ramipril and Renal-Insufficiency

Ramipril/felodipine extended release (ER) [Triapin and Triapin Mite, Unimax] is a once-daily fixed-dose combination of the ACE inhibitor ramipril and the ER formulation of the dihydropyridine calcium channel antagonist felodipine. It is indicated in adult patients with essential hypertension whose blood pressure (BP) is inadequately controlled with ramipril or felodipine monotherapy. In this patient population, commercially available fixed-dose combinations (i.e. 2.5 mg/2.5 mg and 5 mg/5 mg) of ramipril and felodipine ER are more effective at controlling hypertension than the individual components used as monotherapy at the same dosages. Likewise, the 5 mg/5 mg combination is as effective as felodipine ER 10 mg, and more effective than ramipril 10 mg administered as monotherapy. The addition of low-dose ramipril plus felodipine ER (fixed-dose or combination of individual components) to the existing antihypertensive regimen also appears to provide adequate BP control and renal protection in hypertensive patients with non-diabetic chronic renal disease. In these patients, the low-dose combination of ramipril and felodipine ER was as effective as standard-dose felodipine ER, but more effective than standard-dose ramipril, in providing diastolic BP (DBP) control, and as effective as standard-dose ramipril, but more effective than standard-dose felodipine ER, in slowing the rate of regression of glomerular filtration. The ramipril/felodipine ER combination is as well tolerated as ramipril or felodipine ER monotherapy administered at the same dosages, and is better tolerated than felodipine ER monotherapy given at twice the dosage used in the combination. Overall, ramipril/felodipine ER appears to be an effective option for the treatment of adults with essential hypertension that is poorly controlled with monotherapy. In addition, a fixed, low-dose combination of ramipril/felodipine ER is a potential alternative to monotherapy for the initial management of essential hypertension.

Topics: Antihypertensive Agents; Clinical Trials as Topic; Delayed-Action Preparations; Drug Combinations; Drug Interactions; Felodipine; Humans; Hypertension; Ramipril; Renal Insufficiency

Ramipril is an angiotensin-converting enzyme inhibitor that has been extensively studied in randomised, controlled clinical trials in patients with cardiovascular diseases. Therapy with ramipril in patients with various cardiovascular disorders has demonstrated significant and clinically important reductions in cardiovascular death, myocardial infarction, stroke, congestive heart failure, progressive renal impairment and onset of diabetes. Ramipril is usually dosed at 2.5-10 mg/day. Beneficial effects of ramipril are observed in the treatment of hypertension and congestive heart failure, prevention of cardiovascular events in high-risk patients, prevention of congestive heart failure, diabetes and other vascular events.

Topics: Angiotensin-Converting Enzyme Inhibitors; Atherosclerosis; Cardiovascular Diseases; Carotid Arteries; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Heart Failure; Humans; Hypertension; Proteinuria; Ramipril; Randomized Controlled Trials as Topic; Renal Insufficiency; Tissue Distribution

