ramipril and Hypertrophy--Left-Ventricular

Ramipril is a second generation angiotensin converting enzyme (ACE) inhibitor. Like enalapril, it is a prodrug and is hydrolysed in vivo to release the active metabolite, ramiprilat, which has a long elimination half-life, permitting once-daily administration. The antihypertensive efficacy of ramipril has been confirmed in large-scale noncomparative studies conducted in general practice as well as in more rigorously controlled clinical trials. In the former, approximately 85% of patients with mild to moderate essential hypertension have responded successfully to treatment with ramipril 2.5 or 5 mg/day, while comparative trials indicate that the antihypertensive efficacy of the drug is equivalent to that of other established ACE inhibitors and the beta-adrenoceptor antagonist atenolol. As expected, the response rate to ramipril monotherapy is lower in patients with severe hypertension (around 40%), although the blood pressure lowering effect can be enhanced with the addition of a diuretic such as hydrochlorothiazide or piretanide. The antihypertensive efficacy of ramipril is maintained in patients with diabetes mellitus and preliminary data indicate that the drug has the beneficial effect of decreasing urinary albumin excretion in diabetic patients with nephropathy. Ramipril is superior to atenolol in causing regression of left ventricular hypertrophy, although the clinical significance of this effect per se remains to be established. The large-scale Acute Infarction Ramipril Efficacy (AIRE) study demonstrated that ramipril 5 or 10 mg/day significantly decreased the risk of all-cause mortality by 27% in patients with clinical evidence of heart failure after acute myocardial infarction, even if transient. The beneficial effect of ramipril was apparent by 30 days of treatment and appeared to be greatest in patients with more severe ventricular damage after infarction. Ramipril is well tolerated in general practice, with 5% or fewer patients discontinuing therapy because of drug intolerance. The data available suggest that ramipril shares a similar tolerability profile to that of other established ACE inhibitors. Thus, clinical data confirm ramipril as a useful alternative ACE inhibitor for the treatment of patients with mild to moderate hypertension, and indicate a beneficial effect of the drug in patients with clinical evidence of heart failure after acute myocardial infarction. It is also reasonable to assume that ramipril will be of value in the treatment

Topics: Aging; Diabetes Complications; Female; Heart Failure; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Kallikrein-Kinin System; Kidney; Male; Myocardial Infarction; Ramipril; Vascular Resistance

From pharmacologic investigations and clinical studies it is known that angiotensin-converting enzyme (ACE) inhibitors exhibit additional local actions, which are not related to hemodynamic changes and which cannot be explained simply by interference with the renin-angiotensin system with subsequent inhibition of angiotensin II formation. Because ACE is identical to kininase II, which inactivates the nonapeptide bradykinin (BK), potentiation of BK might be responsible for these additional effects of ACE inhibitors. To prove the specificity of BK-mediated effects by ACE inhibition, we used the specific B2 kinin receptor antagonist HOE 140 in different models: endothelial cell cultures; atherosclerosis in high-cholesterol-fed rabbits; neointima formation with smooth cell proliferation and migration after endothelial denudation in rats; myocardial ischemia in rats, rabbits, and dogs; and left ventricular hypertrophy in rats. The beneficial effects of ramipril or BK given in non-blood pressure-lowering doses in these models were abolished by HOE 140 (icatibant). Ramipril exerts cardioprotective effects in different experimental models. The formation of the endothelial autacoids nitric oxide and prostacyclin, enhanced when BK degradation is inhibited by ACE inhibition, may contribute to the observed beneficial effects.

Topics: Amino Acid Sequence; Animals; Arteriosclerosis; Bradykinin; Cattle; Cholesterol; Diet, Atherogenic; Dogs; Drug Interactions; Endothelium, Vascular; Heart; Humans; Hypertrophy, Left Ventricular; Molecular Sequence Data; Muscle, Smooth, Vascular; Myocardial Ischemia; Rabbits; Ramipril; Rats; Rats, Inbred SHR

We report the results of an echocardiographic substudy carried out in a trial comparing the effects of two different treatment strategies - mineralocorticoid receptor blockade (MRB) and dual renin-angiotensin system blockade (RASB) - in patients with resistant hypertension. Both strategies reduce left ventricular mass index (LVMI), but they have not been compared in patients with resistant hypertension.. After 4-week treatment with 300 mg irbesartan + 12.5 mg hydrochorothiazide + 5 mg amlodipine, 86 patients with resistant hypertension were randomized to the add-on 25 mg spironolactone (MRB group, n = 46) or 5 mg ramipril (RASB group, n = 40) groups for 12 weeks. Treatment intensity was increased at week 4, 8 or 10 if home blood pressure (BP) was equal to or above 135/85 mmHg, by sequentially adding 20-40 mg furosemide and 5 mg amiloride (MRB group), or 10 mg ramipril and 5-10 mg bisoprolol (RASB group). Transthoracic echography was performed at baseline and week 12.. Daytime ambulatory BP decreased by 19 ± 12/11 ± 8 mmHg in the MRB group and by 8 ± 13/7 ± 7 mmHg in the RASB group (P = 0.0003/0.03). LVMI decreased by 8.2 ± 18.9 g/m in the MRB group, whereas it increased by 1.8 ± 19.1 g/m in the RASB group (P = 0.03). The decreases in posterior wall thickness, left ventricular (LV) end-systolic diameter, E/e' ratio and left atrial area were significantly greater with MRB than with RASB. The difference between groups remained significant after adjustment for the decrease in ambulatory BP.. In patients with resistant hypertension, MRB-based treatment decreased both BP and LVMI more efficiently than a strategy based on dual RASB.

Topics: Adolescent; Adult; Aged; Aldosterone; Amiloride; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Bisoprolol; Blood Pressure; Blood Pressure Determination; Diuretics; Drug Therapy, Combination; Female; Furosemide; Humans; Hypertension; Hypertrophy, Left Ventricular; Irbesartan; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Ramipril; Renin; Renin-Angiotensin System; Spironolactone; Tetrazoles; Young Adult

