantly reduced AV(BS) and improved aortic valve :outflow tract flow velocity ratio. The intravalvular content of the pro-oxidant thioredoxin-interacting protein was decreased significantly with ramipril treatment. Endothelial function, as measured by asymmetric dimethylarginine concentrations and vascular responses to ACh, was improved significantly with ramipril treatment.. Ramipril retards the development of AVS, reduces valvular thioredoxin-interacting protein accumulation and limits endothelial dysfunction in this animal model. These findings provide important insights into the mechanisms of AVS development and an impetus for future human studies of AVS retardation using an angiotensin-converting enzyme inhibitor.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aortic Valve; Aortic Valve Stenosis; Arginine; Carrier Proteins; Disease Models, Animal; Disease Progression; Echocardiography; Enzyme Inhibitors; Ergocalciferols; Humans; Male; Rabbits; Ramipril; Vitamins

ACE (angiotensin-converting enzyme) 2 is expressed in the heart and kidney and metabolizes Ang (angiotensin) II to Ang-(1-7) a peptide that acts via the Ang-(1-7) or mas receptor. The aim of the present study was to assess the effect of Ang-(1-7) on blood pressure and cardiac remodelling in a rat model of renal mass ablation. Male SD (Sprague-Dawley) rats underwent STNx (subtotal nephrectomy) and were treated for 10 days with vehicle, the ACE inhibitor ramipril (oral 1 mg·kg(-1) of body weight·day(-1)) or Ang-(1-7) (subcutaneous 24 μg·kg(-1) of body weight·h(-1)) (all n = 15 per group). A control group (n = 10) of sham-operated rats were also studied. STNx rats were hypertensive (P<0.01) with renal impairment (P<0.001), cardiac hypertrophy (P<0.001) and fibrosis (P<0.05), and increased cardiac ACE (P<0.001) and ACE2 activity (P<0.05). Ramipril reduced blood pressure (P<0.01), improved cardiac hypertrophy (P<0.001) and inhibited cardiac ACE (P<0.001). By contrast, Ang-(1-7) infusion in STNx was associated with further increases in blood pressure (P<0.05), cardiac hypertrophy (P<0.05) and fibrosis (P<0.01). Ang-(1-7) infusion also increased cardiac ACE activity (P<0.001) and reduced cardiac ACE2 activity (P<0.05) compared with STNx-vehicle rats. Our results add to the increasing evidence that Ang-(1-7) may have deleterious cardiovascular effects in kidney failure and highlight the need for further in vivo studies of the ACE2/Ang-(1-7)/mas receptor axis in kidney disease.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiomegaly; Disease Models, Animal; Drug Evaluation, Preclinical; Hypertension; Male; Nephrectomy; Peptide Fragments; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Sprague-Dawley; Renal Insufficiency

The cardioprotective property of Spondias mombin (SM) was investigated and compared with that of the ACE inhibitor, ramipril. Alterations to markers of myocardial injury and indices of antioxidant capacity by isoproterenol (ISP) intoxication were significantly corrected in groups treated with SM. The inflammatory index was increased by 24% in ISP-intoxicated group compared with control (P < 0.001) but reduced in the groups administered ISP and treated with 100 or 250 mg/kg SM by 17% (P < 0.001) and 11% (P < 0.05) respectively. Serum lactate dehydrogenase activity and cholesterol level which were significantly increased in ISP-intoxicated group compared with control were reduced in groups administered ISP and treated with SM. Serum phosphate levels in groups administered ISP and treated with SM were significantly lower than values obtained for the ISP-intoxicated group (P < 0.001). Tissue catalase and superoxide dismutase activities as well as glutathione level were significantly increased in groups administered ISP and treated with SM compared to ISP-intoxicated group while MDA and nitrite levels were decreased. Disruption in the structure of cardiac myofibrils by ISP intoxication was reduced by treatment with SM. Comparable results were obtained for ramipril. These results are indicative of the potent cardioprotective property of SM.

Topics: Anacardiaceae; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovascular Agents; Catalase; Cholesterol; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; Isoproterenol; L-Lactate Dehydrogenase; Male; Malondialdehyde; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nitrites; No-Reflow Phenomenon; Phosphates; Plant Extracts; Plant Leaves; Ramipril; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Time Factors

Recent studies have shown that inhibition of angiotensin-converting enzyme (ACE) or angiotensin II receptors causes upregulation of the B(1) receptor (B(1)R). Here we tested the hypothesis that activation of the B(1)R partly contributes to the cardiac beneficial effect of ACE inhibitor (ACEi) and angiotensin II receptor blockers (ARB). B(1)R knockout mice (B(1)R(-/-)) and C57Bl/6J (wild-type control animals, WT) were subjected to myocardial infarction (MI) by ligating the left anterior descending coronary artery. Three weeks after MI, each strain of mice was treated with vehicle, ACEi (ramipril, 2.5 mg kg(-1) day(-1) in drinking water) or ARB (valsartan, 40 mg kg(-1) day(-1) in drinking water) for 5 weeks. We found that: (1) compared with WT mice, B(1)R(-/-) mice that underwent sham surgery had slightly but significantly increased left ventricular (LV) diastolic dimension, LV mass and myocyte size, whereas systolic blood pressure, cardiac function and collagen deposition did not differ between strains; (2) MI leads to LV hypertrophy, chamber dilatation and dysfunction similarly in both WT and B(1)R(-/-) mice; and (3) ACEi and ARB improved cardiac function and remodelling in both strains; however, these benefits were significantly diminished in B(1)R(-/-) mice. Our data suggest that kinins, acting via the B(1)R, participate in the cardioprotective effects of ACEi and ARB.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Collagen; Disease Models, Animal; Female; Heart Rate; Hypertrophy, Left Ventricular; Ligation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocytes, Cardiac; Ramipril; Receptor, Bradykinin B1; Tetrazoles; Valine; Valsartan; Ventricular Dysfunction, Left

Inhibition of the angiotensin-converting enzyme (ACE) prevents maladaptive cardiac remodelling. Endothelial progenitor cells (EPC) from the bone marrow contribute to endothelial repair and neovascularization, effects that are potentially important during cardiac remodelling. We hypothesized that ACE inhibitors may exert beneficial effects during pressure-induced myocardial hypertrophy by regulating progenitor cell function.. In C57/Bl6 mice, development of cardiac hypertrophy induced by transaortic constriction (TAC) for 5 weeks was reduced by ramipril, 5 mg/kg p.o., independent of blood pressure lowering. Ramipril prevented TAC-induced apoptosis of cardiac myocytes and endothelial cells. On day 1 after TAC, upregulation of Sca-1(pos)/KDR(pos) EPC was observed, which was further increased by ramipril. EPC were persistently elevated in the TAC mice receiving vehicle treatment but not in the ramipril group after 5 weeks. These effects were independent of hypoxia-inducible factor-1alpha mRNA and protein expression. The ACE inhibitor but not TAC improved the migratory capacity of DiLDL(pos) EPC. Increased cardiac afterload induced upregulation of extracardiac neoangiogenesis. This effect was enhanced by ACE inhibition. Ramipril but not TAC markedly increased cardiac capillary density determined by the ratio of CD31(pos) cells to cardiomyocytes. Bone marrow transplantation studies revealed that TAC increased the percentage of bone marrow-derived GFP(pos) endothelial cells in the myocardium, and ramipril made this effect more pronounced.. ACE inhibition prevents pressure-induced maladaptive cardiac hypertrophy and increases intra- and extracardiac neoangiogenesis associated with the upregulation of EPC and amelioration of EPC migration. The regulation of progenitor cells from the bone marrow identifies a novel effect of ACE inhibitors during cardiac remodelling.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Blood Pressure; Cell Movement; Cells, Cultured; Disease Models, Animal; Endothelium, Vascular; Hypertension; Hypertrophy; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardium; Myocytes, Cardiac; Neovascularization, Physiologic; Ramipril

Glucose-fed rat is a model of insulin resistance that displays sensory polyneuropathy and hypertension. This study aimed at comparing the beneficial effects of N-acetyl-L-cysteine (NAC, antioxidant) and ramipril (angiotensin-1 converting enzyme inhibitor) on tactile and cold allodynia induced by chronic glucose feeding. Impact of these treatments was also assessed on hypertension, plasma glucose and insulin concentrations, insulin resistance and kinin B(1) receptor expression. Male Wistar rats (50-75 g) were given 10% d-glucose in their drinking water for 11 weeks or tap water (controls). Glucose-fed rats were treated either with NAC (1 g/kg/day, gavage), ramipril (1 mg/kg/day in drinking water) or no drug during the last 5 weeks. Glucose feeding for 6 weeks induced a significant increase in systolic blood pressure and hyperglycaemia which was accompanied by tactile and cold allodynia. At 11 weeks, plasma insulin, insulin resistance (HOMA index), kinin B(1) receptor mRNA in spinal cord and renal cortex and B(1) receptor binding sites in spinal cord were enhanced in glucose-fed rats. NAC and ramipril caused a progressive to complete inhibition of tactile and cold allodynia from 6 to 11 weeks. High systolic blood pressure, hyperinsulinemia, insulin resistance and kinin B(1) receptor expression were also normalized or attenuated in glucose-fed rats by either treatment. Results suggest that chronic treatment with an antioxidant or an ACE inhibitor provides similar beneficial effects on sensory polyneuropathy, hypertension and insulin resistance in glucose-fed rats. Both therapies were associated with a reduction of the expression of the pro-nociceptive kinin B(1) receptor.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Antioxidants; Blood Glucose; Blood Pressure; Body Weight; Cystine; Diabetes Complications; Disease Models, Animal; Down-Regulation; Drinking; Eating; Glucose; Hyperalgesia; Hypertension; Insulin; Insulin Resistance; Kidney Cortex; Male; Pain Measurement; Ramipril; Rats; Rats, Wistar; Receptor, Bradykinin B1; RNA, Messenger; Sensation; Spinal Cord; Time Factors

Endothelial dysfunction often precedes Type 2 diabetes-associated cardiovascular complications. One important cause of endothelial dysfunction is oxidative stress, which can lead to reduced nitric oxide (NO) bioavailability. In this study, we examined the effects of ramipril (an angiotensin-converting enzyme inhibitor, ACEI) on reactive oxygen species (ROS) production and endothelium-dependent vasodilation using a Type 2 diabetic (db/db) murine model. Plasma concentration of 8-isoprostane ([8-isoP]) was measured and used as an indication of the amount of ROS production. Six weeks of ramipril (10 mg/kg/day) treatment significantly reduced [8-isoP] and improved acetylcholine(ACh)-induced vasodilation in db/db mice without altering responses in wild-type (WT) mice. Responsiveness of smooth muscle cells to NO, assessed by sodium nitroprusside-induced vasodilation, was not different between db/db and WT mice regardless of ramipril or vehicle treatment. Our results suggest that ramipril specifically improved endothelium-dependent vasodilation in Type 2 diabetic mice, possibly by reducing ROS levels.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Male; Mice; Mice, Inbred Strains; Muscle, Smooth, Vascular; Nitric Oxide; Nitroprusside; Oxidative Stress; Ramipril; Reactive Oxygen Species; Time Factors; Vasodilation; Vasodilator Agents

