ramipril and Hypertension--Renal

Hypertension is an important independent risk factor for renal disease. If hypertension and chronic renal disease co-exist, as is common in patients with diabetes mellitus, the risk of cardiovascular disease is heightened. The importance of rigorous blood pressure control is recognized in current guidelines, with a recommended target of office blood pressure of < 130/80 mmHg; although ambulatory blood pressure may be more appropriate in order to identify the 24-hour hypertensive burden. Even lower blood pressure may further reduce the progression of chronic kidney disease, but the incidence of cardiovascular events may increase. Albuminuria not only indicates renal damage, but is also a powerful predictor of cardiovascular morbidity and mortality at least in patients with high cardiovascular risk and potentially pre-existing vascular damage. Management of the multiple factors for renal and cardiovascular disease is mandatory in the diabetic patient. The renin-angiotensin system (RAS) plays a pivotal role in the progression of renal disease, as well as in hypertension and target-organ damage. The use of agents that target the RAS confer renoprotection in addition to antihypertensive activity. There is extensive evidence of the renoprotective effect of angiotensin II receptor blockers (ARBs), and specifically telmisartan. In addition to providing 24-hour blood pressure control, clinical studies in patients with diabetes show that telmisartan improves renal endothelial function, prevents progression from microalbuminuria to macroalbuminuria, slows the decline in glomerular filtration rate and reduces proteinuria in overt nephropathy. These effects cannot be solely attributed to blood pressure control. In contrast to other members of the ARB class, the renoprotective effect of telmisartan is not confined to the management of diabetic nephropathy; slowing the progression of albuminuria has been demonstrated in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), which included diabetic and non-diabetic patients at high risk of cardiovascular events.

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Diabetic Nephropathies; Humans; Hypertension, Renal; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Telmisartan

Topics: Angioplasty, Balloon, Coronary; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteriosclerosis; Cardiomegaly; Clinical Trials as Topic; Coronary Restenosis; Humans; Hypertension; Hypertension, Renal; Insulin Resistance; Losartan; Ramipril; Receptor, Angiotensin, Type 1

Ramipril is a long acting angiotensin converting enzyme (ACE) inhibitor, which exhibits similar pharmacodynamic properties to Captopril and Enalapril. Like Enalapril, it is a prodrug, which is hydrolyzed after absorption to form the active metabolite ramiprilat which has a long elimination half-life, permitting once daily administration. In the dose range 2.5-10 mg once daily the drug has been effective and well tolerated during treatment for up to two years. In dosages of 5 or 10 mg once daily the antihypertensive efficacy of Ramipril was comparable with usual therapeutic dosages of Captopril, Enalapril, and Atenolol.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Bridged Bicyclo Compounds; Heart Failure; Humans; Hypertension; Hypertension, Renal; Prodrugs; Ramipril

Cardiovascular disease mortality among patients with end stage renal disease (ESRD) exceeds that which is predicted by traditional risk factors. Sudden death accounts for up to 15-38% of patients with ESRD found dead at home. Heart rate variability (HRV) is a reliable measure of autonomic modulation and has a very strong predictive value for ventricular arrhythmias and sudden death. A lower HRV is associated with increased risk. Modifying autonomic tone pharmacologically reduces death from dysrhythmia in the general population but has not been studied in ESRD.. We examined the effect of ramipril, an angiotensin converting enzyme inhibitor (ACEI) known in the general population to increase HRV, on cardiac function and heart rate variability in patients with renal failure. Eligible subjects on haemodialysis underwent a 2-week washout period free of ACEI or beta blockers, during which time hypertension was treated with amlodipine, which has been shown not to affect HRV. Haemodynamic and HRV measurements were obtained at baseline and after subjects were treated for 4 weeks with an ACEI.. Haemodynamics did not differ at 0 and 4 weeks. Baseline HRV values were markedly below those found in the general population, indicating pronounced predominance of sympathetic tone over vagal tone. Actual worsening of HRV with ACEI treatment was evident in several major time domains. The time domain SDNN (the standard deviation of all normal RR intervals) fell from 42.0 +/- 24.8 ms to 20.1 +/- 16.1 ms (P = 0.004) and the triangulation index fell from 178.0 +/- 94.0 to 115 +/- 59.2 (P = 0.01). A trend toward reduced HRV was seen in several other time domains.. These findings suggest that, unlike the general population, treatment of ESRD patients with an angiotensin converting enzyme inhibitor may cause a deleterious shift toward increased cardiac sympathetic nervous system tone.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Case-Control Studies; Death, Sudden, Cardiac; Female; Heart; Heart Rate; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Ramipril; Renal Dialysis; Risk Factors; Sympathetic Nervous System; Uremia; Vagus Nerve