Evidence on new-onset atrial fibrillation in high-risk vascular patients without heart failure is limited. New-onset atrial fibrillation was a prespecified secondary objective of the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) studies.. We studied 30 424 ONTARGET/TRANSCEND patients (mean age ± SD, 66.4 ± 7.0) with vascular disease or complicated diabetes who were in sinus rhythm at entry. A copy of ECG was sent to central office every time new atrial fibrillation was detected by investigators.. During a median follow-up period of 4.7 years, new atrial fibrillation occurred in 2092 patients (15.1 per 1000  patient-years). Risk of atrial fibrillation increased with age, SBP and pulse pressure, left ventricular hypertrophy, BMI, serum creatinine and history of hypertension, coronary artery disease and cerebrovascular disease (all P < 0.01). After adjustment for BMI and other variables, atrial fibrillation risk increased with hip circumference. History of hypertension was associated with a 34% higher risk of new atrial fibrillation. New atrial fibrillation portended an increased risk of congestive heart failure [hazard ratio 2.89, 95% confidence interval (CI) 2.45-3.40, P < 0.01] and cardiovascular death (hazard ratio 1.22, 95% CI 1.05-1.41, P < 0.01). Risk of stroke was unaffected (hazard ratio 1.14, 95% CI 0.93-1.40), whereas that of myocardial infarction was reduced (hazard ratio 0.64, 95% CI 0.50-0.82). Patients with new atrial fibrillation were more likely to receive vitamin K antagonists (P < 0.01), statins (P < 0.05) and β-blockers (P < 0.01) than those in sinus rhythm.. New atrial fibrillation is common in high-risk vascular patients and is associated with several risk factors including history of hypertension. Hip circumference was the strongest anthropometric predictor. Despite extensive use of modern therapies, new atrial fibrillation carries a high risk of congestive heart failure and death over a relatively short term.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Anthropometry; Atrial Fibrillation; Benzimidazoles; Benzoates; Body Mass Index; Cardiovascular Diseases; Diabetes Complications; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy, Left Ventricular; Male; Middle Aged; Placebos; Ramipril; Risk; Risk Factors; Stroke; Telmisartan; Vitamin K

The objective of this study was to compare valsartan or ramipril addition to amlodipine + hydrochlorothiazide (HCTZ) on blood pressure (BP) and left ventricular hypertrophy (LVH) in hypertensive diabetic patients with LVH.. 293 patients were treated with amlodipine 10 mg + HCTZ 12.5 combination and then randomized to receive valsartan 160 mg or ramipril 5 mg, in addition to the previous therapy, for 1 year.. Clinic BP was measured every month; echocardiographic assessments were performed at the end of the placebo period, both before the randomization and after 1-year of triple combination therapy.. Both triple regimens similarly reduced SBP/DBP values (-13.5/10.9 mm Hg in the valsartan group and -13.4/10.4 mm Hg in the ramipril group). Triple combination including valsartan better reduced LVMI (-20.1%, p < 0.001), interventricular septal thickness (IVST) (-20.3%, p < 0.001) and left ventricular posterior wall thickness (PWT) (-16.3%, p < 0.001), compared with triple combination including ramipril (-14%, p < 0.01; -16.2%, p < 0.001 and -9%, p < 0.01, respectively); the difference between treatments being statistically significant (p < 0.05). Triple combination with valsartan gave a greater increase of E/A ratio (p < 0.05 between groups).. Valsartan addition to dual therapy with amlodipine + HCTZ was more effective than ramipril addition in reducing LVH.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Combinations; Female; Humans; Hydrochlorothiazide; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Ramipril; Tetrazoles; Valine; Valsartan

To compare the effects of nebivolol and ramipril on left ventricular hypertrophy in hypertensive patients.. The study was conducted with a pre-randomised blinded endpoint (PROBE) design in which 106 patients with mild-to-moderate hypertension and left ventricular hypertrophy were randomised to ramipril (n = 52) or to nebivolol (n = 54) and treated for 39 weeks. The doses of ramipril and nebivolol were 2.5 and 5 mg/day, respectively. After 4-8 weeks, in patients with not normalised diastolic blood pressure, a thiazide diuretic was added (indapamide 2.5 mg or hydrochlorothiazide 12.5 mg/day). In the ramipril group, thiazide diuretic was added in 97% of subjects and in nebivolol group in 92%. The effect of treatment on left ventricular mass was assessed by two-dimensional guided M-mode transthoracic echocardiography, at baseline and at the end of the treatment. Left ventricular mass index (LVMI) was calculated and indexed to body surface area (g/m2) and height2.7 (g/height2.7). Blood pressure (BP) was measured at baseline, after 4, 8, 12, 24 and 39 weeks with a standard mercury sphygmomanometer.. Both left ventricular mass (LVM) and mass index (LVMI) decreased significantly after treatment with ramipril (LVMI -14.8 g/m2, -7.3 g/height2.7; p < 0.001), and after treatment with nebivolol (LVMI -31.9 g/m2, -15.6 g/height2.7; p < 0.001). The difference between ramipril and nebivolol (-17.1 g/m2, -8.3 g/height2.7) with regards to reduction of LVMI was statistically significant (p < 0.001). No differences were observed between the two groups in terms of normalization of LVMI. Both drugs decreased BP similarly after 39 weeks of treatment. The present study shows that both nebivolol and ramipril decrease LVMI. Nebivolol 5 mg/daily treatment reduced LVMI significantly more than ramipril 2.5 mg/daily. Both drugs similarly decreased BP during the treatment.

Topics: Antihypertensive Agents; Benzopyrans; Blood Pressure; Drug Therapy, Combination; Ethanolamines; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Nebivolol; Prospective Studies; Ramipril; Sodium Chloride Symporter Inhibitors; Treatment Outcome; Ultrasonography

Left ventricular hypertrophy (LVH) and atherosclerosis are frequently observed in uremic patients and they have appeared as an independent predictor of cardiovascular morbidity and mortality. The aim of this study was to compare the effects of ramipril and amlodipine on left ventricular mass index (LVMI) and carotid intima-media thickness (CIMT) in nondiabetic hypertensive hemodialysis patients.. A total of 112 hemodialysis (HD) patients were included in this study. Patients were randomly allocated to receive ramipril or amlodipine for 1 year. Blood pressure (BP) measurements, LVMI, and CIMT were assessed at baseline and 6-month intervals. Biochemical parameters and inflammatory markers were also determined at the initiation and during the study period.. Similar BP decrease was observed in treatment groups. During follow-up, LVMI and CIMT progressed likewise in both treatment groups despite BP control. However, subgrouping analyses due to the pattern of left ventricular geometry showed that LVMI in patients with eccentric LVH increased, whereas LVMI decreased in subjects with concentric LVH under antihypertensive treatment.. BP control with ramipril or amlodipine could not provide adequate protection for development or progression of atherosclerosis and eccentric type of LVH in nondiabetic HD patients.