We investigated whether the angiotensin converting enzyme inhibitor, ramipril, could attenuate white matter lesions caused by chronic hypoperfusion in the rat, and whether suppression of oxidative stress is involved in the resulting neuroprotection. The ramipril treatment group showed significant protection from development of white matter lesions in the optic tract, the anterior commissure, the corpus callosum, the internal capsule and the caudoputamen. The level of malondialdehyde (MDA) and the oxidized glutathione (GSSG)/total glutathione (GSH t) ratio was also significantly decreased in the ramipril group compared to the vehicle-treated group. These results suggest that ramipril can protect against white matter lesions that result from chronic ischemia due to its effects on free radical scavenging. Further efficacy should be studied in the treatment of cerebrovascular insufficiency states and vascular dementia.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Brain Injuries; Brain Ischemia; Chronic Disease; Disease Models, Animal; Free Radicals; Glutathione; Glutathione Disulfide; Malondialdehyde; Neuroglia; Ramipril; Rats; Rats, Sprague-Dawley

The RhoA-Rho kinase (ROCK) signaling pathway has an important role in cardiovascular diseases. However, the effect of Rho kinase inhibition on pressure overload-induced cardiac hypertrophy (POH) and associated diastolic dysfunction has not been evaluated. This study examined the effect of a selective ROCK inhibitor (GSK-576371) in a POH model, induced by suprarenal abdominal aortic constriction. POH rats were divided into the following four groups: 1 (GSK 1, n = 9) or 3 (GSK 3, n = 10) mg/kg bid GSK-576371, 1 mg.kg(-1).day(-1) ramipril (n = 10) or vehicle (n = 11) treatment for 4 wk. Sham animals (n = 11) underwent surgery without banding. Echocardiograms were performed before surgery and posttreatment, and hemodynamic data were obtained at completion of the study. Echocardiography showed an increase in relative wall thickness of the left ventricle (LV) following POH + vehicle treatment compared with sham animals. This was attenuated by both doses of GSK-576371 and ramipril. Vehicle treatment demonstrated abnormal diastolic parameters, including mitral valve (MV) inflow E wave deceleration time, isovolumic relaxation time, and MV annular velocity, which were dose dependently restored toward sham values by GSK-576371. LV end diastolic pressure was increased following POH + vehicle treatment compared with sham (6.9 +/- 0.7 vs. 3.2 +/- 0.7 mmHg, P = 0.008) and was reduced with GSK 3 and ramipril treatment (1.7 +/- 0.7, P < 0.01 and 2.9 +/- 0.6 mmHg, P < 0.01, respectively). Collagen I deposition in the LV was increased following POH + vehicle treatment (32.2%; P < 0.01) compared with sham animals and was significantly attenuated with GSK 1 (21.7%; P < 0.05), GSK 3 (23.8%; P < 0.01), and ramipril (35.5%; P < 0.01) treatment. These results suggest that ROCK inhibition improves LV geometry and reduces collagen deposition accompanied by improved diastolic function in POH.

Topics: Animals; Animals, Newborn; Antihypertensive Agents; Aorta, Abdominal; Body Weight; Cardiomegaly; Cell Proliferation; Cell Size; Cells, Cultured; Collagen; Diastole; Disease Models, Animal; Dose-Response Relationship, Drug; Echocardiography; Fibroblasts; Fibrosis; Hemodynamics; Hypertension; Immunohistochemistry; Ligation; Male; Myocardium; Myocytes, Cardiac; Polymerase Chain Reaction; Protein Kinase Inhibitors; Ramipril; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Ventricular Function, Left

Drugs interfering with the renin-angiotensin system (RAS) have been shown to reduce the incidence of stroke in patients at risk and to afford neuroprotection in experimental brain ischemia. This study aimed to compare potential neuroprotective effects of systemic pretreatment with the angiotensin receptor blocker, candesartan, and the angiotensin-converting enzyme (ACE)-inhibitor, ramipril, in normotensive Wistar rats after focal cerebral ischemia, with special emphasis on the regulation of neurotrophins.. Equipotent subcutaneous doses of candesartan and ramipril were determined via inhibition of pressor responses to intravenously injected angiotensin II (Ang II) or angiotensin I (Ang I), respectively. Accordingly, animals were treated with candesartan (0.1 mg/kg body weight, twice daily), ramipril (0.01 and 0.1 mg/kg body weight, twice daily) or vehicle (0.9% saline, twice daily), respectively, 5 days prior to middle cerebral artery occlusion (MCAO) with reperfusion. Severity of stroke was estimated via infarct size [magnetic resonance imaging (MRI) 48 h after MCAO] and neurological outcome (24 h, 48 h after MCAO). Measurements of neurotrophins/receptors in brain tissue were performed 48 h after MCAO.. Pretreatment with candesartan and ramipril (low dose) did not reduce blood pressure during MCAO, whereas ramipril high dose did. Candesartan, but not ramipril at any dose, significantly reduced stroke volume and improved neurological outcome. Poststroke mRNA and protein of the neurotrophin receptor, TrkB, were significantly elevated in animals treated with candesartan, but not ramipril.. Systemic pretreatment with a sub-hypotensive, RAS-blocking dose of candesartan affords neuroprotection after focal ischemia, associated with increased activity of the neurotrophin BDNF/TrkB system. Ramipril at sub-hypotensive and hypotensive, RAS-blocking doses showed no significant neuroprotective effects.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Brain Ischemia; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Incidence; Male; Pilot Projects; Ramipril; Rats; Rats, Wistar; Receptor, trkB; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; Stroke; Tetrazoles

We hypothesized that left ventricular (LV) remodeling and matrix loss in volume overload (VO) are mediated by bradykinin (BK) and exacerbated by chronic angiotensin-converting enzyme (ACE) inhibition.. Chronic ACE inhibition increases anti-fibrotic BK and does not attenuate LV remodeling in pure VO. The relative contribution of changes in extracellular matrix versus cardiomyocyte elongation in acute and chronic LV chamber remodeling during VO is unknown.. Echocardiography, LV collagen content, and isolated cardiomyocytes were studied in rats after aortocaval fistula (ACF) of 12 h, 2 and 5 days, and 4, 8, and 15 weeks. We also studied ACF rats after BK2 receptor (BK2R) blockade (2 days) or ACE inhibition (4 weeks).. At 2 days after ACF, LV end-diastolic dimension (LVEDD)/wall thickness was increased, and LV interstitial collagen was decreased by 50% without cardiomyocyte elongation. The BK2R blockade prevented collagen loss and normalized LVEDD/wall thickness. From 4 to 15 weeks after ACF, interstitial collagen decreased by 30% and left ventricular end-systolic (LVES) dimension increased despite normal LVES pressure and isolated cardiomyocyte function. The ACE inhibition did not decrease LVEDD/wall thickness, further decreased LV interstitial collagen, and did not improve LV fractional shortening despite decreased LVES pressure.. Immediately after ACF induction, eccentric LV remodeling is mediated by interstitial collagen loss without cardiomyocyte elongation. Acute BK2R blockade prevents eccentric LV remodeling and improves function. Chronic ACE inhibition does not prevent eccentric LV remodeling or improve function. These findings suggest that ACE inhibitor-mediated increase in LV BK exacerbates matrix loss and explains why ACE inhibition is ineffective in VO.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Collagen; Diastole; Disease Models, Animal; Heart Failure; Heart Ventricles; Male; Myocytes, Cardiac; Organ Size; Ramipril; Rats; Rats, Sprague-Dawley; Systole; Ventricular Function, Left; Ventricular Remodeling

Previous studies have demonstrated a high correlation between arterial hypertension and the development of lesions in the carotid glomus (CG) and autonomic ganglia (AG), characterized by extracellular matrix (ECM) expansion and reduction in the number of AG neurons. Because lowering blood pressure (BP) is the first step in controlling the deleterious effects of arterial hypertension, the objective was to evaluate possible differences between the beta-blocker atenolol (AT) and the angiotensin-converting enzyme (ACE) inhibitor ramipril (RAM) regarding a protective role on CG and AG, as target organs in the spontaneously hypertensive rat (SHR).. Male 12-week-old SHR and Wistar-Kyoto rats (WKY) were divided into SHR; SHR-RAM, 1 mg/kg/d; SHR-AT, 100 mg/kg/d; and WKY rats. After 6 months, the animals were sacrificed and CG and AG were processed by hematoxylin and eosin (H&E) and Masson's trichrome and immunohistochemistry (transforming growth factor-beta(1) and plasminogen activator inhibitor-1).. At the end of the experiment, SHR-AT and SHR-RAM showed a similar control in BP compared with SHR. However, SHR-RAM presented a significant reduction in ECM expansion in CG, AG, and autonomic nerves. Moreover, the number of neurons in AG was preserved with AT and even more with RAM, when compared with SHR group. Transforming growth factor-beta(1) and plasminogen activator inhibitor-1 were increased in CG and AG in SHR and in SHR-AT, whereas SHR-RAM showed a similar expression to the WKY group.. According to these results, RAM but not AT provided a significant protective role against structural changes in CG as well as in AG caused by arterial hypertension in SHR. This effect seems to be independent of BP reduction.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atenolol; Blood Pressure; Carotid Body; Disease Models, Animal; Extracellular Matrix; Ganglia, Autonomic; Hypertension; Male; Plasminogen Activator Inhibitor 1; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Time Factors; Transforming Growth Factor beta1

This study compares the effect of two different strategies to inhibit the renin-angiotensin system in the setting of acute myocardial infarction (MI). Male Wistar rats were treated with placebo, the angiotensin-converting enzyme (ACE) inhibitor ramipril (1 mg/kg/day), or the AT1 receptor antagonist, olmesartan (1 mg/kg/day), both initiated 1 week before induction of MI and continued for 6 weeks after MI. The inflammatory reaction in the heart was investigated 7 days post-MI by determination of macrophage infiltration and the expression of tumor necrosis factor (TNF-alpha), interleukin (IL)-1beta and IL-6 at mRNA and protein levels. Six weeks post-MI, cardiac function was measured following chronic implantation of catheters in the LV and femoral artery, and cardiac morphology and coronary structure were investigated in picrosirius-red stained hearts. In placebo-treated rats, macrophage infiltration was accompanied by upregulation of IL-1beta and IL-6 mRNA in the peri-infarct zone. TNF-alpha and IL-1beta mRNA and protein were also upregulated in the non-infarcted myocardium. Whereas both treatment regimes significantly reduced IL-6 upregulation, olmesartan additionally reduced macrophage infiltration and IL-1beta expression. Six weeks post-MI, placebo-treated MI animals developed an impaired cardiac function with structural remodeling of the myocardium and coronaries. While olmesartan and ramipril both improved cardiac function and reduced infarct size and myocardial/coronary remodeling, olmesartan was more effective not only in increasing vascular perimeter, inner vascular diameter and septal thickness but also in lowering media thickness of coronary arteries, inner left ventricular diameter, left ventricular circumference and left ventricular end-diastolic pressure than ramipril. Thus, following MI the AT1 receptor blocker, olmesartan, attenuated cardiac inflammatory reactions and protected myocardial/coronary structure and function of the failing heart proving to be of similar, in some cases superior effectiveness in this respect than the ACE inhibitor, ramipril.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Cardiovascular Diseases; Cardiovascular System; Disease Models, Animal; Dose-Response Relationship, Drug; Imidazoles; Inflammation; Interleukin-1; Interleukin-6; Male; Myocardial Infarction; Placebos; Ramipril; Rats; Rats, Wistar; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Tumor Necrosis Factor-alpha