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

While the antihypertensive and renoprotective potency of angiotensin-converting enzyme (ACE) inhibitors is well-established in adults with hypertension and/or chronic renal failure, little experience exists in pediatric chronic kidney disease.. As part of a prospective assessment of the renoprotective efficacy of ACE inhibition and intensified blood pressure (BP) control, 397 children (ages 3 to 18 years) with chronic renal failure [CRF; glomerular filtration rate (GFR) 11 to 80 mL/min/1.73 m2] and elevated or high-normal BP received ramipril (6 mg/m2) following a 6-month run-in period including a two-month washout of any previous ACE inhibitors. Drug efficacy was assessed by two monthly office BP and proteinuria assessments, and by ambulatory BP monitoring at start and after 6 months of treatment.. In the 352 patients completing six months of treatment, 24-hour mean arterial pressure (MAP) had decreased by a mean of 11.5 mm Hg (-2.2 SDS) in initially hypertensive subjects, but only by 4.4 mm Hg (-0.8 SDS) in patients with initially normal BP. A linear correlation was found between MAP at baseline and the change of MAP during treatment (r= 0.51; P < 0.0001). The antihypertensive response was independent of changes in concomitant antihypertensive medication or underlying renal disease. BP was reduced with equal efficacy during day- and nighttime. Urinary protein excretion was reduced by 50% on average, with similar relative efficacy in patients with hypo/dysplastic nephropathies and glomerulopathies. The magnitude of proteinuria reduction depended on baseline proteinuria (r= 0.32, P < 0.0001), and was correlated with the antihypertensive efficacy of the drug (r= 0.22, P < 0.001). The incidence of rapid rises in serum creatinine and progression to end-stage CRF during treatment did not differ from the pretreatment observation period. Mean serum potassium increased by 0.3 mmol/L. Ramipril was discontinued in three patients due to symptomatic hypotension or hyperkalemia. Hemoglobin levels decreased by 0.6 g/dL in the first two treatment months and remained stable thereafter.. Ramipril appears to be an effective and safe antihypertensive and antiproteinuric agent in children with CRF-associated hypertension. The BP lowering and antiproteinuric effects are greatest in severely hypertensive and proteinuric children.

Topics: Adolescent; Antihypertensive Agents; Blood Pressure; Child; Child, Preschool; Humans; Hypertension, Renal; Kidney Failure, Chronic; Prospective Studies; Proteinuria; Ramipril; Treatment Outcome

The DIABHYCAR (type 2 DIABetes, Hypertension, CArdiovascular Events and Ramipril) study allowed investigators to analyze factors leading to the development of congestive heart failure (CHF) in type 2 diabetic patients with abnormal urinary albumin concentration.. Type 2 diabetic subjects of both sexes aged >or=50 years who had a urinary albumin concentration >or=20 mg/l were randomly allocated to 1.25 mg/day ramipril or placebo in addition to their usual treatment and treated for 3-6 years in a double-blind fashion. Major outcomes including hospitalization for CHF were recorded during the follow-up.. Of the 4912 included patients, 187 developed CHF during the study. There was no significant difference in the incidence of CHF between the two treatment groups. Using a multivariate analysis, independent risk factors for the occurrence of CHF were age, history of cardiovascular disease, baseline urinary albumin concentration, baseline HbA(1c), and smoking habits. A total of 68 of the 187 patients (36.4%) died during the 12 +/- 11-month period after the first hospitalization for CHF, whereas the annual mortality rate of the population who did not develop CHF was 3.2%.. Presence of atherosclerotic disease, baseline urinary albumin concentration, and HbA(1c) level were indicators for further development of CHF. Occurrence of CHF is a major prognostic turn in a diabetic patient's life.

Topics: Aged; Albuminuria; Antihypertensive Agents; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Female; Heart Failure; Humans; Hypertension, Renal; Incidence; Male; Middle Aged; Patient Selection; Predictive Value of Tests; Prognosis; Ramipril; 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

Angiotensin-converting enzyme (ACE) inhibitors are the drugs of choice for the treatment of hypertension in patients with non-diabetic nephropathies. However, not every trial has reported better results with ACE inhibitors (ACE-I) than with other drugs. This study investigates whether the acute and chronic effects of ACE inhibition on renal and glomerular haemodynamics are similar in glomerular and interstitial nephropathies.. We studied 20 hypertensive patients, on their usual diet, with mild-to-moderate chronic renal failure secondary to non-diabetic nephropathy. After a three-week wash out period, we determined plasma clearances of para-amino-hippurate and inulin before, and after acute oral administration of either enalapril or ramipril. This same test was carried out after one and two years of treatment with the same drug.. Acute ACE inhibition causes a decrease of renal perfusion, glomerular filtration and pressure with an increase of afferent resistances. Long-term ACE inhibition is associated only with a decrease in renal perfusion, with a non-significant tendency to higher filtration fraction and lower afferent resistances. All the renal haemodynamic modifications mentioned above are present only in patients with glomerular diseases.. Renal and glomerular haemodynamic responses are not similar after acute and chronic ACE inhibition. Only patients with glomerular diseases show acute or long-term responses to ACE inhibition.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Hypertension, Renal; Inulin; Kidney Failure, Chronic; Kidney Function Tests; Kidney Glomerulus; Male; Middle Aged; Nephritis, Interstitial; p-Aminohippuric Acid; Ramipril; Renal Circulation

Topics: Adult; Aged; Amlodipine; Antihypertensive Agents; Black People; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Metoprolol; Middle Aged; Ramipril

Inhibition of the angiotensin-converting enzyme (ACE) exerts a renoprotective effect in adult patients with chronic kidney disease. We evaluated prospectively changes in blood pressure (BP), protein excretion and renal function after administration of the long-acting ACE inhibitor ramipril as monotherapy during 6 months in 14 moderately hypertensive children aged 5-18 years with various nephropathies. Four patients initially had a decreased glomerular filtration rate (GFR below 60 ml/min/1.73 m2). BP was evaluated by ambulatory 24-h monitoring. After 2 weeks of treatment by oral ramipril (1.5 mg/m2 once daily), mean values of systolic and diastolic 24-h ambulatory BP fell by more than 5 mmHg in nine patients. In eight patients the dose was doubled. At the end of the study systolic BP was below the 95th percentile in 9 and diastolic BP in 13 patients. The initially reduced nocturnal dip increased significantly. Of 11 patients with an increased albumin excretion (median 1.3 g/g creatinine), 6 responded to ramipril by a median reduction of 78% (range 24-83%), whilst in 5 albuminuria increased (median +19%). GFR was well preserved and no other adverse effects from the drug were noted. The study demonstrates that ramipril is an efficacious antihypertensive agent in children with renal hypertension. It is well tolerated, even in mild renal insufficiency. In addition, the drug has a persistent antiproteinuric action in about half of the patients contributing to conserve renal function.