We review the evidence linking mild renal insufficiency (MRI) with increased cardiovascular risk. MRI is associated with a number of cardiovascular risk factors, including nighttime hypertension, and increased levels of lipoprotein (a), homocysteine, asymmetric dimethyl-arginine, and inflammation and insulin resistance markers and mediators. Epidemiologic evidence associates coronary artery disease and nephrosclerosis, a frequent cause of early renal insufficiency in the elderly. In a middle-aged general population MRI was found in 8% of women and 9% of men, but was not associated with cardiovascular disease. Nonetheless, in a representative sample of middle-aged British men the risk of stroke was 60% higher for the sub-group with MRI: in people at high cardiovascular risk (mostly coronary disease), the HOPE study found a 2-fold (unadjusted) or 1.4-fold (adjusted) higher incidence of cardiovascular outcomes with MRI. The combined incidence of cardiovascular death, myocardial infarction and stroke increased with the level of serum creatinine. Several studies have examined the cardiovascular risk associated with MRI in hypertension. In HDFP, as in HOPE, cardiovascular mortality increased with serum creatinine (five-fold difference in cardiovascular mortality between the lowest and the highest creatinine strata). The risk associated with renal insufficiency was independent of other classic cardiovascular risk factors. Two trials of hypertensives with low risk (HOT and a small Italian trial) found that cardiovascular outcomes approximately doubled in subjects with MRI. Another study (MRFIT) found that it was not baseline creatinine, but its increase on follow-up that predicted future cardiovascular disease. These observational data suggest that regardless of etiology MRI is a strong predictor of cardiovascular disease and is found in 10% of populations at low cardiovascular risk and in up to 30% of those at high risk. No prospective therapeutic trials aimed at reducing the cardiovascular burden in people with MRI are available. Subgroup analyses of the HOPE study indicate that angiotensin-converting enzyme (ACE) inhibition with ramipril is beneficial and does not increase the risk of such side effects as acute renal failure or hyperkalemia. Thus the frequent practice of withholding ACE inhibitors from patients with mild renal insufficiency is unwarranted, especially since MRI identifies a group at high risk that appears to benefit most from treatment. Moreove

Topics: Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Creatinine; Diabetes Complications; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Male; Middle Aged; Nephrosclerosis; Prognosis; Ramipril; Randomized Controlled Trials as Topic; Renal Insufficiency; Risk Factors; Sex Factors; Time Factors

To evaluate the effectiveness of ramipril in the prevention and treatment of cardiovascular disease and determine its need for inclusion on a formulary.. A MEDLINE and PubMed database search was conducted (1987-May 2002). Only journals written in the English language were selected for review. DATA EXTRACTION AND STUDY SELECTION: Articles reporting the use of ramipril in humans were evaluated. Emphasis was placed on randomized, controlled trials assessing efficacy.. Ramipril is an angiotensin-converting enzyme (ACE) inhibitor that exerts its effects through inhibition of the renin-angiotensin-aldosterone system. It exhibits a safety profile that is similar to that of other ACE inhibitors and is comparable in cost to the majority of the available agents. Clinical trials have proven the effectiveness of ACE inhibitors in the treatment of hypertension, heart failure, and nephropathy. Ramipril, however, is the only ACE inhibitor currently approved for the prevention of cardiovascular events in high-risk patients without evidence of left-ventricular dysfunction or heart failure, based on the results of the HOPE (Heart Outcomes Prevention Evaluation) trial. Whether this effect is specific to ramipril has yet to be proven. This article emphasizes the major trials involving ramipril including the AIRE (Acute Infarction Ramipril Efficacy), REIN (Ramipril Efficacy in Nephropathy), and HOPE trials.. Although similar to other ACE inhibitors in many aspects, it cannot be assumed that the benefits shown with ramipril in the HOPE trial are a class effect. Ongoing trials should help to clarify this matter. Until this time, current evidence justifies the inclusion of ramipril on a formulary.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Humans; Liver Diseases; Racial Groups; Ramipril; Randomized Controlled Trials as Topic; Renal Insufficiency

Ramipril is a long-acting nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor introduced for clinical use about a decade ago. Ramipril is a prodrug that undergoes de-esterification in the liver to form ramiprilat, its active metabolite. Ramipril rapidly distributes to all tissues, with the liver, kidneys and lungs showing markedly higher concentrations of the drug than the blood. After absorption from the gastrointestinal tract, rapid hydrolysis of ramipril occurs in the liver. In the therapeutic concentration range, protein binding of ramipril and ramiprilat is 73 and 56%, respectively. Ramiprilat binds to ACE with high affinity at concentrations similar to that of the enzyme and establishes equilibrium slowly. Although ramipril is metabolised by hepatic and renal mechanisms to both a glucuronate conjugate and a diketopiperazine derivative, most of the drug is excreted in the urine as ramiprilat and the glucuronate conjugate of ramiprilat. Elimination from the body is characterised by a relatively rapid initial phase with a half-life of 7 hours and a late phase with a half-life of about 120 hours. No clinically significant pharmacokinetic interactions between ramipril and other drugs have been reported. The drug has been generally well tolerated with the most prevalent adverse effects being dizziness (3.4%), headache (3.2%), weakness (1.9%) and nausea (1.7%). Ramipril is an effective and well tolerated drug for the treatment of hypertension and congestive heart failure in all patients, including those with renal or hepatic dysfunction, and the elderly.