Topics: Adult; Aged; Amlodipine; Antihypertensive Agents; Atherosclerosis; Carotid Arteries; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Ramipril; Renal Dialysis; Stroke Volume; Tunica Intima; Tunica Media; Ultrasonography

Hypertension is frequently seen in autosomal dominant polycystic kidney disease (ADPKD), and it has a negative effect on renal progression. Hypertension and left ventricle hypertrophy (LVH) are related in terms of pathogenesis and their effects on renal progression. In this study, we aimed to compare the effects of losartan and ramipril on blood pressure (BP) control, LVH, and renal progression in patients with hypertensive ADPKD.. Thirty-two ADPKD patients with ages ranging between 18 and 70 years who were stage 1-2 hypertensive were included in this study. Routine biochemical tests and echocardiography were obtained at first examination of the patients. Following these, the patients were randomized. One group was given losartan and the other ramipril. They were followed up for 1 year, and their echocardiographies and routine biochemical tests were repeated at the end of the year.. BP values decreased in both the groups at the end of the first year (p < 0.001). There was a statistically significant difference in LVH in both the groups at the end of the first year than at the beginning (losartan, p = 0.007; ramipril, p < 0.001).. In this study, effective BP control was obtained with losartan and ramipril and LVH was found to be regressed significantly in the hypertensive patients with ADPKD. These two groups of antihypertensive drugs may also have beneficial effects on the retardation of renal progression and in reducing cardiovascular mortality in hypertensive patients with ADPKD.

Topics: Adolescent; Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Losartan; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Ramipril; Young Adult

Patients with prosthesis-patient mismatch (PPM) continue to show some degrees of left ventricular hypertrophy after aortic valve replacement for aortic stenosis. The renin-angiotensin system plays a major role in promoting and sustaining hypertrophy. In a controlled, randomized study, we tested the hypothesis that the combination of angiotensin-converting enzyme inhibitors (ACEi) plus angiotensin II receptor blocker (ARB) can be more effective in decreasing hypertrophy than a largely employed association such as ACEi plus ß-blockers in PPM patients.. We enrolled a total of 72 patients with aortic valve replacement and evidence of PPM (effective orifice area <0.85 cm(2)/m(2)) at postoperative echocardiography. At discharge, they were randomly assigned to ramipril plus candesartan (n = 36) or ramipril plus metoprolol (n = 36).. At baseline, age, 24-hour blood pressure, left ventricular measurements, and transprosthetic gradients were similar between the two groups. After 12 months, the extent of 24-hour systolic and diastolic blood pressure decrease was similar between the two groups (-13.3% and 16.3% versus -12.3% and 15.8%, respectively; p = 0.7 and 0.8, respectively). Left ventricular mass index significantly decreased in both groups (ACEi plus ARB 165 ± 19 g/m(2) to 117 ± 17 g/m(2); p < 0.0001; ACEi plus β-blockers 161 ± 15 g/m(2) to 128 ± 20 g/m(2); p < 0.0001). However, patients receiving ACEi plus ARB had a higher decrease of left ventricular mass (-46 ± 15 g/m(2) versus -35 ± 12 g/m(2); p = 0.001) and a lower rate of residual left ventricular hypertrophy (22% versus 47%; p = 0.04).. This study shows that in patients with PPM, the association ACEi and ARB has a greater antiremodeling effect compared with ACEi and β-blockers, and is independent of blood pressure.

Topics: Adrenergic beta-1 Receptor Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Aortic Valve Stenosis; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Dose-Response Relationship, Drug; Drug Therapy, Combination; Echocardiography; Female; Follow-Up Studies; Heart Valve Prosthesis; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Male; Metoprolol; Prosthesis Design; Prosthesis Failure; Ramipril; Renin-Angiotensin System; Retrospective Studies; Tetrazoles; Treatment Outcome

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers reduce left ventricular hypertrophy (LVH). The effect of these drugs on LVH in high-risk patients without heart failure is unknown.. In the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET), patients at high vascular risk and tolerant of ACE inhibitors were randomly assigned to ramipril, telmisartan, or their combination (n=23 165). In the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND), patients intolerant of ACE inhibitors were randomized to telmisartan or placebo (n=5343). Prevalence of LVH at entry in TRANSCEND was 12.7%. It was reduced by telmisartan (10.5% and 9.9% after 2 and 5 years) compared with placebo (12.7% and 12.8% after 2 and 5 years) (overall odds ratio, 0.79; 95% confidence interval [CI], 0.68 to 0.91; P=0.0017). New-onset LVH occurred less frequently with telmisartan compared with placebo (overall odds ratio, 0.63; 95% CI, 0.51 to 0.79; P=0.0001). LVH regression was similar in the 2 groups. In ONTARGET, prevalence of LVH at entry was 12.4%. At follow-up, it occurred slightly less frequently with telmisartan (odds ratio, 0.92; 95% CI, 0.83 to 1.01; P=0.07) and the combination (odds ratio, 0.93; 95% CI, 0.84 to 1.02; P=0.12) than with ramipril, but differences between the groups were not significant. New-onset LVH was associated with a higher risk of primary outcome during follow-up (hazard ratio, 1.77; 95% CI, 1.50 to 2.07).. In patients at high vascular risk, telmisartan is more effective than placebo in reducing LVH. New-onset LVH is reduced by 37%. The effect of combination of the 2 drugs on LVH is similar to that of ramipril alone.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Cardiovascular Diseases; Diastole; Double-Blind Method; Drug Therapy, Combination; Drug Tolerance; Electrocardiography; Female; Humans; Hypertrophy, Left Ventricular; Male; Odds Ratio; Placebos; Prevalence; Proportional Hazards Models; Ramipril; Regression Analysis; Systole; Telmisartan

The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) showed that the angiotensin receptor blocker telmisartan 80 mg was not inferior to the angiotensin-converting enzyme inhibitor ramipril 10 mg, and the combination no more effective than ramipril alone, in decreasing morbidity and mortality in patients with cardiovascular disease or high-risk diabetes. Although therapy targeting angiotensin II is known to decrease left ventricular (LV) mass and volume, the relative influence of angiotensin-converting enzyme inhibitor inhibitors and angiotensin receptor blocker, and their combination, on the heart remains unclear in this population. Magnetic resonance imaging was performed in 287 patients enrolled in ONTARGET, across 8 centers in 6 countries, at randomization and after 2-year treatment (90, 100, and 97 patients in the ramipril, telmisartan, and combination therapy groups, respectively). Baseline patient characteristics showed higher frequencies of coronary artery disease, Asian ethnicity, and use of statins and beta blockers than the main ONTARGET trial. LV mass decreased in all groups (p <0.0001 for each), but there were no significant differences in change in LV mass or volume among groups, except that LV mass index decreased more on combination versus telmisartan (p = 0.04). Key determinants of LV mass decrease were a history of hypertension (p = 0.03), baseline mass (p <0.0001), and decrease in systolic blood pressure (p <0.0001). The best magnetic resonance imaging predictor of composite events was end-systolic volume (p <0.0001). In conclusion, telmisartan and ramipril had similar effects on LV mass and volume, and combination therapy was not more effective, in high-risk patients with cardiovascular disease. These results are consistent with the major outcome findings of the main ONTARGET study.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Atherosclerosis; Benzimidazoles; Benzoates; Diabetes Complications; Drug Therapy, Combination; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Male; Ramipril; Survival Analysis; Telmisartan; Treatment Outcome; Ventricular Dysfunction, Left