Topics: Adolescent; Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Child; Child, Preschool; Diastole; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Male; Ramipril; Systole

Stratum 2 of the Ramipril Efficacy in Nephropathy (REIN) study has already shown that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, angiotensin-converting enzyme (ACE) inhibition reduced the rate of decline in glomerular filtration and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF) found in controls on placebo plus conventional antihypertensives. In REIN stratum 1, reported here, 24 h proteinuria was 1 g or more but less than 3 g per 24 h.. In stratum 1 of this double-blind trial 186 patients were randomised to a ramipril or a control (placebo plus conventional antihypertensive therapy) group targeted at achieving a diastolic blood pressure of less than 90 mm Hg. The primary endpoints were change in glomerular filtration rate (GFR) and time to ESRF or overt proteinuria (> or =53 g/24 h). Median follow-up was 31 months.. The decline in GFR per month was not significantly different (ramipril 0.26 [SE 0.05] mL per min per 1.73m2, control 0.29 [0.06]). Progression to ESRF was significantly less common in the ramipril group (9/99 vs 18/87) for a relative risk (RR) of 2.72 (95% CI 1.22-6.08); so was progression to overt proteinuria (15/99 vs 27/87, RR 2.40 [1.27-4.52]). Patients with a baseline GFR of 45 mL/min/1.73 m2 or less and proteinuria of 1.5 g/24 h or more had more rapid progression and gained the most from ramipril treatment. Proteinuria decreased by 13% in the ramipril group and increased by 15% in the controls. Cardiovascular events were similar. As expected, the rate of decline in GFR and the frequency of ESRF were much lower in stratum 1 than they had been in stratum 2.. In non-diabetic nephropathies, ACE inhibition confers renoprotection even to patients with non-nephrotic proteinuria.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria; Ramipril; Treatment Outcome

Diabetic nephropathy is the most common cause of end-stage renal disease in the United States. We undertook a study to assess the impact of assignment to different levels of blood pressure control on the course of type 1 diabetic nephropathy in patients receiving angiotensin-converting enzyme (ACE) inhibitor therapy. We also examined the long-term course of this well-characterized cohort of patients receiving ACE inhibitor therapy. One hundred twenty-nine patients with type 1 diabetes and diabetic nephropathy who had previously participated in the Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy Study who had a serum creatinine level less than 4.0 mg/dL were randomly assigned to a mean arterial blood pressure (MAP) goal of 92 mm Hg or less (group I) or 100 to 107 mm Hg (group II). Patients received varying doses of ramipril as the primary therapeutic antihypertensive agent. All patients were followed for a minimum of 2 years. Outcome measures included iothalamate clearance, 24-hour creatinine clearance, creatinine clearance estimated by the Cockcroft and Gault formula, and urinary protein excretion. The average difference in MAP between groups was 6 mm Hg over the 24-month follow-up. The median iothalamate clearance in group I was 62 mL/min/1.73 m(2) at baseline and 54 mL/min/1.73 m(2) at the end of the study compared with a baseline of 64 mL/min/1.73 m(2) and final 58 mL/min/1.73 m(2) in group II. There were no statistically significant differences in the rate of decline in renal function between groups. There was a significant difference in follow-up total urinary protein excretion between group I (535 mg/24 h) and group II (1,723 mg/24 h; P = 0.02). Thirty-two percent of 126 patients achieved a final total protein excretion less than 500 mg/24 h. Patients from groups I and II had equivalent rates of adverse events. In patients with type 1 diabetes mellitus and diabetic nephropathy, the MAP goal should be 92 mm Hg or less for optimal renoprotection, if defined as including decreased proteinuria. With the combination of ACE inhibition and intensive blood pressure control, many patients can achieve regression or apparent remission of clinical evidence of diabetic nephropathy.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Hypertension, Renal; Infant, Newborn; Kidney Function Tests; Male; Middle Aged; Ramipril; Treatment Outcome

To study the role of abnormal intrarenal hemodynamics (IRHD) in progression of lupus nephritis (LN) and its response to therapy with inhibitors of angiotensin-converting enzyme (ACE).. The trial included 30 LN patients (27 females, 3 males; age 29.8+(-)10.4 years). 19 had aggravation of active LN. All the patients were free of chronic renal insufficiency. IRHD was studied with estimation of renal functional reserve (RFR) using protein loading, evaluation of clinical activity of LN and renal function, blood pressure. The tests were repeated after 6 months of treatment with ACE inhibitors (captopril and ramiprilol) in 13 patients (11 of them had exacerbation of active LN).. Disturbed IRHD was found in 37% of the patients. Blood hypertension deteriorated this condition. Treatment with ACE inhibitors in 6 months brought about a significant decrease in blood pressure and improvement of IRHD. Before treatment RFR was absent in 46% of patients, after treatment in 1 patient.. Defects in IRHD occur in LN frequently. These are related with the presence of blood hypertension and activity of LN. Inhibitors of ACE seem perspective in management of essential hypertension in LN patients but this hypothesis needs confirmation by the results of further studies.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Captopril; Disease Progression; Female; Hemodynamics; Humans; Hypertension, Renal; Kidney; Kidney Function Tests; Lupus Nephritis; Male; Prognosis; Ramipril