Topics: Drug Interactions; Heart Failure; Humans; Hypertension; Kidney; Liver; Liver Diseases; Ramipril; Renal Insufficiency

It has yet to be determined whether genotyping at the angiotensin-converting enzyme (ACE) locus is predictive of blood pressure response to an ACE inhibitor.. Participants from the African American Study of Kidney Disease and Hypertension trial randomized to the ACE inhibitor ramipril (n = 347) were genotyped at three polymorphisms on ACE, just downstream from the ACE insertion/deletion polymorphism (Ins/Del): G12269A, C17888T, and G20037A. Time to reach target mean arterial pressure (

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Female; Genotype; Haplotypes; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Ramipril; Renal Insufficiency; Time Factors

To verify the benefit of renin-angiotensin system blockade in hypertension, the effects of 24 weeks' losartan and ramipril treatment, both alone and in combination, on urinary albumin excretion (UAE) and circulating transforming growth factor beta1 (TGF beta1) have been evaluated in hypertensive subjects with minor renal abnormalities.. Fifty-one patients with stage 1 and 2 essential hypertension and with UAE > or = 20 mg/24 h but with maintained renal function have been included. After a 4-week run-in with placebo administration, a randomized double-blind, three-arm double-dummy trial was used. All the hypertensives (HT) were allocated randomly to three treatment arms (17 patients for each group) and they were single-matched for age, gender, body mass index (BMI), systolic and diastolic blood pressure. Active treatment consisted of losartan (50 mg/day), ramipril (5 mg/day) and combined (losartan 50 mg/day plus ramipril 5 mg/day) for 24 weeks. Hydrochlorothiazide 12.5 mg/day was added in HT patients with uncontrolled blood pressure (> or = 140/90 mmHg) during the active treatment period. In all patients UAE, by immunonephelometric assay; circulating TGF beta1 by a solid-phase specific sandwich enzyme-linked immunosorbent assay (ELISA); and blood urea nitrogen (BUN), creatinine and creatinine clearance and potassium, by routine laboratory methods, were determined after placebo treatment and 24 weeks follow-up.. The three treatment groups were comparable for gender, age, BMI, blood pressure, UAE and renal function measurements. During the active treatment period it was necessary to add hydrochlorothiazide in five patients--two each of the losartan and ramipril groups and one of the combined group. At the end of treatment, significant (P < 0.05) reductions in systolic, diastolic and mean blood pressure, UAE and TGF beta1 levels were observed in all the groups. No change in renal function measurements were observed. The absolute and percentage reduction in UAE and TGF beta1 were significantly higher in the combined group than in the losartan or ramipril groups. No significant changes in absolute and percentage reduction of systolic, diastolic and mean blood pressure were found. All treatment regimens were well tolerated with few and transient side-effects.. These data indicate an additional renoprotective effect of dual blockade of the renin-angiotensin system (RAS) in hypertensive patients with minor renal abnormalities. In addition, the contemporaneus and marked decrease in TGF beta1 and UAE levels in hypertensives treated with combined therapy might indicate the presence of a subset of subjects who may benefit from complete RAS blockade.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Drug Therapy, Combination; Female; Humans; Hypertension, Renal; Kidney; Losartan; Male; Middle Aged; Ramipril; Renal Insufficiency; Severity of Illness Index; Transforming Growth Factor beta; Transforming Growth Factor beta1