Treatment with erythropoietin and AT1 blockers is protective in experimental acute cerebral ischemia, with promising results in pilot clinical studies in human stroke. This paper examines the effects of using both agents as combination therapy in acute ischemic stroke.. We used the single carotid ligation stroke model in the gerbil. Six groups of 50 gerbils were treated either with placebo, erythropoietin (intraperitoneally, 5000 IU/kg, 2 and 48 h after stroke), olmesartan (10 mg/kg per day in drinking water started 36 h after stroke), ramipril (2.5 mg/kg per day in drinking water started 36 h after stroke), erythropoietin + olmesartan, or erythropoietin + ramipril. Long-term (1 month) Kaplan-Meyer survival curves were obtained, and survivors were submitted at day 30 to immediate (object recognition test) and spatial (Morris water maze) memory function tests.. Erythropoietin alone and olmesartan alone, but not ramipril, significantly increased survival at day 30 compared with untreated controls (38, 30 and 6% versus 12%, respectively). Combined treatment with erythropoietin and olmesartan further increased the survival rate to 56%, whereas combined therapy with erythropoietin and ramipril decreased 30-day survival to 24% (P < 0.0001, erythropoietin + olmesartan versus erythropoietin + ramipril). Untreated stroke survivors had markedly altered performances in both the object recognition test (P = 0.0007) and the Morris water maze (P < 0.0001) tests at day 30 compared with normal gerbils. In erythropoietin-treated animals, ramipril therapy had no beneficial effect whereas olmesartan fully restored normal response to the memory tests.. Post-infarct treatment with olmesartan combined with early erythropoietin therapy has a protective effect on survival, and markedly improves long-term memory dysfunction in this experimental model.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Drug Therapy, Combination; Erythropoietin; Gerbillinae; Imidazoles; Kaplan-Meier Estimate; Male; Memory Disorders; Neuroprotective Agents; Ramipril; Recombinant Proteins; Stroke; Tetrazoles

The spontaneously hypertensive stroke-prone rat (SHR-SP) is an experimental model of malignant hypertension which lead to secondary alterations of the extracellular matrix. Our aim was to determine ACE-inhibitor related changes of proteases involved in the reconstruction of the extracellular matrix in the brain. Twelve SHR-SP rats were randomized into two groups. Each group was treated with either an antihypertensive dose of ramipril or placebo for 6 months. Brain tissue plasminogen activator (t-PA) and urokinase (u-PA) were quantified by using casein-dependent plasminogen zymography, matrix metalloproteinase (MMP)-2 and MMP-9, by MMP-zymography, and tissue inhibitor of MMP (TIMP)-1 and -2, by reverse zymography. The amounts of u-PA, t-PA, and MMPs were significantly reduced in animals treated with ACE inhibitor. Plasminogen zymography showed a 39% reduction of u-PA in the basal ganglia (p < 0.0001); t-PA expression was reduced by 26% in the cortex and by 33% in the basal ganglia (p < 0.0001). MMP-2 expression was reduced by 15% in the cortex (p < 0.05) and by 10% in the basal ganglia (p < 0.05); MMP-9 expression significantly decreased by 37% in the cortex and by 25% in the basal ganglia (p < 0.0001 each). No differences were observed in the amount of TIMP-1 or TIMP-2. These findings provide new insights into the biochemical mechanisms underlying extracellular matrix proliferation and its modulation by ACE inhibitors. Therapeutic alterations that influence the proteolytic systems might prove important in the prevention of extracellular matrix accumulation and secondary microvascular vessel wall changes.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Basal Ganglia; Brain; Cerebral Arteries; Cerebral Cortex; Disease Models, Animal; Down-Regulation; Extracellular Matrix; Hypertension; Intracranial Hemorrhage, Hypertensive; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Peptidyl-Dipeptidase A; Plasminogen; Ramipril; Rats; Tissue Inhibitor of Metalloproteinase-1; Tissue Plasminogen Activator; Treatment Outcome; Urokinase-Type Plasminogen Activator

The stroke-prone spontaneously hypertensive rat is a genetic model of severe hypertension with secondary vascular alterations. The aim of this study was to determine the influence of chronic hypertension and ramipril treatment on the extracellular matrix in the cerebral microvasculature.. The study consisted of three groups: six normotensive Wistar rats, six untreated spontaneously hypertensive rats, and six hypertensive rats treated with an antihypertensive dose of ramipril (1 mg kg(-1)day(-1)) for 6 months. Alterations in the extracellular matrix were examined by western blot, immunohistochemistry, and immunofluorescence using an antibody against collagen type IV.. Western blotting showed a reduction of the total amount of collagen type IV by 50% in the ramipril group compared with the untreated hypertensive group (51.0+/-9.3% reduction, p = 0.0004). Compared with the untreated hypertensive rats, ramipril treatment prevented a loss of vessel density in the cortex (23.4+/-1.0 versus 20.4+/-2.0, p < 0.0001) and revealed a reduction of the amount of collagen per vessel (0.54+/-0.04 versus 0.60+/-0.08, p = 0.037). The ratio between the vessel wall and the lumen (0.69+/-0.08 versus 1.31+/-0.13) and the relative collagen intensity was lowered in the ramipril group (18.1+/-4.7% reduction, p < 0.0001). Using these methods the ramipril group showed similar results than the normotensive group.. Ramipril treatment completely prevented these hypertensive vascular changes. These results may stimulate a therapeutic approach with angiotensin converting enzyme inhibition in human hypertensive small vessel disease.

Topics: Animals; Antihypertensive Agents; Basal Ganglia; Blotting, Western; Cerebral Arteries; Cerebral Cortex; Collagen Type IV; Disease Models, Animal; Hypertension; Immunohistochemistry; Neovascularization, Pathologic; Ramipril; Rats; Rats, Inbred SHR

Therapeutic strategies to prevent atherosclerotic plaque progression and achieve plaque stabilization involve 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase inhibitors (statins) and renin-angiotensin system (RAS)-blockade, but studies investigating the potentially additive effects of a combined treatment strategy are rare. We hypothesised that the adjunction of atorvastatin with telmisartan or ramipril might achieve additional effects on experimental atherosclerosis though statin-induced lipid-lowering is lacking. ApoE-/- mice were fed a high-fat diet for 12 weeks and randomized to either placebo (CON), atorvastatin (ATO), ramipril (RAM), telmisartan (TEL) or RAM+ATO and TEL+ATO (N=23 per group). RAS-blockade, but not ATO, reduced systolic blood pressure. None of the treatment regimens lowered systemic cholesterol levels or lipoprotein fractions. RAM, TEL and the combined therapy, but not ATO, significantly reduced aortic lipid deposition. All substances significantly reduced monocyte chemoattracting protein (MCP)-1 concentrations, macrophages and matrixmetalloproteinase (MMP)-9 content and enhanced plaque's content of tissue inhibitor of MMP (TIMP)-1, collagen and fibrous cap thickness, resulting in an overall decrease of advanced plaques (classified as types IV-VI). Additive effects of the adjunction were observed on MMP-9 gelatinolytic activity, interleukin (IL)-6 and IL-10 plasma levels. These results indicate that a combined treatment with RAS-blockade and statins may have additive effects on systemic cardiovascular risk markers even in the absence of lipid-reduction, although additional effects on atherosclerotic plaque progression and stability were not observed in this model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apolipoproteins E; Atherosclerosis; Atorvastatin; Benzimidazoles; Benzoates; Chemokine CCL2; Disease Models, Animal; Drug Therapy, Combination; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Interleukin-10; Interleukin-6; Macrophages; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Monocytes; Pyrroles; Ramipril; Renin-Angiotensin System; Telmisartan

It has been suggested that the beneficial effects of reperfusing the myocardium might be in part reversed by the occurrence of reperfusion injury. Oxidative stress was suggested to be implicating in the pathogenesis of ischemia-reperfusion (I/R) injury. Many antioxidative plants were shown to be cardioprotective in experimental models of myocardial ischemia-reperfusion (I/R) injury. The present study was designed to investigate the effects of pretreatment with alcoholic extract of Tinospora cordifolia in an in vivo rat model. The model adopted was that of surgically-induced myocardial ischemia, performed by means of left anterior descending coronary artery occlusion (LAD) for 30 min followed by reperfusion for another 4 h. Infarct size was measured by using the staining agent TTC (2,3,5-triphenyl tetrazolium chloride). Lipid peroxide levels in serum and in heart tissue were estimated spectrophotometrically by the methods developed by Yagi and Ohkawa et al. respectively. A lead II electrocardiogram was monitored at various intervals throughout the experiment. A dose dependent reduction in infarct size and in lipid peroxide levels of serum and heart tissue were observed with the prior treatment of T. cordifolia with various doses for 7 d compared to control animals. Hence, the present study suggests the cardioprotective activity of T. cordifolia in limiting ischemia-reperfusion induced myocardial infarction.

Topics: Alcohols; Animals; Antihypertensive Agents; Cardiotonic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Heart Rate; Intubation, Gastrointestinal; Male; Malondialdehyde; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Plant Extracts; Ramipril; Rats; Rats, Sprague-Dawley; Tinospora

Vasopeptidase inhibitors (VPi) may provide a new means of treating hypertension and congestive heart failure, because they simultaneously block angiotensin-converting enzyme (ACE) and neutral endopeptidase-24.11 (NEP-24.11), thereby inhibiting the renin-angiotensin system and enhancing vasodilator and natriuretic substances such as kinins and natriuretic peptides.. Using B(2) kinin receptor gene knockout mice (B(2)-/-), we tested the hypotheses that (1) VPi may provide better cardioprotection than ACE or NEP inhibitors alone (ACEi and NEPi) and (2) the effects of these inhibitors are partially mediated by kinins. Four weeks after myocardial infarction, B(2)-/- mice and B(2)+/+ mice were started on vehicle, ACEi (ramipril, 2.5 mg/kg/d), NEPi (candoxatril, 20 mg/kg/d) or VPi (omapatrilat, 50 mg/kg/d), which was continued for 20 weeks. Systolic blood pressure was measured weekly and cardiac function evaluated monthly by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were measured histopathologically.. We found that ACEi or NEPi improved cardiac function and remodeling and that these effects were more obvious in mice receiving VPi. Furthermore, the beneficial cardiac effects of ACEi, NEPi, and VPi were significantly attenuated in B(2)-/- mice. We concluded that dual inhibition of ACE and NEP with VPi provides better cardioprotection than ACEi or NEPi alone in mice with congestive heart failure induced by myocardial infarction, and these effects are mediated at least in part via kinins.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Collagen; Disease Models, Animal; Echocardiography; Heart; Heart Failure; Indans; Liver; Lung; Mice; Mice, Knockout; Muscle Cells; Neprilysin; Organ Size; Propionates; Pyridines; Ramipril; Thiazepines; Treatment Outcome; Ventricular Function, Left; Ventricular Remodeling

Increased vascular resistance is a hallmark of hypertension and involves structural alterations, which may entail smooth muscle cell hypertrophy or hyperplasia, or qualitative or quantitative changes in extracellular matrix (ECM) proteins. Since the renin-angiotensin-aldosterone system modulates these changes, we investigated the effects of 8 weeks of treatment with an angiotensin-converting enzyme (ACE) inhibitor, ramipril (RAM), or a dual ACE and neutral endopeptidase (NEP) inhibitor, MDL-100240 (MDL), on mesenteric small artery structure and ECM proteins in mRen2-transgenic rats (TGRs), an animal model of hypertension with severe cardiovascular damage.. Thirty-five 5-week-old rats were included in the study: six TGRs received RAM; five TGRs RAM + the bradykinin receptor inhibitor, icatibant; six TGRs, MDL; and five TGRs MDL + icatibant, while eight TGRs and five normotensive Sprague-Dawley controls were kept untreated. Mesenteric small arteries were dissected and mounted on a micromyograph. The media-to-lumen ratio (M/L) was then calculated. Vascular metalloproteinase (MMP) content was evaluated by zymography.. In untreated TGRs severe hypertension was associated with inward eutrophic remodelling of small arteries. Both RAM and MDL prevented the increase in blood pressure and M/L and decreased MMPs. Icatibant blunted the effect of MDL on BP, M/L and MMPs.. Changes in collagenase activity induced by ramipril and MDL are associated with prevention of small artery structural alterations in TGRs. Furthermore, MDL-induced enhancement of bradykinin could play a role in both the prevention of vascular structural alterations and in the stimulation of MMPs.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Benzazepines; Bradykinin; Bradykinin Receptor Antagonists; Disease Models, Animal; Drug Interactions; Hypertension; Immunohistochemistry; Male; Matrix Metalloproteinases; Mesenteric Arteries; Myography; Neprilysin; Pyridines; Ramipril; Rats; Rats, Sprague-Dawley; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Vascular Resistance; Vasoconstriction