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Ramipril; Renal Circulation; Renal Plasma Flow; Time Factors

Recurrent focal segmental glomerulosclerosis (FSGS) after renal transplantation with nephrotic syndrome is a serious problem with a high risk of graft loss. The therapeutic role of renin-angiotensin-system (RAS) blockers in recurrent FSGS is not clear. We present the safety and efficacy of an intensified triple RAS blockade with an ACE-inhibitor, an AT 1 receptor blocker and the direct renin inhibitor aliskiren in a 29-year-old renal transplant recipient with biopsy proven recurrence of FSGS and relapsing severe nephrotic syndrome. We subsequently used full dose ramipril, candesartan and aliskiren under a close monitoring of kidney function and electrolytes and examined the effect on proteinuria, clinical course and tolerability over 12 months. We found a significant and sustained antiproteinuric effect under triple RAS blockade. RAS blockade was generally well tolerated. This can offer a new therapeutic approach in selected hypertensive patients with recurrent FSGS.

Topics: Adult; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Benzimidazoles; Biphenyl Compounds; Drug Therapy, Combination; Female; Fumarates; Glomerulosclerosis, Focal Segmental; Humans; Hypertension, Renal; Kidney Transplantation; Nephrotic Syndrome; Plasma Exchange; Proteinuria; Ramipril; Recurrence; Renin; Renin-Angiotensin System; Rituximab; Tetrazoles

Adiponectin is secreted by adipose tissue and may play a role in cardiovascular disease. We examined adiponectin levels in patients with type 2 diabetes who participated in the Telmisartan vs. Ramipril in Renal Endothelial Dysfunction (TRENDY) study.. A total of 87 patients were assessed at baseline and following 9 weeks treatment with the angiotensin-receptor blocker telmisartan (final dose, 80 mg; n = 45) or the angiotensin-converting enzyme inhibitor ramipril (final dose, 10 mg; n = 42). Adiponectin levels were measured in plasma by radioimmunoassay.. Adiponectin levels were inversely correlated with systolic (SBP; r = -0.240, P < 0.05) and diastolic (DBP; r = -0.227, P < 0.05) blood pressure at baseline and following treatment with telmisartan or ramipril (SBP: r = -0.228, P < 0.05; DBP: r = -0.286, P < 0.05). Changes in adiponectin levels were related to changes in SBP (r = -0.357, P < 0.01) and DBP (r = -0.286, P < 0.01). There was a significant increase in adiponectin levels in the telmisartan (0.68 (95% confidence interval (CI), 0.27 to 1.10) microg/ml, P < 0.01) but not in the ramipril group (0.17 (95% CI, -0.56 to 0.90) microg/ml, P = 0.67). Blood pressure reduction in the telmisartan group (DeltaSBP: -13.5 (95% CI, -17.0 to -10.0) mm Hg; DeltaDBP: -7.6 (95% CI, -9.8 to -5.3) mm Hg, each P < 0.001) was significantly (P < or = 0.01 for SBP and P < 0.01 for DBP) greater than in the ramipril group (DeltaSBP: -6.1 (95% CI, -6.2 to -2.0) mm Hg; DeltaDBP: -2.7 (95% CI, -5.0 to -0.5) mm Hg; P < 0.01 and P < 0.05, respectively).. Adiponectin is correlated with blood pressure in patients with type 2 diabetes. Whether increased adiponectin contributes to the blood pressure-lowering effect of telmisartan needs further study.

Topics: Adiponectin; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Biomarkers; Blood Pressure; Cohort Studies; Confidence Intervals; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Hypertension, Renal; Male; Middle Aged; Ramipril; Telmisartan

The African American Study of Kidney Disease and Hypertension was a multicenter trial of African Americans with hypertensive kidney disease randomized to an angiotensin-converting enzyme inhibitor (ramipril), a beta-blocker (metoprolol succinate), or a calcium channel blocker (amlodipine besylate). We compared the incidence of type 2 diabetes mellitus (DM) and the composite outcome of impaired fasting glucose or DM (IFG/DM) for the African American Study of Kidney Disease and Hypertension interventions.. Cox regression models were used to evaluate (post hoc) the association of the randomized interventions and the relative risk (RR) of DM and IFG/DM and to assess the RR of DM and IFG/DM by several prerandomization characteristics.. Among 1017 participants, 147 (14.5%) developed DM; 333 (42.9%) of 776 participants developed IFG/DM. Respective DM event rates were 2.8%, 4.4%, and 4.5% per patient-year in the ramipril-, amlodipine-, and metoprolol-treated groups. The RRs of DM with ramipril treatment were 0.53 (P = .001) compared with metoprolol treatment and 0.49 (P = .003) compared with amlodipine treatment. Respective IFG/DM event rates were 11.3%, 13.3%, and 15.8% per patient-year in the ramipril-, amlodipine-, and metoprolol-treated groups. The RRs of IFG/DM with ramipril treatment were 0.64 (P<.001) compared with metoprolol treatment and 0.76 (P = .09) compared with amlodipine treatment. The RRs of DM and IFG/DM with amlodipine treatment compared with metoprolol treatment were 1.07 (P = .76) and 0.84 (P = .26), respectively.. Ramipril treatment was associated with a significantly lower risk of DM in African Americans with hypertensive kidney disease than amlodipine or metoprolol treatment.