In people with diabetes, renal disease tends to progress from microalbuminuria to clinical proteinuria to renal insufficiency. Little evidence has been published for the nondiabetic population. This study retrospectively analyzed changes of proteinuria over 4.5 yr in the HOPE (Heart Outcomes and Prevention Evaluation) study, which compared ramipril's effects to placebo in 9297 participants, including 3577 with diabetes and 1956 with microalbuminuria. This report is restricted to 7674 participants with albuminuria data at baseline and at follow-up. Inclusion criteria were known vascular disease or diabetes plus one other cardiovascular risk factor, exclusion criteria included heart failure or known impaired left ventricular function, dipstick-positive proteinuria (>1+), and serum creatinine >2.3 mg/dl (200 microM). Baseline microalbuminuria predicted subsequent clinical proteinuria for the study participants overall (adjusted odds ratio [OR], 17.5; 95% confidence interval [CI], 12.6 to 24.4), in participants without diabetes (OR, 16.7; 95% CI, 8.6 to 32.4), and in participants with diabetes (OR, 18.2; 95% CI, 12.4 to 26.7). Any progression of albuminuria (defined as new microalbuminuria or new clinical proteinuria) occurred in 1859 participants; 1542 developed new microalbuminuria, and 317 participants developed clinical proteinuria. Ramipril reduced the risk for any progression (OR, 0.87; 95% CI, 0.78 to 0.97; P = 0.0146). People without and with diabetes who are at high risk for cardiovascular disease are also at risk for a progressive rise in albuminuria. Microalbuminuria itself predicts clinical proteinuria in nondiabetic and in diabetic people. Ramipril prevents or delays the progression of albuminuria.

Topics: Aged; Albuminuria; Antihypertensive Agents; Cardiovascular Diseases; Diabetic Nephropathies; Disease Progression; Female; Follow-Up Studies; Humans; Male; Middle Aged; Predictive Value of Tests; Ramipril; Renal Insufficiency; Risk Factors

An interim analysis of the AASK trial at three years demonstrates a renoprotective effect [slower decline in glomerular filtration rate (GFR), delayed onset of significant decrease in GFR, end-stage renal disease (ESRD) or death, and a decrease in urinary protein excretion] of the angiotensin converting enzyme (ACE) inhibitor, ramipril, as compared to the dihydropyridine calcium channel blocker (DHP-CCB), amlodipine, in patients with mild-to-moderate renal insufficiency. The beneficial effect occurred in the presence of similar levels of blood pressure control and was apparent in patients with proteinuric (beyond the threshold of "dipstick positive" proteinuria, 300 mg/day) and non-proteinuric hypertensive nephrosclerosis. At the time of the interim analysis, the effectiveness of the beta-blocker metoprolol was not significantly different from that of the ACE inhibitor. The data suggest that DHP-CCBs should be used with caution in the presence of mild-to-moderate renal insufficiency.

Topics: Adrenergic beta-Antagonists; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Black or African American; Calcium Channel Blockers; Glomerular Filtration Rate; Humans; Hypertension, Renal; Metoprolol; Nephrosclerosis; Ramipril; Renal Insufficiency

In patients with type 2 diabetes with overt nephropathy, the risk for progressive renal failure is high. This risk is less well established for those with type 2 diabetes and microalbuminuria or normalbuminuria. We studied changes in serum creatinine levels during 3.5 to 5.5 years in a large cohort of people with diabetes at high cardiovascular risk with microalbuminuria or normalbuminuria.. Retrospective analysis of serum creatinine levels at baseline and yearly thereafter was performed in the Microalbuminuria and Renal Outcomes in the Heart Outcomes and Prevention Evaluation study comparing ramipril's effects with placebo during 4.5 years in 3,577 participants with diabetes, including 1,139 participants with microalbuminuria and 333 participants with renal insufficiency. Participants with dipstick-positive proteinuria (>1+) or serum creatinine levels greater than 2.3 mg/dL (200 micromol/L) were excluded.. Serum creatinine levels did not increase significantly during the study if all participants with diabetes are considered or for subgroups with microalbuminuria and/or renal insufficiency at baseline. However, slopes of serum creatinine over time showed a significant trend for increasing values. There were no differences between the placebo and ramipril-treated groups. A serum creatinine level of 1.4 mg/dL (125 micromol/L) or greater newly developed in 474 of 3,238 people (243 patients, placebo; 231 patients, ramipril; P = 0.5033). A doubling of baseline serum creatinine level or end-stage renal disease developed in 8 of 333 participants with renal insufficiency at baseline.. In people with type 2 diabetes, but without overt nephropathy, who are at high risk for cardiovascular disease, progression of renal insufficiency is slow on the basis of changes in creatinine levels. On the basis of reaching threshold levels of renal function, progression rates are clinically meaningful, especially considering population life expectancy.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Double-Blind Method; Female; Humans; Male; Middle Aged; Ramipril; Renal Insufficiency; Retrospective Studies; Risk Factors; Statistics as Topic