Several studies have shown antifibrotic effects of angiotensin converting enzyme (ACE) inhibitors as well as of angiotensin receptor 1 (AT1) antagonists, however, prospective trials with clinical end points comparing these effects do not exist. COL4A3-/- mice develop a non-hypertensive progressive renal fibrosis. We used this animal model to compare the potential of ACE inhibitor vs AT1 antagonist to prevent renal fibrosis irrespective of blood pressure-dependent involvement by the renin system.. COL4A3-/- mice were treated with placebo, ramipril or candesartan. Blood pressure, proteinuria, serum urea and lifespan were monitored. Renal matrix was characterized by immuno-histochemistry, light and electron microscopy. Further biochemical analysis was provided using cDNA microarray and western blot techniques.. Untreated mice died of renal failure after 71+/-6 days. Ramipril and candesartan both delayed onset and reduced the extent of proteinuria. Both had minor effects on blood pressure and postponed onset of uraemia. Ramipril increased lifespan by 111% to 150+/-21 days (P<0.01), whereas candesartan resulted in only a 38% prolongation to 98+/-16 days (P<0.01). Ramipril reduced glomerular and tubulo-interstitial fibrosis and numbers of activated fibroblasts to a greater extent than candesartan. Microarray and western blot analysis revealed a higher antifibrotic potential of ramipril in terms of downregulation of TGFbeta, connective tissue growth factor, metalloproteinases and extracellular matrix proteins.. The results indicate an antifibrotic, nephroprotective effect of ACE inhibitors and AT1 antagonists in an animal model of progressive renal fibrosis. The greater antifibrotic effect of ramipril at the maximal therapeutic doses employed may not be explained by different antiproteinuric or blood pressure lowering properties, but by-in contrast to candesartan-its ability to hinder the proinflammatory, profibrotic activation of the angiotensin receptor 2.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Disease Models, Animal; Fibrosis; Hypertension, Renal; Kidney; Mice; Ramipril; Tetrazoles; Time Factors

The insulin-resistant, hyperinsulinemic, normoglycemic, and obese JCR:LA-cp rat was used to study the effects of ramipril (an ACE inhibitor) and AVE7688 (a dual inhibitor of ACE and neutral endopeptidases) on insulin sensitivity and vascular function. Both compounds reduced the surge of plasma insulin in a meal tolerance test by approximately 50%. Ramipril had no effect on acetylcholine-induced relaxation but increased the sensitivity to sodium nitroprus-side at low concentrations. AVE7688 significantly reduced the EC50 for acetylcholine to relax phenylephrine-contracted aortic rings. None of the compounds affected the baseline coronary flow and reactive hyperemia. Coronary flow response to bradykinin in AVE7688- and ramipril-treated rat hearts showed a significantly lower EC50 than in control rats. Maximum flow rate was not different between groups. In summary, both ramipril and AVE7688 had significant hypoinsulinemic and insulin-sensitizing effects. Whereas ramipril had limited vascular effects, AVE7688 had more marked beneficial vascular effects, probably of endothelial origin and possibly related to lowered insulin levels.

Topics: Acetylcholine; Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Aorta, Thoracic; Blood Glucose; Body Weight; Bradykinin; Diet; Disease Models, Animal; Eating; Endothelium, Vascular; Fasting; Heart; Heart Rate; Heterocyclic Compounds, 3-Ring; Insulin; Insulin Resistance; Male; Muscle, Smooth, Vascular; Neprilysin; NG-Nitroarginine Methyl Ester; Nitroprusside; Obesity; Organ Size; Phenylephrine; Ramipril; Rats; Vasoconstriction; Vasodilation

Acute pancreatitis is an inflammatory disease characterized by pancreatic tissue edema, acinar cell necrosis, hemorrhage and inflammation of the damaged gland. It is believed that acinar cell injury is initiated by the activation of digestive zymogens inside the acinar cells, leading finally to the autodigestion of the pancreas. Previous study in our laboratory demonstrated that cerulein-induced acute pancreatitis was associated with an up-regulation of local renin-angiotensin system (RAS) in rat pancreas. Therefore, the utilization of RAS inhibitors may provide a novel and alternative treatment for acute pancreatitis. By means of a rat model of cerulein-induced acute pancreatitis, results from the present study showed that an intravenous injection of saralasin, an antagonist for angiotensin II receptors, at a dose of 40 microg/kg 30 min before the induction of acute pancreatitis significantly attenuated pancreatic edema. Results from the biochemical measurements showed that pretreatment with saralasin at a dose of 20 microg/kg markedly reduced pancreatic injury, as evidenced by the decreased activities of alpha-amylase and lipase in plasma. However, the same recipe of ramiprilat, a specific inhibitor for angiotensin-converting enzyme, at a dose of 20 microg/kg did not provide any protective effect against acute pancreatitis. On the contrary, pretreatment with ramiprilat at a dose 40 microg/kg enhanced cerulein-induced pancreatic injury. Results from histopathological analysis of these RAS inhibitors further confirmed with those results as obtained from biochemical analysis. These data indicate that administration of saralasin but not ramiprilat could be protective against acute pancreatitis and that activation of pancreatic RAS in acute pancreatitis may play a role in pancreatic tissue injury.

Topics: Acute Disease; alpha-Amylases; Angiotensin Receptor Antagonists; Animals; Ceruletide; Disease Models, Animal; Edema; Injections, Intravenous; Lipase; Necrosis; Pancreatitis; Ramipril; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Saralasin

Alport syndrome (AS) is a common hereditary cause of end-stage renal failure in adolescence due to defects in type IV collagen genes. Molecular genetics allows early diagnosis, however, no preventive strategy can be offered. Using the COL4A3 -/- mouse, an animal model for human AS, we evaluated therapy with ramipril in mice.. One hundred and twenty-two Alport-mice were treated with 10 mg/kg/day ramipril added to drinking water. Proteinuria, serum-urea and lifespan were monitored. Renal matrix was characterized by immunohistochemistry, light- and electron microscopy, and Western blot.. Untreated COL4A3 -/- mice died from renal failure after 71 +/- 6 days. Early therapy starting at four weeks of age and continuing to death delayed onset and reduced the extent of proteinuria. Uremia was postponed by three weeks in treated animals. Lifespan increased by more than 100% to 150 +/- 21 days (P < 0.01). In parallel, decreased deposition of extracellular matrix and lessened interstitial fibrosis as well as reduced amounts of renal transforming growth factor-beta1 (TGF-beta1) could be demonstrated. Late therapy starting at seven weeks decreased proteinuria, however, lifespan did not increase significantly.. The results indicate an antiproteinuric and antifibrotic nephroprotective effect of ramipril in COL4A3 -/- mice is mediated by down-regulation of TGF-beta1. This effect in mice is enhanced by initiation of therapy during pre-symptomatic disease. The data in COL4A3 -/- mice as an animal-model for Alport syndrome suggest that ramipril might as well delay renal failure in humans with AS. Early diagnosis and preemptive treatment also may be crucial in humans.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autoantigens; Basement Membrane; Collagen Type IV; Disease Models, Animal; Extracellular Matrix; Fibrosis; Kidney; Kidney Glomerulus; Longevity; Mice; Mice, Knockout; Nephritis, Hereditary; Proteinuria; Ramipril; Renal Insufficiency; Transforming Growth Factor beta; Transforming Growth Factor beta1; Uremia

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cytoprotection; Disease Models, Animal; Kidney; Mice; Mice, Knockout; Nephritis, Hereditary; Ramipril

The development of left ventricular hypertrophy (LVH) and of structural abnormalities of the heart is a key abnormality in renal failure that potentially contributes to the high rate of cardiac death. In renal failure, the behavior of cardiomyocyte volume and number in the development of LVH has so far not been investigated. A potential role of the (local) renin-angiotensin system (RAS) in the genesis of LVH has been suspected. It was the aim of the present study in short-term experimental renal failure (1) to characterize cardiomyocyte volume and number and (2) to study whether they are affected by the angiotensin-converting enzyme (ACE) inhibitor ramipril.. Sprague-Dawley rats (N = 8 to 10 per group) had a subtotal nephrectomy (SNX) or sham operation and followed for 8 weeks. One SNX group received the ACE inhibitor ramipril (0.5 mg/kg body weight) in the drinking fluid. After perfusion fixation, the morphology of the heart was investigated using stereologic techniques.. Systolic blood pressure was slightly, but not significantly, higher in untreated SNX, but the left ventricular (LV) weight and LV weight/body weight ratio (2.32 +/- 0.20 mg/g) were significantly higher in SNX than in sham-operated animals (1.90 +/- 0.16 mg/g). Sarcomeric length was not significantly different between SNX and sham-operated animals. There was an increase in the number of terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL)-positive myocytes in SNX compared to sham-operated animals and a significant increase in cardiomyocyte volume (15,713 +/- 4557 microm3 vs. 10,067 +/- 2242 microm3, P < 0.01) as well as a decrease of cardiomyocyte numbers per unit myocardial volume (61.2 +/- 16.2 vs. 92.2 +/- 20.9 x 103/mm3) and per left ventricle (70.9 +/- 16.5 x 106 vs. 94.8 +/- 18.1 x 106, P < 0.05). Both abnormalities were abrogated by treatment with ramipril (6347 +/- 972.4 microm3 and 106 +/- 18.9 103/mm3 or 118 +/- 39.5 x 106, respectively), which also completely prevented the increase in LV weight/body weight ratio (1.83 +/- 0.14 mg/g).. LVH in renal failure is characterized by cardiomyocyte hypertrophy, but also cardiomyocyte drop out. A role of the RAS is suggested by the beneficial effect of ramipril treatment that is not accounted for by differences in blood pressure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Hypertrophy, Left Ventricular; Immunohistochemistry; In Situ Nick-End Labeling; Male; Myocytes, Cardiac; Ramipril; Rats; Rats, Sprague-Dawley; Renal Insufficiency; Renin-Angiotensin System; Sarcomeres