The renin-angiotensin system (RAS) plays a major role in promoting left ventricular (LV) remodeling in essential hypertension. We designed a controlled, randomized pilot study aimed to test the hypothesis that the dual RAS blockade with angiotensin-converting enzyme (ACE) inhibitor (ACEi) + angiotensin II receptor blocker (ARB) can be more effective in decreasing LV hypertrophy and improving diastolic function than a largely employed association such as ACEi + calcium-antagonist (Ca-A).. Twenty-four never-treated hypertensive patients with LV concentric hypertrophy were randomized to ramipril + candesartan or ramipril + lercanidipine. Before and after the 6-month treatment they underwent a 24-h blood pressure (BP) monitoring and echocardiographic examination.. At baseline, age, body mass index (BMI), 24-h BP, and LV morpho-functional parameters were similar between the two groups. The 6-month treatment induced in both groups a significant decrease of 24-h BP, septal and posterior wall thickness, and LV mass index (LVMi) (ACEi + ARB 155 +/- 19 to 122 +/- 17 g/m(2), P < 0.0001; ACEi + Ca-A 146 +/- 18 to 127 +/- 20 g/m(2), P < 0.0001). Systolic function remained unchanged; LV diastolic parameters increased significantly in both groups. The extent of 24-h BP decrease was similar between the two groups (-13.3/16.3% vs. -12.3/15.8%, P = 0.63/P = 0.71), whereas the decrease of LV mass (-22% vs. -12.8%, P < 0.005) and the improvement of diastolic function were greater in ACEi + ARB group.. In comparison with ACEi + Ca-A, ACEi + ARB treatment showed a greater antiremodeling effect, that can be reasonably ascribed to a BP-independent effect of the dual RAS blockade.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Drug Synergism; Drug Therapy, Combination; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Pilot Projects; Ramipril; Renin-Angiotensin System; Tetrazoles; Treatment Outcome

The effects of 24 weeks losartan and ramipril treatment, both alone and in combination, on left ventricular mass (LVM), circulating transforming growth factor beta1 (TGFbeta1), procollagen type I (PIP) and III (PIIIP), have been evaluated in hypertensive (HT) patients. A total of 57 HT with stage 1 and 2 essential hypertension were included. After 4 weeks run in, a randomized double-blind, three arms, double dummy, independent trial was used. All HT patients were randomly allocated to three treatment arms consisting of losartan (50 mg/daily), ramipril (5 mg/ daily) and combined (losartan 50 mg/daily + ramipril 5 mg/daily) for 24 weeks. TGFbeta1, PIP and PIIIP, LVM, LVM/h(2.7) and other echocardiographic measurements, blood urea nitrogen, creatinine and clearance and potassium were determined after run in and after 24 weeks. All groups were comparable for gender, age, body mass index, blood pressure and LVM. The prevalence of baseline left ventricular hypertrophy (LVH) was not significantly different among three groups. At the end of treatment, a significant (P<0.05) reduction in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), TGFbeta1, PIP, PIIIP, LVM and LVM/h(2.7) was observed in all groups. The absolute and percent reduction in TGFbeta1 and LVM/h(2.7) were significantly higher in combined than losartan or ramipril groups and also in HT patients with LVH. No significant change in absolute and percent reduction of SBP, DBP and MBP were found. Our data indicate an additional cardioprotective effect of dual blockade of renin-angiotensin in HT patients.

Topics: Adult; Analysis of Variance; Antihypertensive Agents; Biomarkers; Blood Pressure; Collagen Type I; Collagen Type III; Double-Blind Method; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Italy; Losartan; Male; Middle Aged; Prevalence; Ramipril; Renin-Angiotensin System; Severity of Illness Index; Transforming Growth Factor beta1; Treatment Outcome; Ultrasonography; Ventricular Function, Left

Normotensive hemodialysis patients may still have left ventricular hypertrophy in the absence of significant pressure or volume overload. We examined the hypothesis that treatment with an angiotensin-converting enzyme inhibitor could be beneficial in the reversal of left ventricular hypertrophy in these patients.. Forty-six normotensive patients with end-stage renal disease on regular hemodialysis therapy were randomly assigned to administration of ramipril, 2.5 mg 3 times/wk, or placebo for 1 year. Left ventricular mass index and parameters of cardiovascular structure and function were evaluated noninvasively by means of echocardiography and arterial tonometry at baseline, 6 and 12 months after treatment, and 1 month after washout.. In the ramipril group, blood pressure decreased significantly at 6 and 12 months after treatment. There were no significant within-group or between-group differences in left ventricular mass index at entry, 6 and 12 months after treatment, and 1 month after washout. There were no significant differences in left atrial dimension, left ventricular size and wall thickness, left ventricular ejection fraction, aortic dimension, intima-media thickness, elastic modulus and augmentation index of the common carotid artery, and aortic pulse wave velocity between the ramipril and placebo groups at entry, 6 and 12 months after treatment, and 1 month after washout.. A 12-month treatment with ramipril did not cause significant regression of left ventricular hypertrophy in normotensive hemodialysis patients. Results may suggest that the renin-angiotensin system has little role in the pathogenesis of mild left ventricular hypertrophy in these patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Double-Blind Method; Female; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Ramipril; Renal Dialysis

Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve cardiovascular disease outcomes in high-risk patients, but evidence for the cardio-protective effects of angiotensin II receptor blockers (ARBs) is less extensive. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the parallel Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease (TRANSCEND)--which together form The ONTARGET Trial Programme--are long-term, large-scale, double-blind, multinational outcome studies with the primary objectives of determining if the combination of the ARB telmisartan 80 mg and the ACE inhibitor ramipril 10 mg is more effective than ramipril 10 mg alone, and if telmisartan is at least as effective as ramipril (in the case of ONTARGET), and if telmisartan is superior to placebo (in the case of TRANSCEND), in providing cardiovascular protection for high-risk patients. A pre-defined substudy is being conducted within The ONTARGET Trial Programme to compare the effects of these agents, alone and in combination, on cardiac structure and function. The substudy overcomes criticisms of many previous studies, which have been performed in small numbers of patients using suboptimal methodology, by evaluating changes in left ventricular structure and function using sophisticated technology provided by magnetic resonance imaging (MRI). Some 300 randomized patients within ONTARGET, recruited from selected centres in Australia, Canada, Germany, Hong Kong, New Zealand and Thailand, will have MRI undertaken at baseline and at 2-year follow-up. As this method of assessing left ventricular dysfunction is somewhat timeconsuming, expensive and complex, and in the light of current interest in the role of B-type natriuretic peptide (BNP) as a simple, inexpensive diagnostic and prognostic tool, the substudy will also examine whether changes in BNP during follow-up correlated with changes in left ventricular dysfunction.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Double-Blind Method; Drug Therapy, Combination; Follow-Up Studies; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Middle Aged; Natriuretic Peptide, Brain; Patient Selection; Ramipril; Research Design; Telmisartan; Time Factors