The cardiovascular risk associated with early renal insufficiency is unknown. Clinicians are often reluctant to use angiotensin-converting enzyme inhibitors in patients with renal insufficiency.. To determine whether mild renal insufficiency increases cardiovascular risk and whether ramipril decreases that risk.. Post hoc analysis.. The Heart Outcomes and Prevention Evaluation (HOPE) study, a randomized, double-blind, multinational trial involving 267 study centers.. 980 patients with mild renal insufficiency (serum creatinine concentration >/= 124 micromol/L [>/=1.4 mg/dL]) and 8307 patients with normal renal function (serum creatinine concentration < 124 micromol/L [<1.4 mg/dL]) Patients with a baseline serum creatinine concentration greater than 200 micromol/L (2.3 mg/dL) were excluded.. The primary outcome measure was incidence of cardiovascular death, myocardial infarction, or stroke.. Cumulative incidence of the primary outcome was higher in patients with renal insufficiency than in those without (22.2% vs. 15.1%; P < 0.001) and increased with serum creatinine concentration. Patients with renal insufficiency had a substantially increased risk for cardiovascular death (11.4% vs. 6.6%) and total mortality (17.8% vs. 10.6%) (P < 0.001 for both comparisons). The effect of renal insufficiency on the primary outcome (adjusted hazard ratio, 1.40 [95% CI, 1.16 to 1.69]) was independent of known cardiovascular risks and treatment. Ramipril reduced the incidence of the primary outcome in patients with and those without renal insufficiency (hazard ratio, 0.80 vs. 0.79; P > 0.2 for the difference).. In patients who had preexisting vascular disease or diabetes combined with an additional cardiovascular risk factor, mild renal insufficiency significantly increased the risk for subsequent cardiovascular events. Ramipril reduced cardiovascular risk without increasing adverse effects.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Creatinine; Diabetes Complications; Double-Blind Method; Female; Follow-Up Studies; Humans; Middle Aged; Prognosis; Ramipril; Regression Analysis; Renal Insufficiency; Risk Factors; Statistics, Nonparametric; Vascular Diseases

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Creatinine; Diabetes Complications; Double-Blind Method; Female; Follow-Up Studies; Humans; Middle Aged; Prognosis; Ramipril; Renal Insufficiency; Risk Factors; Vascular Diseases

The purpose of this study was to compare the effects of ramipril and nitrendipine on urinary albumin excretion (UAE) in hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM) and impaired renal function. Forty patients with mild hypertension with NIDDM and persistent albuminuria (> 300 mg/24h) were studied. After a 3-week run-in period on placebo, patients were randomly treated with ramipril 5 mg once daily or nitrendipine 20 mg once daily for 6 months, according to a double-blind design. Blood pressure (BP), UAE, creatinine clearance and glycosilated haemoglobin were evaluated at the end of the placebo period and after 1,3 and 6 months of active treatment. Both ramipril and nitrendipine significantly lowered BP values without affecting glucose homeostasis and renal function. Despite equivalent BP control, only ramipril afforded a significant reduction in UAE, thus suggesting that the antiproteinuric effect of ramipril is at least partially independent of its anti-hypertensive effect.