Cardiac angiotensin converting enzyme (ACE) is activated by an increase in wall stress and is involved in remodeling processes. Heart failure is often treated with ACE inhibitors and diuretics although diuretic treatment could activate the renin-angiotensin system (RAS).. To examine the effects of diuretic treatment on cardiac and circulating RAS in post-infarction chronic heart failure.. Myocardial infarction was produced by coronary artery ligation in spontaneously hypertensive rats. The rats were randomly assigned to receive either ramipril (1 mg/kg/day), furosemide (4 mg/kg/day), or combination therapy for 6 weeks, commencing 2 weeks after infarction.. All three treatment protocols equivalently attenuated reactive hypertrophy of the right ventricle and ventricular septum and improved left ventricular systolic function. Both cardiac ACE mRNA and activity were significantly increased in untreated rats. This increase was attenuated by both ramipril and furosemide and further depressed by the combination. The increase in activity was completely inhibited by either agent alone. Plasma renin activity was upregulated by ramipril or ramipril plus furosemide but not influenced by infarction or furosemide alone.. Furosemide and ramipril significantly reduced cardiac ACE and remodeling. Diuretics work favorably and do not interfere with the effects of ACE inhibitors. Possibly, a reduction in wall stress due to decreased volume overload accounts for the effects of diuretics on cardiac ACE in the treatment of post-infarction remodeling in hypertensive hearts. These data suggest a new mechanism for the frequently observed beneficial effect of diuretics in heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Chronic Disease; Disease Models, Animal; Diuretics; Drug Therapy, Combination; Furosemide; Heart Failure; Heart Ventricles; Hypertrophy, Left Ventricular; Male; Models, Cardiovascular; Myocardial Infarction; Peptidyl-Dipeptidase A; Placebos; Ramipril; Randomized Controlled Trials as Topic; Rats; Rats, Inbred SHR; Renin; Renin-Angiotensin System; RNA, Messenger; Statistics as Topic; Survival Analysis; Treatment Outcome; Ventricular Pressure; Ventricular Remodeling

Cardiovascular disease is the major cause of death in Western nations, although improved possibilities regarding diagnosis and therapy now exist. Endothelial dysfunction is triggered by cardiovascular risk factors such as hypercholesterolaemia, hypertension, adiposity and smoking, contributing to the common endpoint of atherosclerosis. This study examined the pharmacological effects of angiotensin-converting enzyme (ACE) and combined ACE-neutral endopeptidase (NEP) (vasopeptidase) inhibitors on endothelial dysfunction in the model of hyperlipidaemic rabbits. The focus of the study was to assess endothelial function after treatment with the ACE-NEP inhibitor AVE 7688 (30 mg/kg/day) in comparison to the ACE inhibitor (ACE-I) ramipril (1 mg/kg/day). Different parameters, such as endothelial function, blood pressure (BP), expansion of plaques, endothelial nitric oxide (NO) and superoxide (O2-) release and plasma levels of various lipidaemic parameters were analysed. Control groups consisted of one group fed only with normal diet, one group fed only with atherogenic diet and the direct control group fed with varied diets (six weeks atherogenic diet followed by 12 weeks normal diet). Since for the treatment of atherosclerosis, a change in feeding is absolutely necessary, in the present study, at the start of the treatments with AVE 7688 and ramipril, the rabbits food was changed to a normal diet. At the end of the study, mean arterial blood pressure (MAP) was measured in the anaesthetised animals. The values in standard, atherogenic and varied diet-fed rabbits were around 73 2 mmHg. Angiotensin I (Ang I) given intravenous (i.v.) induced a strong increase in MAP of about 20%. In both the treated groups Ang I-induced BP increase was inhibited. In contrast, i.v. bradykinin led to a strong reduction in MAP in both the treated groups of around 50%. Six weeks feeding with an atherogenic diet in the rabbits induced an enduring endothelial dysfunction despite the food subsequently being changed to a normal chow. All measured parameters indicated a significant favourable effect on endothelial dysfunction as a result of the two treatment regimens. Endothelial function measured in the organ chamber showed somewhat greater improvement in the ACE-NEP treated group than in the ACE-I treated group. The treatment with ramipril, as well as with AVE 7688, restored endothelial function by increasing the ratio of NO to O2- concentration and bioavailability of NO. In this study, a

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Arteriosclerosis; Blood Pressure; Body Weight; Diet, Atherogenic; Disease Models, Animal; Drug Therapy, Combination; Endothelium, Vascular; Heterocyclic Compounds, 3-Ring; Hypercholesterolemia; Male; Neprilysin; Prodrugs; Rabbits; Ramipril

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arteriosclerosis; Diabetes Mellitus; Disease Models, Animal; Humans; Hypertension; Imidazoles; Myocardial Infarction; Olmesartan Medoxomil; Rabbits; Ramipril; Rats; Tetrazoles; Time Factors

To investigate the effects of the dual angiotensin-converting enzyme (ACE) + neutral endopeptidase (NEP) inhibitor, MDL-100,240 (MDL), on hypertension and cardiovascular damage in male heterozygous transgenic Ren2 rats.. Blood-pressure-matched 5-week-old transgenic rats were allocated to receive a placebo, MDL (40 mg/kg body weight) or ramipril (5 mg/kg body weight) for 8 weeks. During the last 4 weeks, the bradykinin B2 receptor antagonist, icatibant (0.5 mg/kg body weight), was also administered subcutaneously via osmotic minipumps to 50% of the transgenic rats receiving MDL or ramipril. We measured blood pressure, heart weight, structural changes in the aorta and small resistance mesenteric arteries, and the plasma concentrations of adrenomedullin, aldosterone, atrial natriuretic peptide and cGMP. To verify if MDL could regress long-standing hypertension and full-blown cardiovascular damage, 3-month-old transgenic rats received MDL subcutaneously (3 and 10 mg/kg body weight, osmotic minipumps) for 4 weeks.. Compared with placebo, MDL decreased blood pressure (P < 0.001) and prevented left ventricular hypertrophy (P < 0.001), being as effective as ramipril. Hypertrophy and dilatation of the aorta and hypertrophy of the resistance arterioles were all prevented by MDL. Plasma aldosterone was decreased by MDL (P < 0.001), but not by ramipril. Icatibant blunted the decrease in blood pressure (P < 0.001), decreased cGMP concentrations and blunted the decrease in cross-sectional area of the resistance arteries in MDL-treated, but not in ramipril-treated, transgenic rats. In 3-month-old transgenic rats, MDL normalized blood pressure, regressed left ventricular hypertrophy and decreased adrenomedullin concentrations.. The dual ACE+NEP inhibitor MDL prevented and regressed severe hypertension and cardiovascular damage, even in this model of severe angiotensin II-dependent hypertension with pronounced cardiovascular damage. Enhancement of the effects of bradykinin has a role in such favourable outcomes.

Topics: Adrenomedullin; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Antihypertensive Agents; Benzazepines; Biomarkers; Blood Pressure; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Inhibitors; Heart; Hypertension; Male; Models, Cardiovascular; Neprilysin; Organ Size; Peptides; Pyridines; Ramipril; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Receptors, Bradykinin; Severity of Illness Index; Systole; Treatment Outcome; Vasoconstrictor Agents

The effect of ACE inhibition on the formation of advanced glycation end products (AGEs) and oxidative stress was explored. Streptozocin-induced diabetic animals were randomized to no treatment, the ACE inhibitor ramipril (3 mg/l), or the AGE formation inhibitor aminoguanidine (1 g/l) and followed for 12 weeks. Control groups were followed concurrently. Renal AGE accumulation, as determined by immunohistochemistry and both serum and renal fluorescence, were increased in diabetic animals. This was attenuated by both ramipril and aminoguanidine to a similar degree. Nitrotyrosine, a marker of protein oxidation, also followed a similar pattern. The receptor for AGEs, gene expression of the membrane-bound NADPH oxidase subunit gp91phox, and nuclear transcription factor-kappaB were all increased by diabetes but remained unaffected by either treatment regimen. Two other AGE receptors, AGE R2 and AGE R3, remained unchanged for the duration of the study. The present study has identified a relationship between the renin-angiotensin system and the accumulation of AGEs in experimental diabetic nephropathy that may be linked through oxidative stress

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Glycation End Products, Advanced; Guanidines; Male; Nitric Oxide Synthase; Ramipril; Rats; Rats, Sprague-Dawley; Time Factors

Left ventricular (LV) hypertrophy increases susceptibility to reperfusion arrhythmias and the angiotensin-converting enzyme inhibitor, ramipril, may reduce that susceptibility via regression of LV hypertrophy. Rats (n=12 per group) were subjected to abdominal aortic constriction (AC) or sham-operation (SH) and from 3 to 6 weeks after surgery, 3 AC groups received ramipril (0.01, 0.1, or 1 mg/kg per day p.o.) while the SH and 1 AC group received vehicle. Six weeks after surgery (ie after 3 weeks of treatment), the hearts were excised and subjected to independent Langendorf perfusion of left and right coronary beds. The left coronary bed was then subjected to ischemia (7 min) and reperfusion (5 min). Hypertrophied hearts from the vehicle AC group showed a significant increase in the incidence of reperfusion-induced ventricular fibrillation (VF) compared with control hearts from the SH group (92%* vs 33%: *p<0.05); this difference was abolished by ramipril (42%, 50%, and 42%, at 0.01, 0.1, or 1 mg/kg per day, respectively). The LV weight/body weight ratio was significantly increased in all AC groups (regardless of ramipril treatment) relative to the SH group. At the cellular level, myocyte length was significantly increased in the vehicle AC group, but was normalized by ramipril treatment (1 mg/kg per day). At the molecular level, atrial natriuretic factor (ANF) mRNA expression was also significantly increased in the vehicle AC group, but was again normalized by ramipril treatment (1 mg/kg per day). In conclusion, short-term treatment with ramipril reduced susceptibility to severe ventricular arrhythmias in hypertrophied rat hearts. This protection was achieved in the absence of a significant reduction in LV weight, but was accompanied by regression of myocyte hypertrophy, as reflected by reductions in cell size and ANF expression.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiomegaly; Disease Models, Animal; Heart Ventricles; Male; Myocardial Reperfusion Injury; Myocytes, Cardiac; Ramipril; Rats; Rats, Wistar; RNA, Messenger; Ventricular Fibrillation

Foam cell formation, the hallmark of early atherosclerosis, results from cholesterol accumulation in arterial macrophages. Angiotensin-II stimulates foam cell formation and angiotensin converting enzyme (ACE) inhibitors reduce atherosclerosis in animal models. The goal of the present study was to determine the effect of the ACE inhibitor Ramipril on the progression of atherosclerosis in apolipoprotein-E-deficient (E0) mice with already advanced atherosclerosis. Therefore, 4-month-old atherosclerotic E0 mice were treated with Ramipril for 2 and 4 months and compared to age-matched placebo-treated mice, as well as to control young (4-month-old) non-treated E0 mice, for their atherosclerosis. Histomorphometry showed that Ramipril treatment substantially inhibited atherogenesis as shown by 48 and 72% reduction in lesion size at 6 and 8 months of age, respectively, compared to the lesion size in age-matched placebo-treated mice. Moreover, the size of the atherosclerotic lesions in 6- and 8-month-old Ramipril-treated mice was almost identical to the size of atherosclerosis of the 4-month-old control mice. Moreover, Ramipril treatment of E0 mice, significantly reduced oxidized low-density lipoprotein (Ox-LDL) uptake by their peritoneal macrophages (MPM) by 32%, compared to Ox-LDL uptake by MPM from 6-month-old placebo mice, and even reduced it by 12% in comparison to Ox-LDL uptake by MPM from 4-month-old control mice. A significant decrease in the mRNA levels of the Ox-LDL receptor CD36 by 58% was observed in macrophages from 6-month-old Ramipril-treated mice compared to macrophages from the 6-month-old placebo-treated mice. There was even a significant reduction (by 32%) in CD36 mRNA levels in macrophages from the 6-month-old Ramipril-treated mice, compared to the CD36 mRNA levels in macrophages from the 4-month-old control mice. We thus conclude that administration of the ACE inhibitor Ramipril to E0 mice, which already exhibit significant atherosclerosis, blocked the progression of the atherosclerotic lesion build-up, a phenomenon that could be related to Ramipril-induced inhibition of Ox-LDL uptake by macrophages.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apolipoproteins E; Arteriosclerosis; CD36 Antigens; Cholesterol; Disease Models, Animal; Foam Cells; Lipoproteins, LDL; Macrophages, Peritoneal; Mice; Ramipril; RNA, Messenger