To elucidate the relationship between regression of hypertensive left ventricular hypertrophy (LVH) and changes of coronary flow reserve (CFR).. Ninety-six essential hypertensive patients with LVH were randomly divided into 3 groups: ramipril group, losartan group, and combination group. Before the treatment and 6 months after the treatment, left ventricular mass (LVM) was calculated by three-dimensional echocardiography and CFR was evaluated by transesophageal echocardiography with left anterior descending artery. CFR was calculated as the ratio of coronary flow velocity, after intravenous injection of dipyridamole (D), to rest peak velocity (R). All the indexes of the CFR were corrected by LVM.. (1) The systolic blood pressure (SBP), diastolic blood pressure (DBP) and LVM were significantly decreased in ramipril group, losartan group and combination group after 6 months treatment (all P < 0.01). Diastolic flow velocity integral was used as one representative index of CFR. Compared with baseline values, the diastolic flow velocity intergral corrected by LVM (D/R DVi(C)) was significantly increased in ramipril group, losartan group and combination group (1.83 +/- 0.61 vs 1.57 +/- 0.58, P < 0.05; 1.94 +/- 0.45 vs 1.53 +/- 0.64, P < 0.01; 2.03 +/- 0.38 vs 1.49 +/- 0.34, P < 0.01). (3) The changes of D/R DVi(C) showed a positive correlation with the changes of LVM (r = 0.579, P < 0.05) and no significant correlation with the decrease of blood pressure (r = 0.288 and 0.295,both P > 0.05).. Ramipril, losartan and combination of these two drugs all reduce blood pressure and LVH, and increases CFR. CFR corrected by LVM may help assess drug's effect on CFR. Improvement of CFR is associated with the regression of hypertensive LVH.

Topics: Adult; Aged; Coronary Circulation; Echocardiography, Three-Dimensional; Echocardiography, Transesophageal; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Losartan; Male; Middle Aged; Ramipril

Electrocardiographic markers of left ventricular hypertrophy (LVH) predict poor prognosis. We determined whether the ACE inhibitor ramipril prevents the development and causes regression of ECG-LVH and whether these changes are associated with improved prognosis independent of blood pressure reduction.. In the Heart Outcomes Prevention Evaluation (HOPE) study, patients at high risk were randomly assigned to ramipril or placebo and followed for 4.5years. ECGs were recorded at baseline and at study end. We compared prevention/regression and development/persistence of ECG-LVH in the two groups and related these changes to outcomes. At baseline, 676 patients had LVH (321 in the ramipril group and 355 in the placebo group) and 7605 patients did not have LVH (3814 in the ramipril group and 3791 in the placebo group). By study end, 336 patients in the ramipril group (8.1%) compared with 406 in the placebo group (9.8%) had development/persistence of LVH; in contrast, 3799 patients in the ramipril group (91.9%) compared with 3740 in the placebo group (90.2%) had regression/prevention of LVH (P=0.007). The effect of ramipril on LVH was independent of blood pressure changes. Patients who had regression/prevention of LVH had a lower risk of the predefined primary outcome (cardiovascular death, myocardial infarction, or stroke) compared with those who had development/persistence of LVH (12.3% versus 15.8%, P=0.006) and of congestive heart failure (9.3% versus 15.4%, P<0.0001).. The ACE inhibitor ramipril decreases the development and causes regression of ECG-LVH independent of blood pressure reduction, and these changes are associated with reduced risk of death, myocardial infarction, stroke, and congestive heart failure.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Double-Blind Method; Electrocardiography; Female; Follow-Up Studies; Heart Failure; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Placebos; Prognosis; Ramipril; Risk Factors; Treatment Outcome

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetes Mellitus, Type 2; Furosemide; Humans; Hypertrophy, Left Ventricular; Ramipril

This perspective study was performed to demonstrate the prevention of left ventricular hypertrophy by ACE-inhibitor, ramipril, in hypertensives of recent onset. Thirty-four hypertensive patients, treated with ramipril (group I), and 32 controls who received another frequently employed drug (the calcium channel-antagonist, felodipine (group II), were evaluated. Neither of two groups received any anti-hypertensive drug and did not suffer from left ventricular hypertrophy. All selected patients underwent M-mode echocardiography for measuring the following parameters: diastolic diameter of left ventricle, (DDLV); systolic diameter of left ventricle (SDLV); inter-ventricular septum (IVS); thickness of the posterior wall (PW); and left ventricular mass index (LVMI). Two anti-hypertensive drugs reduce systemic hypertension the same way. But, in hypertensives receiving ramipril (group I), the echocardiographic parameters of the left ventricle increased non-significantly. On the other hand, in those treated with felodipine (II group), these parameters significantly changed. The mechanisms of non-increase in cardiac and non-cardiac proteins, due to the ACE-inhibitors, are illustrated.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Echocardiography; Felodipine; Female; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Prognosis; Prospective Studies; Ramipril; Treatment Outcome

An open and multicentric study was conducted with 66 patients with mild to severe diastolic arterial hypertension and echocardiographic left ventricular hypertrophy, the evolution of diastolic function, by means of doppler transmitral flow echocardiography, under treatment with ramipril, an angiotensin converting enzyme inhibitor, at a dose of 2.5 and 5 mg/day, or combined with a diuretic, after three and six months of treatment. Despite not obtaining the tensional control in all patients, a decrease in the mass, both in absolute values and mass index, was obtained. This decrease was observed both in male and female patients from the first three months, which went on until the sixth month, thus suggesting an independent action of the hemodynamic load decrease for the obtention of this effect. There was also a change in the ventricular geometry with a displacement of patients from concentric enlargement to normal, remodelling and eccentric enlargement. The diastolic function improved both for the early and for the late maximal filling velocity, relationship between both, and deceleration time, although the time during which this improvement occurred was different for each parameter, thus indicating the different influence of the dynamic and structural factors on these parameters. No correlation was found between the improvement in diastolic function and hypertrophy regression. We can conclude that ramipril is useful for the control of the left ventricular hypertrophy and diastolic function, irrespective of arterial tension values.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Diastole; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Ramipril