Topics: Aged; Albuminuria; Analysis of Variance; Confidence Intervals; Creatinine; Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Humans; Hypertension; Kidney Function Tests; Male; Middle Aged; Nitrendipine; Ramipril; Renal Insufficiency

We previously reported that exogenous angiotensin (Ang) 1-7 has adverse cardiac effects in experimental kidney failure due to its action to increase cardiac angiotensin converting enzyme (ACE) activity. This study investigated if the addition of an ACE inhibitor (ACEi) to Ang 1-7 infusion would unmask any beneficial effects of Ang 1-7 on the heart in experimental kidney failure. Male Sprague-Dawley rats underwent subtotal nephrectomy (STNx) and were treated with vehicle, the ACEi ramipril (oral 1mg/kg/day), Ang 1-7 (subcutaneous 24 μg/kg/h) or dual therapy (all groups, n = 12). A control group (n = 10) of sham-operated rats were also studied. STNx led to hypertension, renal impairment, cardiac hypertrophy and fibrosis, and increased both left ventricular ACE2 activity and ACE binding. STNx was not associated with changes in plasma levels of ACE, ACE2 or angiotensin peptides. Ramipril reduced blood pressure, improved cardiac hypertrophy and fibrosis and inhibited cardiac ACE. Ang 1-7 infusion increased blood pressure, cardiac interstitial fibrosis and cardiac ACE binding compared to untreated STNx rats. Although in STNx rats, the addition of ACEi to Ang 1-7 prevented any deleterious cardiac effects of Ang 1-7, a limitation of the study is that the large increase in plasma Ang 1-7 with ramipril may have masked any effect of infused Ang 1-7.

Topics: Analysis of Variance; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiomegaly; Heart; Hypertension; Male; Myocardium; Nephrectomy; Peptide Fragments; Peptidyl-Dipeptidase A; Ramipril; Rats, Sprague-Dawley; Renal Insufficiency

There are various reasons for renal dysfunction after cardiac surgery; however, activation of the renin-angiotensin system has an important role following cardiac surgery. We investigated the effect of preoperative angiotensin-converting enzyme (ACE) inhibitors on renal functions after cardiovascular surgery.. Three hundred sixty-six patients awaiting elective cardiac surgery were allocated to two groups, namely the treatment group, comprising the ACE inhibitor group (n = 186), and the control group, which was without ACE inhibitor (n = 180). The renal parameters [blood urea nitrogen, creatinine, creatinine clearance, and glomerular filtration rate (GFR)] and the need for dialysis were evaluated associated with renal functions between the two groups in the postoperative period.. After cardiac surgery, renal dysfunction requiring dialysis developed in 11 (3.8%) patients in the control group patients. There was no required dialysis in the treatment group (p < 0.05). As an indicator of renal dysfunction, the increase in creatinine and blood urea nitrogen levels and the decrease in GFR and creatinine clearance were higher in the control group (p < 0.05). The multivariate analysis indicated that therapy with ACE inhibitors was found to decrease the incidence of postoperative renal dysfunction (odds ratio, 1.07; 95% confidence interval, 0.45-2.50; p < 0.05). The other independent predictors were age, preoperative intra-aortic blood pump, hypertension, diabetes mellitus, and a left ventricular ejection fraction below 0.40.. Preoperative therapy with ACE inhibitors has an influence on renal functions. This study demonstrates that administration of ACE inhibitors provides better renal protection after cardiac surgery.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiac Surgical Procedures; Female; Humans; Logistic Models; Male; Middle Aged; Postoperative Complications; Preoperative Care; Ramipril; Renal Insufficiency; Renin-Angiotensin System; Retrospective Studies

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

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Cardiovascular Diseases; Clinical Trials as Topic; Comorbidity; Drug Interactions; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Multicenter Studies as Topic; Myocardial Ischemia; Ramipril; Renal Insufficiency; Risk; Stroke; Telmisartan; Treatment Outcome