Activity and functional significance of the renal kallikrein-kinin-system in polycystic kidney disease of the rat.. The kallikrein-kinin-system is a complex multienzymatic system that has been implicated in the control of systemic blood pressure, glomerular filtration rate, and proteinuria. The present study investigated its functional role in rat polycystic kidney disease (PKD), which is characterized by progressive renal failure and proteinuria in the absence of systemic hypertension and stimulated renin-angiotensin-system.. Kallikrein and bradykinin levels were measured in plasma and urine of rats with polycystic kidneys and compared to non-affected controls (SD) and rats with reduced renal mass. The functional relevance of the kallikrein-kinin system (KKS) was assessed by the effects of a short-term treatment with either a selective bradykinin (BK) B1-receptor antagonist (des-Arg9-[Leu8]-BK), a B2-receptor antagonist (HOE 140), an angiotensin converting enzyme inhibitor (ramipril), or an angiotensin II-receptor blocker (HR 720) on systemic and renal parameters.. Urine levels of kallikrein were increased threefold in 9-month-old PKD, and BK excretion was increased tenfold in 3-month and 30-fold in 9-month-old PKD compared to age-matched SD rats. Blood pressure in 9-month-old PKD rats was decreased to the same degree by ramipril and HR 720. In contrast, only ramipril and HOE 140 significantly reduced proteinuria and albuminuria, independent from creatinine clearance. This effect was accompanied by an increased excretion of bradykinin. The B1 receptor antagonist had no influence on functional renal parameters.. The present study demonstrates an age-dependent activation of the renal KKS in rats with polycystic kidney disease. The bradykinin B2-receptor is involved in the pathogenesis of proteinuria, independent from systemic blood pressure or creatinine clearance. The antiproteinuric effect of ramipril in this model is angiotensin II-independent and related to its influence on the renal KKS.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Bradykinin; Bradykinin Receptor Antagonists; Disease Models, Animal; Imidazoles; Kallikreins; Kidney; Kinins; Male; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Ramipril; Rats; Rats, Sprague-Dawley

Using B(2) kinin receptor gene knockout mice (B(2)(-/-)), we tested the hypothesis that (l) lack of B(2) receptors may affect blood pressure and cardiac function and aggravate cardiac remodeling after myocardial infarction (MI), and (2) kinins partially mediate the cardiac beneficial effect of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT(1)-ant), whereas lack of B(2) receptors may diminish this cardioprotective effect. Chronic heart failure (HF) was induced by MI, which was caused by coronary artery ligation in both B(2)(-/-) and 129/SvEvTac mice (wild-type control, B(2)(+/+)). An ACEi (ramipril, 2.5 mg/kg/d) or AT(1)-ant (L-158809, 3 mg/kg/d) was given 1 week after MI and was continued for 12 weeks. Left ventricular (LV) ejection fraction, cardiac output (CO), diastolic LV dimension (LVDd), and LV mass were evaluated by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were studied histopathologically. We found that basal blood pressure and cardiac function were similar in B(2)(+/+) and B(2)(-/-) mice. After MI, development of HF and remodeling were also similar between the 2 strains. The ACEi improved cardiac function and remodeling in both strains; however, its effects were attenuated in B(2)(-/-) mice (respective values for B(2)(+/+) versus B(2)(-/-) mice: overall increase in ejection fraction, 64+/-10% versus 21+/-5% [P<0.01]; increase in CO, 69+/-17% versus 23+/-9% [P<0.01]; overall decrease in LVDd, -24+/-3% versus -7+/-4% [P<0.01]; and decrease in LV mass, -38+/-3% versus -6+/-6% [P<0.01]). AT(1)-ant had a beneficial cardiac effect similar to that produced by ACEi, and this effect was also diminished in B(2)(-/-) mice (respective values for B(2)(+/+) versus B(2)(-/-) mice: overall increase in ejection fraction, 46+/-10% versus 25+/-9% [P<0.01]; increase in CO, 44+/-14% versus 15+/-5% [P<0.01]; overall decrease in LVDd, -14+/-4% versus -6+/-3% [P<0.01]; and decrease in LV mass, -33+/-4 versus -16+/-7% [P<0.01]). The effect of ACEi or AT(1)-ant on myocyte cross-sectional area was similar between strains; however, their effect on the interstitial collagen fraction was diminished in B(2)(-/-) mice. We concluded that (1) lack of B(2) kinin receptors does not affect cardiac phenotype or function, either under normal physiological conditions or during the development of HF; and (2) kinins acting via the B(2) receptor play an important role in the cardioprotective effect

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Collagen; Cytoprotection; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Heart Failure; Heart Function Tests; Imidazoles; Mice; Mice, Inbred Strains; Mice, Knockout; Myocardial Infarction; Myocardium; Ramipril; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B2; Receptors, Bradykinin; Tetrazoles; Ventricular Remodeling

ACE inhibition (ACEI) attenuates post-myocardial infarction (MI) LV remodeling, but the effects of angiotensin II type 1 receptor (AT(1)) antagonism alone or in combination with ACEI are unclear. Accordingly, we investigated the effects of AT(1) antagonism, ACEI, and their combination in a well-characterized ovine postinfarction model.. Beginning 2 days after transmural anteroapical MI, 62 sheep were treated with 1 of 5 treatment regimens: no therapy (control, n=12), standard-dose ACEI (sACEI; ramipril 10 mg/d, n=14), high-dose ACEI (hACEI; ramipril 20 mg/d, n=8), AT(1) blockade (losartan 50 mg/d, n=13), and combination therapy with sACEI+AT(1) blockade (CT; ramipril 10 mg/d+losartan 50 mg/d, n=15). MRI was performed before and 8 weeks after MI to quantify changes in LV end-diastolic and end-systolic volume indices (DeltaEDVI, DeltaESVI) and ejection fraction (DeltaEF). Change in regional percent intramyocardial circumferential shortening in noninfarcted segments adjacent to the infarct (Adj Delta%S) was measured by tagged MRI. CT resulted in the most marked blunting of LV remodeling: DeltaESVI (+1.0+/-0.4, +0.7+/-0.4, +0.6+/-0.3, +0.9+/-0.5, and +0.4+/-0.2* mL/kg); DeltaEDVI (+0.9+/-0.4, +0.7+/-0.5, +0.6+/-0.5, +0.9+/-0.5, and +0.4+/-0.3 mL/kg); DeltaEF (-24+/-7, -18+/-6, -14+/-7, -18+/-10, and -11+/-9* %); and Adj Delta%S (-8+/-4, -7+/-3, -5+/-3, -5+/-3, and -2+/-3* %) for Control, sACEI, hACEI, AT(1) blockade, and CT, respectively (*P<0.04 versus sACEI, AT(1) blockade, and control; P<0.05 versus control; P<0.002 versus AT(1) blockade and control). EDVI and ESVI at 8 weeks after MI were smallest with CT (P<0.02 versus all).. Combination therapy with sACEI+AT(1) blockade shows promise in attenuating postinfarction LV remodeling but was not clearly superior to hACEI in the present study.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Electrocardiography; Female; Image Processing, Computer-Assisted; Losartan; Magnetic Resonance Imaging, Cine; Myocardial Infarction; Myocardium; Ramipril; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Sheep; Stroke Volume; Systole; Ventricular Function, Left; Ventricular Remodeling

Changes in podocyte number and morphology have been implicated in the pathogenesis of proteinuria and the progression of human and experimental kidney disease. This study sought to examine podocyte foot process and slit pore architecture in experimental diabetic nephropathy and to determine whether such changes were modified with renoprotective intervention by blockade of the renin-angiotensin system.. The number of filtration slits per 100 microm of glomerular basement membrane was assessed by transmission electron microscopy and quantitated histomorphometrically in control animals and in rats with 24 weeks of streptozotocin-induced diabetes. Diabetic rats were either untreated or received the angiotensin converting enzyme inhibitor ramipril, or the angiotensin II type 1 receptor antagonist, valsartan.. When compared with control animals, diabetes was associated with a decrease in the number of slit pores per unit length of glomerular basement membrane, indicative of podocyte foot process broadening. Both ramipril and valsartan attenuated these ultrastructural changes to a similar degree. These differences remained after correcting for glomerular volume as a possible confounding variable.. Preservation of podocyte architecture could contribute to the renoprotective effects of renin-angiotensin system blockade in diabetic nephropathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Basement Membrane; Blood Pressure; Diabetes Mellitus, Experimental; Disease Models, Animal; Disease Progression; Humans; Kidney; Kidney Glomerulus; Male; Organ Size; Ramipril; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

The role of kinins in the cardioprotective effects of ACE inhibitors remains controversial.. Right ventricular pressure overload in rabbits was produced by pulmonary artery banding for 21 days. Rabbits were untreated, or they received the ACE inhibitor ramipril with or without bradykinin B(1) and B(2) receptor blockers or the angiotensin (Ang) II type I (AT(1)) receptor blocker losartan. Pulmonary artery banding caused right ventricular hypertrophy, depressed papillary muscle contractility, and loss of Ang II contractile effects because of a signaling defect downstream of AT(1) receptors. Paradoxically, AT(1) receptor density and G protein alpha subunits alphaq and alphai1/2 increased. Inotropic responsiveness to the alpha-receptor agonist phenylephrine was normal. Ramipril preserved cardiac contractility, but this effect was attenuated by simultaneous use of kinin receptor blockers. Ramipril also maintained responsiveness to Ang II and prevented AT(1) receptor and G protein upregulation. The simultaneous use of a kinin receptor blocker attenuated but did not prevent upregulation in the AT(1) receptor and G protein. Losartan had no effect on baseline contractility, but it maintained cardiac inotropic responsiveness to Ang II, prevented upregulation of AT(1) receptors, but did not modify G protein upregulation.. Pressure overload of the right ventricle decreases contractility, uncouples AT(1) receptors to downstream signaling pathways, and changes the expression of components of the AT(1) receptor signaling pathway. Ramipril attenuates these effects via kinins. Interventions that prevent local increases in Ang II or block AT(1) receptors also prevent decreased responsiveness of the AT(1) receptor in this model.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; GTP-Binding Proteins; Hemodynamics; In Vitro Techniques; Kinins; Losartan; Male; Myocardial Contraction; Myocardium; Organ Size; Papillary Muscles; Protein Subunits; Pulmonary Artery; Rabbits; Ramipril; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Signal Transduction; Ventricular Dysfunction, Right

Osteopontin (OPN) is a macrophage chemotactic and adhesion molecule and has been shown to play a role in glomerular and tubulointerstitial injury in several kidney disease models.. The present study examined whether OPN expression is involved in the progression of renal disease following subtotal (5/6) nephrectomy (STNx) in rats and whether angiotensin II (Ang II) mediates the up-regulation of renal OPN expression and macrophage accumulation in this model by administering valsartan, an Ang II type I (AT1) receptor antagonist, or ramipril, an angiotensin-converting enzyme (ACE) inhibitor.. In normal and sham-operated rat kidneys, OPN was expressed in a few tubules (<5%) and was absent in glomeruli. Following STNx (weeks 2 to 16), there was substantial up-regulation of OPN mRNA and protein expression in glomeruli [2 to 12 cells/glomerular cross section (gcs)] and tubular epithelial cells (20 to 75% OPN+). The up-regulation of OPN expression was associated with macrophage accumulation within the kidney, severe proteinuria, loss of renal function, and severe histologic damage, including tubulitis and tubulointerstitial fibrosis (all P < 0.001). Treatment with either valsartan or ramipril completely abrogated the up-regulation of OPN mRNA and protein expression in glomeruli and tubules. The reduction in OPN expression was associated with a significant inhibition of macrophage accumulation and progressive renal injury (P < 0.001).. An up-regulation of OPN expression may play a role in progressive renal injury following STNx. Inhibition of OPN expression may be one of the mechanisms by which Ang II blockade attenuated renal injury after renal ablation.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Blotting, Northern; Disease Models, Animal; Gene Expression; In Situ Hybridization; Kidney; Macrophages; Male; Nephrectomy; Nephritis, Interstitial; Osteopontin; Ramipril; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sialoglycoproteins; Tetrazoles; Valine; Valsartan