Topics: Adrenergic beta-Antagonists; Adult; Amlodipine; Antihypertensive Agents; Black or African American; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Hypertension, Renal; Incidence; Male; Metoprolol; Middle Aged; Multicenter Studies as Topic; Ramipril; Randomized Controlled Trials as Topic; Regression Analysis

Vasopeptidase inhibition has been shown to be an effective antihypertensive principle but its long-term effects on hypertensive target organ damage are not known. We investigated the myocardial, vascular and renal effects of chronic vasopeptidase inhibition in arterial hypertension.. One hundred and thirty-nine male spontaneously hypertensive rats aged 15 months were treated chronically with either the pure angiotensin-converting enzyme (ACE) inhibitor, ramipril (1 mg/kg/d in drinking water, n=46), or the vasopeptidase inhibitor AVE7688 (30 mg/kg/d in chow, n=46), or placebo (n=47) and followed up until they died. After six months, both ramipril and AVE7688 had markedly reduced plasma ACE activity, normalised blood pressure (BP), reduced left ventricular mass and improved systolic function to similar extents. Acetylcholine mediated relaxation of aortic rings was improved by both ramipril and AVE7688. There was substantial albuminuria in the placebo group (albumin-to-creatinine ratio 107+/-54 microg/mg), which was significantly reduced by ramipril to 57+/-34 microg/mg, and practically abolished in the AVE7688 group (22+/-12 microg/mg, p<0.05 vs. placebo and ramipril). Tubulo-interstitial damage (semi-quantitative score) was significantly reduced by AVE7688 and ramipril. Overall mortality was markedly reduced in the ramipril and AVE7688 groups (13% and 16% at six months, respectively), both p<0.05 vs. placebo (71%).. Vasopeptidase inhibition effectively controls BP and reduces myocardial, vascular and renal target organ damage, resulting in a markedly prolonged survival. At similar degrees of plasma ACE inhibition, AVE7688 compared to ramipril offers superior protection against hypertensive kidney damage.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Endothelium, Vascular; Fibrosis; Heterocyclic Compounds, 3-Ring; Hypertension; Hypertension, Renal; Kidney; Male; Myocardium; Peptide Hydrolases; Peptidyl-Dipeptidase A; Placebos; Protease Inhibitors; Ramipril; Rats; Rats, Inbred SHR; Ventricular Function, Left

Vasopeptidase inhibitors by definition inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), therefore they may exceed the effect of ACE inhibitors in the treatment of hypertension. The present study investigated the effect of the vasopeptidase inhibitor AVE7688 in comparison to the ACE inhibitor ramipril on systolic blood pressure (SBP) and endothelial function in renovascular hypertension.. Wistar-Kyoto rats with renovascular hypertension (two-kidney one-clamp-model) were randomized 2 weeks after unilateral clamping of the right renal artery for 3 weeks' oral treatment with either AVE7688 (30 mg/kg/day), ramipril (1 mg/kg/day) or placebo. SBP was measured by the tail-cuff method and endothelium-dependent and -independent vascular function was assessed in isolated preconstricted (norepinephrine 10(-7) mol/l) aortic rings as relaxation to acetylcholine (10(-10)-10(-4) mol/l) and sodium nitroprusside (10(-10)-10(-4) mol/l), respectively.. Two weeks after clamping, SBP was significantly elevated (196 +/- 16 vs. 145 +/- 8 mm Hg for sham-operated rats; p < 0.01) and further increased in placebo-treated animals to 208 +/- 19 mm Hg. Treatment with AVE7688 and ramipril had a similar blood pressure-lowering effect (119 +/- 8 and 124 +/- 10 mm Hg, respectively; p < 0.01 vs. placebo). Maximum endothelium-dependent relaxation was reduced in hypertensive rats (72 +/- 6 vs. 99 +/- 7% in control rats; p < 0.05). Endothelium-dependent relaxation was restored by AVE7688 (101 +/- 6%) and ramipril (94 +/- 8%), respectively, whereas endothelium-independent relaxation was comparable in all groups.. In renovascular hypertension the vasopeptidase inhibitor AVE7688 exhibited similar blood pressure-lowering and endothelial protective properties as compared to the ACE inhibitor ramipril. Therefore, in high renin models of hypertension, vasopeptidase inhibition may be considered an alternative treatment option to ACE inhibition.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Endothelin-1; Endothelium, Vascular; Heart Rate; Heterocyclic Compounds, 3-Ring; Hypertension, Renal; Male; Neprilysin; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Inbred WKY; Vasodilation

Scleroderma renal crisis is the most severe renal manifestation of scleroderma and has been reported to recur rarely early after renal transplantation. Angiotensin II blockade is critical in preventing and treating scleroderma renal crisis, but some concern exists as to whether angiotensin II receptor blockers are clinically equivalent to angiotensin-converting enzyme inhibitors. The current case indicates that late recurrences of scleroderma renal crisis are possible in renal transplant recipients and that angiotensin-converting enzyme inhibitors, rather than angiotensin II receptor blockers, may be the superior drugs for such patients.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arterioles; Basement Membrane; Female; Humans; Hypertension, Renal; Immunosuppression Therapy; Kidney Diseases; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Transplantation; Losartan; Postoperative Complications; Ramipril; Recurrence; Renal Artery; Scleroderma, Diffuse