Topics: Acute Kidney Injury; Administration, Oral; Adult; Angiotensin-Converting Enzyme Inhibitors; Cathartics; Colitis; Humans; Nephrocalcinosis; Phosphates; Ramipril; Renal Insufficiency; Risk Factors

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

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

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Hypertension; Hypertrophy, Left Ventricular; Ramipril; Renal Insufficiency; Telmisartan

Topics: Angiotensin Receptor Antagonists; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Hypertension; Ramipril; Renal Insufficiency

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Humans; Ramipril; Renal Insufficiency; Risk Factors; Vascular Diseases

In this post hoc, secondary analysis of the Ramipril Efficacy In Nephropathy (REIN) trial, an angiotensin-converting enzyme (ACE) inhibition risk/benefit profile was assessed in 322 patients with nondiabetic, proteinuric chronic nephropathies and different degrees of renal insufficiency. The rate of GFR decline (Delta GFR) and the incidence of end-stage renal disease (ESRD) during ramipril or non-ACE inhibitor treatment were compared within three tertiles of basal GFR. Delta GFR was comparable in the three tertiles, whereas the incidence of ESRD was higher in the lowest tertile than in the middle and highest tertiles. Ramipril decreased Delta GFR by 22%, 22%, and 35% and the incidence of ESRD by 33% (P < 0.05), 37%, and 100% (P < 0.01) in the lowest, middle, and highest tertiles, respectively. Delta GFR reduction was predicted by basal systolic (P < 0.0001), diastolic (P = 0.02), and mean (P < 0.001) BP and proteinuria (P < 0.0001) but not by basal GFR (P = 0.12). ESRD risk reduction was predicted by basal proteinuria (P < 0.01) and GFR (P < 0.0001) and was strongly dependent on treatment duration (P < 0.0001). Adverse events were comparable among the three tertiles and within each tertile in the two treatment groups. Thus, disease progression and response to ACE inhibition do not depend on severity of renal insufficiency. The risk of ESRD and the absolute number of events saved by ACE inhibition is highest in patients with the lowest GFR. However, renoprotection is maximized when ACE inhibition is started earlier and when long-lasting treatment may result in GFR stabilization and definitive prevention of ESRD.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Drug Administration Schedule; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria; Ramipril; Renal Insufficiency

Inhibition of the angiotensin converting enzyme (ACE) with ramipril was studied in male Wistar rats during long-term inhibition of nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester (L-NAME). Chronic treatment with L-NAME in a dose of 25 mg/kg per day over 6 weeks caused myocardial hypertrophy and a significant increase in systolic blood pressure (245 +/- 16 mmHg) as compared to controls (155 +/- 4 mmHg). Animals receiving simultaneously L-NAME and ramipril were protected against blood pressure increase and partially against myocardial hypertrophy. L-NAME caused a significant reduction in glomerular filtration rate (GFR: 2.56 +/- 0.73 ml.kg-1.min-1) and renal plasma flow (RPF: 6.93 +/- 1.70 ml.kg-1.min-1) as compared to control (GFR: 7.29 +/- 0.69, RPF: 21.36 +/- 2.33 ml.kg-1.min-1). Addition of ramipril prevented L-NAME-induced reduction in GFR and renal plasma flow. L-NAME produced an elevation in urinary protein excretion and serum creatinine and a decrease in potassium excretion which was antagonised by ramipril. L-NAME-induced increase in plasma renin activity (PRA) was further elevated with ramipril treatment. Isolated hearts from rats treated with L-NAME showed increased post-ischaemic reperfusion injuries. Compared to controls duration of ventricular fibrillation was increased and coronary flow reduced. During ischemia the cytosolic enzymes lactate dehydrogenase and creatine kinase, as well as lactate in the venous effluent were increased. Myocardial tissue values of glycogen, ATP, and creatine phosphate were decreased, whereas lactate was increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Blood Pressure; Cardiomegaly; Cyclic GMP; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Ramipril; Rats; Rats, Wistar; Renal Insufficiency; Ventricular Fibrillation