To evaluate the effect of the ACE inhibitor ramipril as compared with placebo on left ventricular mass index (LVMI) in normotensive, nonalbuminuric NIDDM patients with left ventricular hypertrophy (LVH). Patients with NIDDM are characterized by excessive cardiovascular morbidity and mortality, and LVH, an independent risk factor for cardiac events, is often present in NIDDM patients.. A total of 38 normotensive, nonalbuminuric (albuminuria < 100 mg/24 h) NIDDM patients with LVH (LVMI > 131 g/m2 in men and > 100 g/m2 in women) were enrolled in a 6-month randomized, double-blind parallel group study to compare the effects of ramipril (5 mg/day) with placebo on LVMI (echocardiography, Vingmed CFM725, Diasonics Sonotron), QTc dispersion determined as the interlead variation in QTc interval on standard electrocardiogram (ECG), and 24-h ambulatory blood pressure (A&D TM2420, Tokyo, Japan). A total of 16 ramipril (10 men, 60 +/- 9 years [mean +/- SD]) and 15 placebo-treated (8 men, 55 +/- 10 years) patients completed the study, and their data are presented.. Ambulatory blood pressure was almost identical at baseline (132/76 +/- 3/1 vs. 133/74 +/- 5/2 mmHg [mean +/- SEM]) and remained stable during follow-up (134/76 +/- 3/1 vs. 136/74 +/- 6/2 mmHg) in the ramipril and placebo group, respectively. LVMI was comparable at baseline (137.1 +/- 7.0 vs. 129.6 +/- 3.7 g/m2) in the ramipril and placebo group, respectively, and decreased significantly more in the ramipril group as compared with the placebo group (17.6 +/- 3.0 vs. 5.7 +/- 4.6 g/m2, respectively, 11.9 [0.7-23.1] g/m2, mean difference [95% CI]; P = 0.037). QTc dispersion was comparable at baseline (60.2 [5.5] vs. 64.1 [6.5] ms) and did not change significantly during follow-up: -2.5 [7.0] vs. -12.2 [9.5] ms; mean difference 9.8 (-14.2 to 33.8 ms) in the ramipril and placebo group, respectively.. Ramipril induces regression of LVH in normotensive, nonalbuminuric NIDDM patients, independent of reduction in systemic blood pressure.

Topics: Aged; Albuminuria; Antihypertensive Agents; Biomarkers; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Electrocardiography; Female; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Ramipril; Reference Values; Treatment Outcome

Diuretic-based therapy is less effective in reducing the cardiac complications of hypertension than the risk of stroke and may be less effective in reducing left ventricular (LV) mass than is therapy with angiotensin converting enzyme (ACE) inhibition. In view of the strong association of LV hypertrophy with cardiovascular risk, this study was designed to compare the impact of therapy with a diuretic and ACE inhibition on cardiac and vascular structure. Fifty essential hypertensives (74% male, 88% nonwhite) participated in a double-blind study for 6 months and were randomized to either ramipril or hydrochlorothiazide (HCTZ). Echocardiography, carotid ultrasonography, and ambulatory blood pressure (BP) monitoring were performed at baseline and 3 and 6 months after initiation of therapy. The 22 ramipril patients were comparable to the 28 HCTZ patients at baseline in age, race, and 24-h BP. Although HCTZ resulted in a greater reduction in 24-h BP, only treatment with ramipril resulted in a decrease in LV mass (193 to 179 g, P < .005, v 184 to 182 g, P = NS), attributable to a reduction in wall thicknesses but not in chamber diameter. In multivariate analysis, both change in BP and treatment group were independent predictors of change in LV mass. Importantly, although neither drug reduced carotid artery cross-sectional area, relative wall thickness increased due to a tendency for vessel diameter to decrease and wall thickness to increase, particularly in the diuretic group. Ramipril caused a sustained fall in plasma angiotensin II, whereas HCTZ increased angiotensin II levels. Although diuretic therapy was more effective in lowering ambulatory BP in this predominantly nonwhite population, only therapy with ACE inhibition was associated with regression of LV mass. Vascular geometry was altered consistent with the reduction in distending pressure resulting in vascular remodelling.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Carotid Artery, Common; Diuretics; Double-Blind Method; Female; Heart Ventricles; Humans; Hydrochlorothiazide; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Ramipril; Renin-Angiotensin System

We evaluated global and segmental left ventricular (LV) mass and LV mass/volume ratio in patients with LV dysfunction receiving angiotensin-converting enzyme (ACE) inhibitor therapy after acute myocardial infarction (MI).. ACE inhibitors attenuate LV dilatation and compensatory hypertrophy after acute MI in animal models. However, LV remodeling in patients after acute MI has been largely defined on the basis of changes in chamber volume alone.. Twenty-nine patients with LV ejection fraction <40% received the ACE inhibitor ramipril (range 2.5 to 20 mg/day) within 5 days of their first Q-wave MI. Magnetic resonance imaging was performed at baseline and at 3 months, providing global and regional LV volumes and mass from summated serial short-axis slices. Mean arterial blood pressure was unchanged from baseline to 3-month follow-up (89 +/- 10 to 92 +/- 17 mm Hg). LV mass decreased (90 +/- 25 to 77 +/- 21 gm/m2, p < 0.0005) as LV end-diastolic volumes increased (65 +/- 13 to 73 +/- 22 ml/m2, p < 0.01). Global LV mass to volume ratio decreased from 1.40 +/- 0.28 to 1.08 +/- 0.18 gm/ml (p < 0.0001), as did circumferential wall thickness to volume ratio of noninfarcted myocardium at the base of the LV (0.06 +/- 0.02 to 0.05 +/- 0.02 mm/ml, p < 0.001). LV ejection fraction increased from 35 +/- 6 to 40 +/- 9% (p < 0.001) in the presence of an increase in calculated end-systolic wall stress (185 +/- 57 to 227 +/- 54 gm/cm2, p < 0.01).. ACE inhibitor therapy was associated with improved LV function in the face of a decrease in mass to volume ratio of the LV as well as a decrease in wall thickness to volume ratio of noninfarcted myocardium. Whether ACE inhibitor therapy had direct or indirect effects on these changes in LV mass and function are open questions that require further investigation.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiac Volume; Electrocardiography; Female; Follow-Up Studies; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Myocardial Infarction; Ramipril; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

We tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitor therapy decreases left ventricular (LV) mass in patients with a left ventricular ejection fraction (LVEF) > 40% and no evidence of heart failure after their first acute Q wave myocardial infarction (MI).. Recently, ACE inhibitor therapy has been shown to have an early mortality benefit in unselected patients with acute MI, including patients without heart failure and a LVEF > 35%. However, the effects on LV mass and volume in this patient population have not been studied.. Thirty-five patients with a LVEF > 40% after their first acute Q wave MI were randomized to titrated oral ramipril (n = 20) or conventional therapy (control, n = 15). Magnetic resonance imaging (MRI) performed an average of 7 days and 3 months after MI provided LV volumes and mass from summated serial short-axis slices.. Left ventricular end-diastolic volume index did not change in ramipril-treated patients (62 +/- 16 [SD] to 66 +/- 17 ml/m2) or in control patients (62 +/- 16 to 68 +/- 17 ml/m2), and stroke volume index increased significantly in both groups. However, LV mass index decreased in ramipril-treated patients (82 +/- 18 to 73 +/- 19 g/m2, p = 0.0002) but not in the control patients (77 +/- 15 to 79 +/- 23 g/m2). Systolic arterial pressure did not change in either group at 3-month follow-up.. In patients with a LVEF > 40% after acute MI, ramipril decreased LV mass, and blood pressure and LV function were unchanged after 3 months of therapy. Whether the decrease in mass represents a sustained effect that is associated with a decrease in morbid events requires further investigation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Female; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Infarction; Ramipril; Stroke Volume; Ventricular Function, Left

Studies have shown that angiotensin converting enzyme (ACE) inhibition prevents left ventricular remodeling and cardiovascular events after an acute myocardial infarction. The role of aldosterone in ventricular remodeling after a myocardial infarction has not been addressed.. To compare the effects of an ACE inhibitor, an aldosterone receptor antagonist and placebo on left ventricular remodeling after a first episode of transmural acute myocardial infarction.. Patients hospitalized for a first episode of acute myocardial infarction were blindly and randomly assigned to receive ramipril (2.5 mg bid), spironolactone (25 mg tid) or placebo. Ejection fraction, left ventricular end diastolic and end systolic volumes were measured by multigated radionuclide angiography, at baseline and after six months of treatment.. Twenty four patients were assigned to placebo, 31 to ramipril and 23 to spironolactone. Age, gender, Killip class, treatment with thrombolytics, revascularization procedures and use of additional medications were similar in the three groups. After six months of treatment, ejection fraction increased from 34.5 +/- 2.3 to 40.2 +/- 2.4% in patients on ramipril, from 32.6 +/- 2.9 to 36.6 +/- 2.7% in patients on spironolactone, and decreased from 37 +/- 3 to 31 +/- 3% in patients on placebo (ANOVA between groups p < 0.05). Basal end systolic volume was similar in all three groups, increased from 43.4 +/- 3.4 to 61.4 +/- 6.0 ml/m2 in patients on placebo and did not change in patients on spironolactone or ramipril (ANOVA p < 0.05). End diastolic volume was also similar in the three groups, increased from 70.6 +/- 4.3 to 92.8 +/- 6.4 ml/m2 in patients on placebo and did not change with the other treatments.. Ramipril and spironolactone had similar effects on ventricular remodeling after acute myocardial infarction, suggesting that aldosterone contributes to this phenomenon and that inhibition of its receptor may be as effective as ACE inhibition in its prevention.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Disease-Free Survival; Double-Blind Method; Female; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Ramipril; Spironolactone; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

The interlead variation in QT length on a standard electrocardiograph reflects regional repolarization differences in the heart. To investigate the association between this interlead variation (QT dispersion) and left ventricular hypertrophy, we subjected 100 untreated subjects to 12-lead electrocardiography and echocardiography. Additionally, 24 previously untreated subjects underwent a 6-month treatment study with ramipril and felodipine. In the cross-sectional part of the study, QT dispersion corrected for heart rate (QTc dispersion) was significantly correlated with left ventricular mass index (r = .30, P < .01), systolic pressure (r = .30, P < .01), the ratio of peak flow velocity of the early filling wave to peak flow velocity of the atrial wave (E/A ratio) (r = -.22, P = .02), isovolumic relaxation time (r = .31, P < .01), and age (r = .21, P < .04). In the treatment part of the study, lead-adjusted QTc dispersion decreased from 24 to 19 milliseconds after treatment, and after a subsequent 2 weeks of drug washout remained at 19 milliseconds (P < .01). The changes in left ventricular mass index at these stages were 144, 121, and 124 g/m2 (P < .01). Systolic pressure decreased from 175 to 144 mm Hg and increased again to 164 mm Hg after drug washout (P < .01). The E/A ratio (0.97, 1.02, and 1.02; P = 69) and isovolumic relaxation time (111, 112, and 112; P = .97) remained unchanged through the three assessment points. In conclusion, QT dispersion is increased in association with an increased left ventricular mass index in hypertensive individuals. Antihypertensive therapy with ramipril and felodipine reduced both parameters. If an increased QT dispersion is a predictor of sudden death in this group of individuals, then the importance of its reduction is evident.

Topics: Adult; Antihypertensive Agents; Echocardiography; Electrocardiography; Felodipine; Female; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Ramipril

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

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

Most studies of the regression of left ventricular hypertrophy by antihypertensive treatment have methodological weaknesses and have not shown if regression of left ventricular hypertrophy can be obtained independently of blood pressure reduction. In the HYCAR study, after an inclusion phase of 4 to 6 weeks on furosemide (20 mg/day), 115 patients with left ventricular hypertrophy were randomised in a double blind manner to placebo group (N = 40), ramipril, 1.25 mg/day, (N = 38) or 5 mg/day (N = 37) for a period of 6 months. Furosemide was continued during the double blind treatment period. Echocardiography and ambulatory blood pressure monitoring were performed just before the randomisation and at 6 months. At the end of the study, there was no significant difference between the casual and ambulatory blood pressure changes. Expressed in g/m, the left ventricular mass index decreased significantly with respect to placebo in the ramipril 5 mg group (-12.2 +/- 3.9 versus +5.5 +/- 4.3 g/m2, p = 0.003) and in the 1.25 mg group (-7.5 +/- 4.6 g/m2, p = 0.04). The reduction in left ventricular mass index expressed in g/m2 was significant in the 5 mg ramipril (p = 0.008) but not in the 1.25 mg ramipril group (p = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Electrocardiography; Female; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Ramipril; Time Factors

The objective of this trial was to assess the effects of 6-month daily treatment with two doses of ramipril on left ventricular mass and the dependence of this on blood pressure changes in hypertensive patients with left ventricular hypertrophy. After a selection phase of 4 to 6 weeks with patients under antihypertensive therapy with 20 mg furosemide daily, 115 patients with either controlled or uncontrolled hypertension and left ventricular hypertrophy were randomized in a double-blind manner to receive either placebo (n = 40), 1.25 mg (low dose, n = 38), or 5 mg (regular dose, n = 37) ramipril daily for 6 months. Treatment with furosemide was continued unchanged during this phase. The main outcome measured was left ventricular hypertrophy regression as assessed from central blind reading of echocardiograms recorded at randomization and after 6 months. No significant differences were observed for changes in casual or ambulatory blood pressure between the three groups. Left ventricular mass index was found to be significantly reduced in patients receiving 5 mg ramipril compared with those receiving placebo (-10.8 +/- 3.7 versus +4.1 +/- 4.0 g/m2, P = .008); in patients receiving 1.25 mg ramipril, the difference was close to borderline significance compared with placebo (-7.0 +/- 4.3 g/m2, P = .06). Similar results were observed for changes in left ventricular mass (-20.3 +/- 6.6 and -13.0 +/- 7.8 g in the 5- and 1.25-mg ramipril groups, respectively, versus +9.1 +/- 7.2 g in the placebo group; P = .004 and .04, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Pressure; Double-Blind Method; Echocardiography; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Patient Compliance; Ramipril; Regression Analysis