Glucose uptake is increased in hypertension. Thus we investigated Na+-glucose cotransporter (SGLT2) activity and expression in proximal tubules from renovascular hypertensive rats. Sham-operated rats, aortic coarctation rats, and aortic coarctation rats treated with either ramipril (2.5 mg.kg-1.day-1 for 21 days) or losartan (10 mg.kg-1.day-1 for 21 days) were used. Na+-dependent glucose uptake was measured in brush-border membrane vesicles (BBMV). Vmax in BBMV from hypertensive rats was greater compared with those from normotensive rats (3 +/- 0.2 vs. 1.5 +/- 0.1 nmol.mg protein-1.min-1) without a change in Km. Renal immunostaining was greater, and Western blot analysis and RT-PCR showed a higher expression of SGLT2 in hypertensive rats than in normotensive rats (1,029 +/- 71 vs. 5,003 +/- 292, 199 +/- 15 vs. 95 +/- 10, and 1.4 +/- 0.2 vs. 0.3 +/- 0.1 arbitrary units, respectively). In rats treated with either ramipril or losartan, Vmax decreased to 2.1 +/- 0.3 and 1.8 +/- 0.4 nmol.mg protein-1.min-1, respectively, as well as did the intensity of immunostaining and levels of protein and mRNA. We suggest that in renovascular hypertension, angiotensin II induced SGLT2 via the AT1 receptor, which was evidenced at both the functional and expression levels, probably contributing to increased absorption of Na+ and thereby to the development or maintenance of hypertension.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Cell Membrane; Gene Expression; Glucose; Hypertension, Renal; Immunoblotting; Kidney Cortex; Losartan; Male; Monosaccharide Transport Proteins; Ramipril; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; RNA, Messenger; Sodium; Sodium-Glucose Transporter 2

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 present study examined non-insulin-treated streptozotocin (STZ)-induced diabetic rats to determine the role of kinins in diabetic nephropathy. Their involvement in the renoprotective effect of the angiotensin-converting enzyme inhibitor (ACEI) ramipril was investigated using the bradykinin (BK) B(2)-receptor antagonist, icatibant (HOE 140), or a combination of the two drugs.Although, none of the treatments prevented the decline of the glomerular filtration rate (GFR) in diabetic rats, ramipril (3 mg/kg/day), but not icatibant (HOE 140; 500 microg/kg/day), prevented proteinuria in these animals. However, the antiproteinuric effect of ramipril was reduced by 45% when combined with icatibant. To explore whether the renal kallikrein-kinin system (KKS) belongs to the underlying mechanisms of these findings, we also determined urinary BK levels, renal kallikrein (KLK) and angiotensin-converting enzyme (ACE) activity as well as renal cortical mRNA levels of neutral endopeptidase 24.11 (NEP) and low-molecular weight (LMW) kininogen. STZ led to a reduction of renal KLK and ACE activity and NEP expression and to a three-fold increase of urinary BK excretion and renal kininogen expression. Icatibant given alone had no effect on these parameters. In contrast, ramipril treatment normalized urinary protein and BK excretion as well as kininogen mRNA expression without affecting NEP mRNA expression or KLK and ACE activity. Our data demonstrate that renal BK is increased in severe STZ-induced diabetes mellitus, but may affect glomerular regulation only to a minor degree under this condition. However, kinins are partly involved in the antiproteinuric action of ACEI at this stage of diabetic nephropathy.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Bradykinin; Bradykinin B2 Receptor Antagonists; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Hypertension, Renal; Hypoglycemic Agents; Insulin; Kallikrein-Kinin System; Kidney Cortex; Kidney Function Tests; Kininogens; Kinins; Male; Neprilysin; Peptidyl-Dipeptidase A; Proteinuria; Ramipril; Rats; Rats, Wistar

Experts have long thought that African Americans were less responsive to ACE inhibitors than other racial or ethnic groups. The African American Study of Kidney Disease and Hypertension (AASK) provides the first evidence of a beneficial effect of ACE inhibition on renal function in African American patients, in addition to excellent blood pressure control.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Black or African American; Female; Humans; Hypertension, Renal; Male; Middle Aged; Ramipril; Randomized Controlled Trials as Topic

We studied the effect of ramipril on proteinuria and mild hypertension in a 21-year-old patient affected by glycogen storage disease type I non-A. After few months of therapy we obtained a decrease in total urine protein excretion that later re-increased in spite of the high dose of ACE inhibitor. Even if ACE inhibitors are the only effective therapy for GSD I nephropathy, further studies are requested.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Glucose-6-Phosphatase; Glycogen Storage Disease Type I; Humans; Hypertension, Renal; Kidney Diseases; Male; Proteinuria; Ramipril

Our study aimed to assess the roles of nitric oxide derived from endothelium NO-synthase (eNOS) and macula densa neuronal NO-synthase (nNOS) in the regulation of renal renin expression. For this purpose renin mRNA levels and renin content were determined in kidneys of wild-type (wt), nNOS-deficient (nNOS-/-), and eNOS-deficient (eNOS-/-) mice, in which the renin system was suppressed by feeding a high-salt diet (NaCl 4%), or was stimulated by feeding a low-salt (NaCl 0.02%) diet together with the converting-enzyme inhibitor ramipril (10 mg kg(-1) day(-1)). In all mouse strains, renin mRNA levels were inversely related to the rate of sodium intake. In eNOS-/- mice renin mRNA levels and renal renin content were 50% lower than in wt mice at each level of salt intake, whilst in nNOS-/- mice renin expression was not different from wt controls. Administration of the general NO-synthase inhibitor nitro-L-arginine methyl ester (L-NAME, 50 mg kg(-1) day(-1)) to mice kept on the low-salt/ramipril regimen caused a decrease of renal renin mRNA levels in wt and nNOS-/- mice, but not in eNOS-/- mice. These observations suggest that neither eNOS nor nNOS is essential for up- or downregulation of renin expression. eNOS-derived NO appears to enhance renin expression, whereas nNOS-derived NO does not.