The effects of angiotensin converting enzyme inhibition and angiotensin II receptor blockade on the development of cardiac hypertrophy and myocardial insulin-like growth factor I (IGF-I) in volume overload were studied in male Wistar rats with aorto-caval fistulas (ACF). Rats were treated with ramipril (RAM, 3 mg kg(-1) day(-1)) for 4-20 days or losartan (LOS, 10 mg kg(-1) day(-1)) for 2-7 days. Myocardial IGF-I and IGF-I receptor (IGF-I-R) mRNA were determined by solution hybridization. ACF caused hypertrophy of left (LV) and right ventricles (RV). Hypertrophy appeared on day 2 and reached maximal values of +60% in LV and +75% in RV at day 12. Systolic blood pressure was initially reduced 15% but recovered by day 12. RAM abolished the recovery of blood pressure. Furthermore, RAM attenuated RV hypertrophy by 17% on day 7 and on day 20, RV weights were close to values found in controls. Beginning on day 9, RAM reduced LV weight back to control levels in parallel to blood pressure. In contrast, LOS affected neither RV nor LV hypertrophy. RV IGF-I mRNA increased 60-100% on day 7 alone in RV in ACF. RAM potentiated the increase in RV IGF-I to +400% and induced an increase in RV IGF-I-R mRNA on day 7 (+90%) in ACF. LOS did not affect RV IGF-I. Development of cardiac hypertrophy in ACF seemed independent of angiotensin II. RV hypertrophy was associated with activation of IGF-I independent of the renin-angiotensin system. IGF-I was further potentiated when development of hypertrophy was attenuated, possibly indicative of a greater urge for compensational growth in a relatively thinner and more volume-distended chamber.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta, Abdominal; Aortic Diseases; Arteriovenous Fistula; Cardiomegaly; Disease Models, Animal; Follow-Up Studies; Hemodynamics; Insulin-Like Growth Factor I; Losartan; Male; Myocardium; Pilot Projects; Ramipril; Rats; Rats, Wistar; Receptor, IGF Type 1; Renin-Angiotensin System; RNA, Messenger; Vena Cava, Inferior

High dosages of catecholamines induce cardiomyocyte necrosis and interstitial fibrosis in rats. We investigated whether this initial damage is followed by the development of heart failure and assessed the particular role of the renin-angiotensin system using ramipril.. Following the administration of 0 mg or 150 mg isoproterenol/kg 6 groups of Wistar rats were followed for 2 or 16 weeks: Sham, isoproterenol, isoproterenol + ramipril. Isoproterenol induced significant increases of echocardiographically measured left ventricular end-diastolic posterior wall thickness and dimension, whereas ramipril treatment significantly attenuated these changes. Left ventricular end-diastolic pressure was markedly increased in isoproterenol-treated rats and normalized following ramipril. Isoproterenol rats were further characterized by hormonal activations including transient elevations of plasma renin activity, aldosterone and cardiac angiotensin converting enzyme activity. Histomorphological characterization of isoproterenol-treated hearts demonstrated cardiomyocyte necrosis and reparative fibrosis. Ramipril treatment only slightly reduced the amount of necrosis as well as the expression of extracellular matrix proteins.. In rats, a toxic dosage of isoproterenol caused characteristic myocardial damage that subsequently resulted in mild heart failure. Ramipril administration following isoproterenol was highly effective to attenuate hemodynamic and hormonal alterations as well as the development of left ventricular hypertrophy, but had only little influence on the expression of extracellular matrix proteins. Since angiotensin converting enzyme inhibition had no impact on the initial myocardial injury, the development of heart failure in this model seems to require functional integrity of the renin-angiotensin system.

Topics: Adrenergic beta-Agonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Echocardiography; Female; Fibronectins; Heart Failure; Image Processing, Computer-Assisted; Immunohistochemistry; Isoproterenol; Laminin; Myocardium; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Sprague-Dawley; Rats, Wistar; Renin-Angiotensin System; Statistics, Nonparametric

Cardioprotective effects of the angiotensin-converting enzyme inhibitors captopril and ramiprilat were studied in two in vivo canine models of myocardial ischemic injury: 90 min of regional ischemia with 18 h reperfusion (protocol I) and 6 h of continuous ischemia without reperfusion (protocol II). In protocol I, neither ramiprilat (50 micrograms/kg) nor captopril (5 mg/kg + 0.25 mg/kg/h) reduced infarct size after 18 h of reperfusion (vs. controls). In protocol II, drugs were administered directly into both left anterior descending coronary artery and left circumflex branch. Compared to controls, continuous intracoronary administration of ramiprilat (40 ng/kg/min) or captopril (400 ng/kg/min) did not reduce infarct size. Thus neither captopril nor ramiprilat protected the heart from injury under conditions of ischemia with reperfusion or ischemia without reperfusion.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Coronary Circulation; Coronary Vessels; Disease Models, Animal; Dogs; Evaluation Studies as Topic; Heart Rate; Hemodynamics; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Ramipril

A increase in left ventricular mass after ventricular damage has been identified as an initial response to injury. However, the functional significance of this response has not been clearly established and is the focus of this study.. Twelve mongrel dogs underwent transmyocardial direct current shock to produce transmural left ventricular damage. Six were assigned to converting enzyme inhibitor therapy initiated 24 hours after damage and continued for 4 weeks. The remaining six dogs served as a control group. Left ventricular structure (mass and end diastolic volume) and systolic function (regional and global ejection fraction at rest and during afterload stress) were assessed by magnetic resonance imaging before damage and at the end of the 4-week period. After myocardial damage, left ventricular mass increased from 93.6 +/- 4.0 to 107.5 +/- 3.4 gm in the control group (P < .01) with no change in ventricular volume. Ramipril-treated dogs displayed a reduction in mass (83.2 +/- 2.2 to 74.6 +/- 2.9 gm, P < .05). In the control group, there was greater reduction in global ejection fraction in response to afterload stress at 4 weeks compared with baseline (-16 +/- 4 vs -4 +/- 3%, P = .03). Ejection fraction response to afterload stress was maintained at 4 weeks in the converting enzyme inhibitor-treated group (-5 +/- 3 vs - 1 +/- 4%) and was different at 4 weeks from the control group (-1 +/- 4 vs -16 +/- 4%, P = .004).. The increase in left ventricular mass noted after direct current shock was associated with the impairment of systolic function during afterload stress. Inhibition of this mass increase results in preservation of function, thus further supporting the concept that attenuation of ventricular remodeling should be a therapeutic goal.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Output; Disease Models, Animal; Dogs; Electroshock; Heart Injuries; Heart Rate; Hemodynamics; Hypertrophy, Left Ventricular; Myocardial Ischemia; Ramipril; Reference Values; Stress, Mechanical; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Remodeling

Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT1-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT1-ant may block the RAS at the level of the AT1 receptor and activate the angiotensin II type 2 (AT2) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT1-ant has a similar effect and whether these effects are partly due to activation of the AT2 receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B2 receptor antagonist icatibant (B2-ant); or (c) an AT1-ant with and without an AT2-antagonist (AT2-ant) or B2-ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT1-ant. The B2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT1-ant was blocked by the AT2-ant. The decreases in LVEDV and LVESV caused by the AT1-ant were also partially blocked by the B2-ant. We concluded that (a) in HF both ACEi and AT1-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT1-ant is triggered by activation of the AT2 receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT1 receptors increases both renin and angiotensins; these angiotensins stimulate the AT2 receptor, which in turn may play an important role in the therapeutic effect of the AT1-ant via kinins and other autacoids.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Cardiovascular System; Disease Models, Animal; Drug Interactions; Heart Failure; Imidazoles; Kinins; Male; Models, Cardiovascular; Myocardial Infarction; Myocardium; Pyridines; Ramipril; Rats; Rats, Inbred Lew; Receptor, Angiotensin, Type 1; Tetrazoles

The main objective of this study was to determine if the components of the kallikrein-kinin system are released into the venous effluent from isolated perfused rat hearts. To assess the contribution of kinins and the vascular and cardioprotective effects of the ACE inhibitor ramipril, we determined the status of cardiac kallikrein (CKK), potent kinin-generating enzyme, in rats with right ventricular hypertrophy induced by chronic volume overload and left ventricular hypertrophy by aortic banding. CKK was measured as previously described (Nolly, H.L., Carbini, L., Carretero, O.A., Scicli, A.G., 1994). Kininogen by a modification of the technique of Dinitz and Carvalho (1963) and kinins were extracted with a Sep-Pak C18 cartridge and measured by RIA. CKK (169 +/- 9 pg Bk/30 min), kininogen (670 +/- 45 pg Bk/30 min) and immunoreactive kinins (62 +/- 10 pg Bk/30 min) were released into the perfusate. The release was almost constant over a 120 min period. Pretreatment with the protein synthesis inhibitor puromycin (10 mg i.p.) lowered the release of kallikrein (42 +/- 12 pg Bk/30 min, p < 0.001) and kininogen (128 +/- 56 pg Bk/30 min, p < 0.001). Addition of ramiprilat (10 micrograms/ml) increased kinin release from 54 +/- 18 to 204 +/- 76 pg Bk/30 min (p < 0.001). Aortic banding of rats increased their blood pressure (BP) (p < 0.001), relative heart weight (RHW) (p < 0.001) and CKK (p < 0.001). Ramipril treatment induced a reduction in BP (p < 0.05) and RHW (p < 0.005) while CKK remained elevated. Aortocaval shunts increased their ANF plasma levels (p < 0.05), RHW (p < 0.001) and CKK (p < 0.01). Ramipril treatment induced a reduction in RHW (p < 0.05), while CKK and ANF increased significantly (p < 0.05). The present data show that the components of the kallikrein-kinin system are continuously formed in the isolated rat heart and that ramipril reduces bradykinin breakdown with subsequent increase in bradykinin outflow. The experiments with aorta caval shunt and aortic banding show that cardiac tissues increase their kinin-generating activity and this was even higher in ramipril-treated animals. This may suggest that the actual level of kinins is finely tuned to the local metabolic demands. In this experimental model of cardiac hypertrophy. ACE inhibitors potentiate the actions of kinins and probably try to normalise endothelial cell function.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arteriovenous Shunt, Surgical; Atrial Natriuretic Factor; Blood Pressure; Bradykinin; Disease Models, Animal; Heart; Heart Failure; Hypertension; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Kallikrein-Kinin System; Kallikreins; Kininogens; Male; Myocardium; Organ Size; Protein Synthesis Inhibitors; Puromycin; Radioimmunoassay; Ramipril; Rats; Rats, Wistar