Topics: Animals; Antihypertensive Agents; Blood Pressure; DNA, Complementary; Enzyme Inhibitors; Female; Gene Expression Regulation, Enzymologic; Hypertension, Renal; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Ramipril; Renin; RNA, Messenger; Sodium, Dietary; Water-Electrolyte Balance

Cardiovascular death continues to be a major problem in renal failure. Structural abnormalities of the heart and the vasculature contribute to the increased cardiovascular risk. They are ameliorated by angiotensin-converting enzyme (ACE) inhibitors, but because of the nonspecifity of ACE inhibition, it is uncertain whether the beneficial effect is mediated by interfering with angiotensin II (Ang II) or by modulating other effector systems, for example, bradykinin.. To assess a potential role of bradykinin, subtotally nephrectomized Sprague-Dawley rats (SNX) received either the ACE inhibitor Ramipril (Rami, 0.2 mg/kg body weight p.o.), the specific B2 bradykinin receptor antagonist Hoe140 (0.2 mg/kg body weight, s.c.), or a combination of both, and were compared to sham-operated controls. To separately assess the effect of Ramipril on development and reversal of structural abnormalities, animals were either treated from the third day after SNX or from the fourth week after SNX onward (0.01 mg/kg body weight, p.o.).. Heart and aorta were evaluated by morphometric and stereologic techniques. The weight of the perfused left ventricle, as an index of cardiac hypertrophy, was significantly higher in untreated SNX. While it was significantly lower in animals with early and late Ramipril treatment, the beneficial effect was completely antagonized by Hoe140. The wall-to-lumen ratio of intramyocardial arterioles was significantly higher in untreated SNX compared with controls, but failed to be modified by administration of either Ramipril or Hoe140. In the heart, the intercapillary distance was significantly higher in SNX, but it was not lowered by either early or late Ramipril or Hoe140 treatment. Treatment of SNX with Hoe140 alone, however, resulted in a marked further increase in intercapillary distance. The wall thickness of the aorta was significantly higher in SNX than in controls; early and late Ramipril treatment prevented such increase, and this effect was antagonized by Hoe140.. These findings illustrate that bradykinin plays an important role for the beneficial effect of Ramipril in preventing (and potentially reversing) abnormal cardiovascular structure in uremic hypertensive rats.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Arterioles; Bradykinin; Capillaries; Cardiomegaly; Coronary Circulation; Creatinine; Heart; Hypertension, Renal; Kidney Failure, Chronic; Male; Nephrectomy; Organ Size; Ramipril; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Uremia; Ventricular Function, Left

To investigate the roles of cardiac output and systemic and regional resistances in corticotropin (ACTH)-induced hypertension in the rat. This study consisted of three series of experiments with eight groups of male Sprague-Dawley rats (n = 132). Series 1 comprised groups 1-4, where group 1 = sham (0.9% NaCl, subcutaneous (s.c.) injection); group 2 = ACTH (0.5 mg/kg per day, s.c.); group 3 = atenolol + sham; group 4 = atenolol + ACTH treatments. Series 2 comprised groups 5 and 6, where group 5 = minoxidil + sham and group 6 = minoxidil + ACTH treatments. Series 3 comprised groups 7 and 8, where group 7 = ramipril + sham and group 8 = ramipril + ACTH treatments. Systolic blood pressure, water and food intakes, urine volume, and body weight were measured every second day. After 10 days of treatment, mean arterial blood pressure was measured by intra-arterial cannulation, and cardiac output (CO), and renal, mesenteric and hindquarter blood flows (RBF, MBF and HBF) determined using transonic small animal flowmeters.. ACTH treatment increased blood pressure (P < 0.001) with a rise in CO (P < 0.01) and renal vascular resistance (RVR, P < 0.05), but did not affect total peripheral resistance (TPR). Atenolol blocked the rise in CO without affecting the rise in blood pressure produced by ACTH treatment Minoxidil lowered TPR, but did not prevent the rise in blood pressure or renal vascular resistance. Ramipril blunted the rise in RVR and blood pressure without significantly affecting TPR.. Neither preventing rise in CO nor lowering TPR altered the ACTH-induced rise in blood pressure in the rat However, both the hypertension and rise in RVR were prevented by ramipril. These data suggest that increase in RVR may play a role in the pathogenesis of ACTH-induced hypertension in the rat.

Topics: Adrenocorticotropic Hormone; Animals; Antihypertensive Agents; Atenolol; Blood Pressure; Cardiac Output; Energy Metabolism; Hypertension, Renal; Male; Organ Size; Ramipril; Rats; Rats, Sprague-Dawley; Renal Circulation; Splanchnic Circulation; Vascular Resistance

To compare the effects of an angiotensin-converting enzyme inhibitor on circulating and tissue renin-angiotensin system, we measured different renin-angiotensin system parameters during the first day of treatment (Day 1) as well as after two weeks of treatment (Day 14). Ramipril was given orally once daily to adult male spontaneously hypertensive rats. Renin activity, angiotensin-converting enzyme activity and levels of angiotensin I and angiotensin II in the plasma, renal cortex and renal medullar were assessed at Day 1 and Day 14 of the treatment. In the plasma, both renin activity and angiotensin I increased 10 to 15 fold one to four hours after acute as well as at Day 14 of ramipril treatment and then returned to basal values within 24 hours. Plasma angiotensin II levels were not significantly decreased at Day 1 or Day 14. The decrease in the angiotensin II/angiotensin I ratio suggested a sustained inhibition of plasma angiotensin-converting enzyme at Day 14. In the renal cortex and medulla, a clearly different pattern was observed: in ramipril treated rats, renin activity in the renal cortex and medulla did not change at Day 1 but at Day 14 we observed a slight and sustained increase in renin activity. Despite very high basal levels of renin activity, angiotensin I levels in the renal cortex were comparable to those in the plasma. The angiotensin I level increased only one-fold one hour after ramipril intake at Day 1 and Day 14. This suggests that angiotensinogen may have a limiting role in the synthesis of angiotensin I in the kidney. Angiotensin II levels were slightly higher in the renal cortex and medulla than in the plasma suggesting local synthesis of the peptide. In the kidney, angiotensin II levels decreased one and four hours after the acute or prolonged ramipril treatment and the angiotensin II/angiotensin I ratio was reduced at the same time. Our results show that the responses of the plasma and kidney components of the renin-angiotensin system to angiotensin-converting enzyme inhibition are different in the plasma and the kidney suggesting that the circulating and tissue renin-angiotensin system are at least in part independent.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Dose-Response Relationship, Drug; Hypertension, Renal; In Vitro Techniques; Kidney; Male; Ramipril; Rats; Rats, Inbred SHR; Renin; Time Factors

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

In an open trial, the pharmacokinetics of ramipril and its active metabolite ramiprilat were studied in 23 hypertensive patients with various degrees of renal insufficiency. During a 2-week treatment period, each subject took daily a 5-mg tablet of ramipril. Serum profiles and urinary excretion of the parent compound and ramiprilat, the active metabolite, were then evaluated. Peak concentrations of ramipril were slightly greater in patients with severe renal insufficiency; however, most of the ramipril was metabolized in the liver. The drug concentration-time curve was almost independent of renal function and no accumulation was observed after multiple dosing. In contrast, ramiprilat kinetics were significantly influenced by renal function. Initial apparent half-lives (8-16 h), mean trough concentrations (5-19 ng/ml), and absolute accumulation all increased with worsening renal function, and renal clearance of ramiprilat was significantly correlated with creatinine clearance. The subsequent long terminal phase at low ramiprilat serum concentration represents the slow dissociation of the angiotensin converting enzyme (ACE)-bound drug. This study indicates that in patients with severe renal insufficiency (creatinine clearance below 30 ml/min), smaller doses of ramipril will be required than in patients with normal or borderline normal renal function.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Half-Life; Humans; Hypertension, Renal; Kidney Failure, Chronic; Middle Aged; Radioimmunoassay; Ramipril

In an open trial, the antihypertensive and hormonal effects of ramipril, a new nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor, were studied in 23 hypertensive patients with various degrees of renal failure: group I, creatinine clearance 5-15 ml/min, n = 10; group II, creatinine clearance 15-40 ml/min, n = 7; group III, creatinine clearance 40-80 ml/min, n = 6. In a 2-week placebo run-in period, antihypertensive agents were reduced or discontinued. During the treatment phase, patients received a 5-mg tablet of ramipril once daily for a period of 2 weeks. Concomitant medication remained unchanged. In all groups, ramipril significantly decreased mean arterial blood pressure. Blood pressure response was not different in the three groups, although plasma ramipril levels were higher in patients with severe renal failure. In patients with high plasma renin activity (PRA), reduction of blood pressure was greater than in subjects with low PRA. Plasma ACE activity was suppressed to less than 20% of its initial value in all groups during the whole treatment period, and the suppression was more marked and lasted longer in patients with severe renal failure. A strong correlation between the plasma ramiprilat levels and the inhibition of plasma ACE activity was noted for all groups. Mean serum creatinine did not increase significantly; serum potassium levels rose from 4.5 to 4.9 mmol/L on day 14 (p less than 0.01). In conclusion, in patients with various degrees of renal failure, ramipril represents an effective and well-tolerated antihypertensive agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Humans; Hypertension, Renal; Kidney Failure, Chronic; Middle Aged; Ramipril

In an open trial, the pharmacokinetics of ramipril and its active metabolite ramiprilat were studied in 25 hypertensive patients with various degrees of renal insufficiency given 5 mg ramipril p.o. for 14 days. Ramipril was rapidly absorbed and reached a peak concentration after 1-2 h. Cmax was greater in patients with severe renal insufficiency, which might indicate a reduced renal elimination rate, although, the rapid decline of the concentration-time curve for ramipril was almost independent of renal function. The mean initial apparent half-lives on Days 1 and 12, respectively, were 2.8 and 3.4 h (Group I: creatinine clearance 5-15 ml/min), 1.8 and 2.3 h (Group II: creatinine clearance 15-40 ml/min), and 1.9 and 1.9 h (Group III: creatinine clearance 40-80 ml/min). No accumulation was observed after multiple dosing. In contrast, the kinetics of its active acid metabolite ramiprilat was significantly influenced by renal function. The mean times to the peak plasma concentration were 5.7 h in Group I, 4.4 h in Group II and 3.8 h in Group III. The initial decline in plasma ramiprilat was dependent upon renal function; the mean initial apparent half-lives (Days 1 and 12, respectively) were 16.0 and 14.8 h (Group I), 10.1 and 9.5 h (Group II) and 10.6 and 8.0 h (Group III). Mean trough concentrations and absolute accumulation also increased with worsening renal function, and the renal clearance of ramiprilat was significantly correlated with the creatinine clearance. The subsequent long terminal phase at low plasma ramiprilat concentrations represented slow dissociation of the ACE-inhibitor complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Creatinine; Female; Humans; Hypertension, Renal; Kidney Diseases; Male; Middle Aged; Pyrroles; Ramipril

Topics: Adult; Blood Pressure; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Hypertension, Renal; Kidney Function Tests; Male; Middle Aged; Nephrotic Syndrome; Proteinuria; Ramipril; Renin