Angiotensin-converting enzyme inhibitors have been shown to potentiate relaxations to kinins in several arteries, but the effects of long-term therapy on the responses to bradykinin in normotensive and hypertensive animals remain largely unknown. Therefore, the effects of 12-week-long ramipril therapy (1 mg kg-1 day-1) on responses of mesenteric arterial rings in vitro were studied in spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. Endothelium-dependent relaxations of noradrenaline-precontracted rings to acetylcholine were similar in normotensive rats and ramipril-treated hypertensive rats and more pronounced than in untreated hypertensive group. Higher concentrations of bradykinin (0.1-1 microM) induced slight contractions in noradrenaline-precontracted endothelium-intact rings of normotensive groups and untreated hypertensive group, whereas no response or a transient relaxation were observed in ramipril-treated hypertensive rats. Interestingly, in ramipril-treated hypertensive rats but not in the other groups, 20-min. pretreatment of arterial rings with ramiprilat unmasked or potentiated the relaxations to bradykinin, and these bradykinin-induced relaxations were effectively inhibited by the B2-kinin receptor antagonist Hoe-140. In conclusion, ramipril treatment clearly improved endothelium-dependent arterial relaxation to acetylcholine, and potentiated of even unmasked the dilatory response mediated via the endothelial B2-kinin receptor in spontaneously hypertensive rats. Since these enhancing effects on arterial relaxation in vitro could not be attributed to reduced breakdown of bradykinin, the present results suggest that long-term angiotensin-converting enzyme inhibition potentiated the actions of kinins at level of B2-kinin receptors.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Bradykinin; Disease Models, Animal; Endothelium, Vascular; Heart; Hypertension; Male; Mesenteric Arteries; Muscle Relaxation; Muscle, Smooth, Vascular; Norepinephrine; Organ Size; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Bradykinin; Serotonin

Isolated rat neonatal cardiac myocytes were subjected to immersion in hypoxic (PO2 < 2 mm Hg), glucose-free Tyrode's solution for 5 h followed by concomitant reoxygenation and staining with the membrane-impermeant fluorophore, propidium iodide, in normoxic (PO2 > 150 mm Hg), serum-free culture media for 15 min in order to assess sarcolemmal damage indicative of myocyte viability due to hypoxia/reoxygenation injury. Prior to hypoxic exposure, cells were pretreated for 90 min with the angiotensin-converting enzyme inhibitor cyclopenta[b]pyrrole-2-carboxylic acid, 1-[2-[(1-carboxy-3-phenylpropyl)amino]-l-oxopropyl]octahydro-[2S-[1[R* (R*)]2 alpha, 3a beta, 6a beta]] (ramiprilat), concomitantly with ramiprilat and H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (bradykinin B2 receptor antagonist HOE 140), the bioactive peptide Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg (bradykinin) or concomitantly with bradykinin and HOE 140. Hypoxia/reoxygenation injury to untreated control cardiac myocytes was characterized by a significant loss of sarcolemmal integrity measured at 75 +/- 4% of total cell fluorescence (mean +/- S.E., n = 42 cultures). Compared to propidium iodide staining of the above untreated control myocytes, those pretreated with 30 or 100 microM ramiprilat showed a significant reduction of propidium iodide staining to 45 +/- 9% and 40 +/- 8% (n = 9, P < 0.05) of untreated controls, respectively. Pretreatment with the protective concentrations of ramiprilat concomitant with 10 microM HOE 140 abolished the significant reduction in propidium iodide staining observed with ramiprilat alone. Similarly, pretreatment with 10 or 100 nM bradykinin significantly reduced propidium iodide staining to 35 +/- 5% and 60 +/- 10% (n = 6, P < 0.05) of the untreated hypoxic controls, respectively. In addition, concomitant pretreatment with protective concentrations of bradykinin and 10 microM HOE 140 also abolished the significant reduction in propidium iodide staining observed with bradykinin alone. The results indicate that the angiotensin-converting enzyme inhibitor ramiprilat has a protective effect on isolated cardiac myocytes exposed to hypoxia/reoxygenation and that this effect is most likely related to a local action of bradykinin on the cardiac myocyte via the activation of the kinin B2 receptor.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Coloring Agents; Disease Models, Animal; Myocardial Reperfusion Injury; Propidium; Ramipril; Rats; Rats, Sprague-Dawley

This study was done to investigate the mechanisms that underly the changes of renal renin gene expression upon hypoperfusion of one kidney. To this end the left renal arteries of male Sprague-Dawley rats were clipped with 0.2 mm silver clips and renal renin mRNA levels were assayed by RNase protection during the first ten days after clipping. Unilateral reduction of renal blood flow led to transient maximal fivefold increases of renin mRNA levels in the clipped kidneys and to sustained suppression of renin gene expression to 20% of the control value in the contralateral intact kidneys. Inhibition of prostaglandin (PG) formation by meclofenamate or EDRF synthesis by L-NAME markedly attenuated the increase of renin mRNA levels in response to clipping, and a combination of PG/EDRF inhibition almost abolished the increase of renin mRNA levels. Inhibition of PG/EDRF formation did not change the suppression of renin mRNA levels in the contralateral intact kidneys. Neither did renal denervation nor inhibition of macula densa function by furosemide prevent the suppression of renin gene expression in response to unilateral renal artery clipping. Only converting enzyme inhibition by ramipril and blockade of Ang II-AT1 receptors by losartan attenuated the decrease of renin mRNA levels in the contralaterals to clipped kidneys. These findings suggest that intact PG and EDRF synthesis represent stimulatory signals for renin gene expression that are required for the elevation of renin mRNA levels upon unilateral renal hypoperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arginine; Denervation; Disease Models, Animal; Furosemide; Gene Expression Regulation; Hypertension, Renovascular; Kidney; Male; Meclofenamic Acid; NG-Nitroarginine Methyl Ester; Nitric Oxide; Prostaglandin Antagonists; Ramipril; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger

Studies have shown that angiotensin-converting enzyme (ACE) inhibitor treatment in young genetically hypertensive rats prevents the full expression of blood pressure and vascular abnormalities in the adult. This model provides unique conditions with which to study the pathogenesis of altered Ca++ regulation. Normotensive (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP) received at 6 to 10 weeks of age either ACE inhibitor (ramipril), hydralazine/hydrochlorothiazide or no treatment. At 17 weeks of age, rats were anesthetized, and vascular tissue was excised. Thoracic aorta challenged with 20 mM caffeine in Ca(++)-free buffer produced a phasic contractile response. The magnitude of this phasic response was used as a measure of Ca++ released from intracellular stores; a direct correlation between this phasic response and systolic blood pressure was observed. A concentration-response curve to Bay K8644 was performed on carotid arteries; a direct correlation of force development to Bay K8644 and systolic blood pressure was observed. All WKY groups showed lower blood pressure and force development in response to Bay K8644 than did SHRSP. Treatment with ramipril reduced blood pressure and force development in response to Bay K8644 in adult SHRSP, although not to levels of WKY rats, whereas WKY rats were unaffected by treatment. These data support the hypothesis that contractile responses to Bay K8644 in carotid arteries and caffeine in aorta parallel changes in systolic blood pressure. We conclude that alteration of Ca++ regulation in hypertension is directly related to elevated blood pressure and mediated by an angiotensin II-sensitive mechanism during development.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Caffeine; Calcium; Calcium Channels; Cell Membrane; Disease Models, Animal; Hydralazine; Hydrochlorothiazide; Hypertension; Male; Muscle Contraction; Muscle, Smooth, Vascular; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sarcoplasmic Reticulum

We investigated the chronic effect of bradykinin B2-receptor blockade on the antihypertensive actions of the angiotensin-converting enzyme (ACE) inhibitor ramipril in three different hypertensive rat models, the two-kidney/one-clip (2K1C) hypertensive Wistar rat, the kinin-deficient 2K1C hypertensive Brown Norway Katholieke (BN-K) rat, and the spontaneously hypertensive rat (SHR). Chronic blockade of bradykinin B2 receptors by subcutaneous infusion of the new bradykinin antagonist HOE 140 (500 micrograms/kg/day) attenuated the antihypertensive effect of ramipril only in 2K1C hypertensive Wistar rats, but not in 2K1C BN-K rats and SHR. Our data demonstrate for the first time that potentiation of endogenous kinins contributes to chronic antihypertensive actions of ACE inhibitors in experimental renal hypertension. Whether this holds also true for other forms of hypertension remains to be answered.

Topics: Animals; Blood Pressure; Bradykinin; Disease Models, Animal; Heart Rate; Hypertension; Hypertension, Renal; Male; Ramipril; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Bradykinin; Receptors, Neurotransmitter

Two models of right ventricular (RV) hypertrophy in rats have been created and characterized: chronic myocardial infarction and pulmonary artery stenosis. A Millar ultraminiature catheter pressure transducer designed specifically for right heart catheterization was used for the measurement of RV function in closed-chest, anesthetized rats. Four weeks after coronary artery ligation, left ventricular (LV) function was depressed as evidenced by the reduction of LV systolic pressure (LVSP), the maximal rate of rise in LV pressure (LV dp/dtmax), cardiac output, and by the elevation of LV end-diastolic pressure (LVEDP). There was an increase in RVSP and an elevation in RV dp/dtmax as well as an increase in the RV weight/body weight ratio. Myocytes isolated from the RV 4 weeks after coronary artery ligation had a greater volume and cross-sectional area. In addition, 14 days after pulmonary artery stenosis, there also was an elevation in RVSP and in RV dp/dtmax. In this model, the effect of angiotensin-converting enzyme (ACE) inhibition with ramipril (1 mg/kg daily) was examined. The increase in RVSP from 35 +/- 2 to 61 +/- 4 mm Hg after pulmonary artery stenosis was not influenced by ramipril (63 +/- 4 mm Hg), neither was the elevation of RV weight. However, the increase in cell volume and cross-sectional area of myocytes isolated from the RV was less pronounced in the ramipril-treated group (+27% compared with +58% in untreated animals). Thus, ACE inhibition with ramipril altered the hypertrophic response at the cellular level.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bridged Bicyclo Compounds; Cardiomegaly; Disease Models, Animal; Female; Hemodynamics; Myocardial Infarction; Myocardium; Pulmonary Valve Stenosis; Ramipril; Rats; Rats, Inbred Strains; Ventricular Function, Left; Ventricular Function, Right

Paw oedema in the rat by carrageenin and kaolin partially caused by Hageman factor activation was potentiated by the new angiotensin converting enzyme (ACE) inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl-L-alanyl]-(lS,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid] (ramipril, Hoe 498) due to its inhibition of kininase II which results in increased bradykinin levels. A dose of 1 microgram ramipril injected into the hind paw of Sprague-Dawley rats concomitantly with, or 1 mg/kg given orally 30 min before administration of the irritants, led to significantly increased inflammatory reactions. The same effects were observed when ramipril was administered 3 h after carrageenin. In the kallikrein-kinin-deficient Brown-Norway rat strain Mai Pfd/f, ramipril did not significantly alter the paw oedema induced as described above. In addition, pretreatment of Sprague-Dawley rats with 10 mg/kg i.v. bromelains completely prevented the potentiation of inflammation by ramipril. Paw oedema provoked by the Hageman factor non-activators serotonin, dextran, ovalbumin and anti-rat IgG was not potentiated by ramipril. The chronic adjuvant arthritis in Lewis rats was not influenced by daily oral treatment with 0.1-3 mg/kg ramipril. Thus, in the rat only those inflammatory reactions involving kinins, presumably generated by Hageman factor activators, are potentiated by ramipril and presumably by other ACE-inhibitors.

Topics: Acute Disease; Angiotensin-Converting Enzyme Inhibitors; Animals; Arthritis; Arthritis, Experimental; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Disease Models, Animal; Inflammation; Male; Ramipril; Rats; Rats, Inbred Strains