Renin-angiotensin system blockade slows but does not prevent the cardiovascular complications of chronic kidney disease (CKD). Angiotensin-converting enzyme (ACE) 2 is differentially regulated in acute kidney injury, with increased cardiac ACE2 but decreased kidney ACE2 levels. This study investigated the effect of long-term ACE inhibition on cardiac and renal ACE2 in rats with CKD induced by subtotal nephrectomy (STNx). Sprague-Dawley rats had sham (control) or STNx surgery. Control rats received vehicle (n = 9) and STNx rats ramipril (1 mg kg(-1) day(-1); n = 10) or vehicle (n = 10) for 28 days. Subtotal nephrectomy resulted in impaired creatinine clearance (P < 0.05), proteinuria (P < 0.05), renal fibrosis (P < 0.05) and reduced renal cortical ACE2 mRNA (P < 0.05) and activity (P < 0.05). In rats with CKD, ramipril improved creatinine clearance (P < 0.05) and was associated with an increase in cortical but not medullary ACE2 activity (P < 0.05). Compared with control rats, STNx rats were hypertensive (P < 0.01), with increased left ventricular end-diastolic pressure (LVEDP; P < 0.01), left ventricular hypertrophy (LVH; P < 0.05) and interstitial (P < 0.05) and perivascular fibrosis (P < 0.01). In rats with CKD, ramipril decreased blood pressure (P < 0.001) and reduced LVEDP (P < 0.01), LVH (P < 0.01) and perivascular fibrosis (P < 0.05) but did not significantly reduce interstitial fibrosis. There was no change in cardiac ACE2 in rats with CKD compared with control rats. In rats with CKD, ACE inhibition had major benefits to reduce blood pressure and cardiac hypertrophy and to improve creatinine clearance, but did not significantly impact on cardiac ACE2, cardiac interstitial fibrosis, renal fibrosis or proteinuria. Thus, in rats with CKD, renal ACE2 deficiency and lack of activation of cardiac ACE2 may contribute to the progression of cardiac and renal tissue injury. As long-term ACE inhibition only partly ameliorated the adverse cardio-renal effects of CKD, adjunctive therapies that lead to further increases in ACE2 activity may be needed to combat the cardio-renal complications of CKD.

Topics: Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Gene Expression Regulation, Enzymologic; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Myocardium; Nephrectomy; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Sprague-Dawley; Treatment Outcome

This study aimed to determine the role of the renin-angiotensin system (RAS) in high-salt (HS) diet-induced left ventricular hypertrophy (LVH).. Swiss mice were subjected to regular salt (RS) diet (0.6% NaCl), HS diet (4% NaCl), and HS plus irbesartan (50 mg/kg/day) or ramipril (1 mg/kg/day). After 8 weeks, arterial pressure was similar in all groups and similar to baseline, whereas left ventricle/body weight ratio was higher in HS mice than in RS mice (P < 0.005). There were also significant increases in collagen density, angiotensin-converting enzyme activity, angiotensin II type 1 receptor (AT1 receptor) density, and extracellular signal-regulated kinase (ERK1/2) phosphorylation in the left ventricle. Interestingly, increases in wall thickness and ERK1 phosphorylation were more marked in the septum than in the rest of the left ventricle. Irbesartan or ramipril treatment prevented LVH and the increase in ERK phosphorylation and reduced collagen content and AT1 up-regulation but up-regulated AT2 receptors.. In normal mice, HS diet induces septum-predominant LVH and fibrosis through activation of the cardiac RAS-ERK pathway, which can be blocked by irbesartan or ramipril, indicating a key role of the cardiac RAS in HS diet-induced LVH.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Autoradiography; Biphenyl Compounds; Blotting, Western; Female; Fibrosis; Heart Ventricles; Hypertrophy, Left Ventricular; Immunohistochemistry; Irbesartan; JNK Mitogen-Activated Protein Kinases; Mice; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Ramipril; Renin; Renin-Angiotensin System; Sodium, Dietary; Tetrazoles; Ultrasonography

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

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

Left-ventricular hypertrophy (LVH) is a risk factor for cardiovascular morbidity. Antihypertensive treatment with angiotensin-converting enzyme inhibitors (ACEI) is able to induce the regression of LVH in adults. However, there has been no study of the ability of ACEI to induce the regression of LVH in children. Our aim was to investigate the effect of ramipril on left-ventricular mass and blood pressure (BP) in hypertensive children.. Twenty-one children (median age, 15 years) with renal (76%) or primary (24%) hypertension were prospectively treated with ramipril monotherapy for 6 months. Blood pressure was evaluated using ambulatory BP monitoring, with hypertension defined as mean BP >or=95th percentile. Left-ventricular hypertrophy was defined either as left-ventricular mass index (LVMI) >38.6 g/m(2.7) (pediatric definition) or as LVMI >51.0 g/m(2.7) (adult definition).. Nineteen children completed the study. The median LVMI decreased from 36.8 g/m(2.7) (range, 18.9 to 55.8 g/m(2.7)) to 32.6 g/m(2.7) (range, 19.0 to 52.1 g/m(2.7); P < .05) after 6 months. The prevalence of LVH decreased from 42% to 11% using the pediatric definition (P < .05) and did not change using the adult definition (ie, it remained at 5%). The median ambulatory BP decreased by 11, 7, 8, and 7 mm Hg for daytime systolic, daytime diastolic, nighttime systolic, and nighttime diastolic BP (P < .05), respectively. A positive correlation was found between LVMI and nighttime systolic BP at the start of the study (r = 0.46, P < .05).. Ramipril is an effective drug in children with hypertension, for its ability to reduce not only BP but also left-ventricular mass and induce regression of LVH.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Body Mass Index; Child; Child, Preschool; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney; Male; Ramipril; Ultrasonography

To check whether antihypertensive effects are additive or synergistic upon blockade of both angiotensin (AT1)-receptors and angiotensin-converting enzyme (ACE), spontaneously hypertensive rats (SHR) were treated with candesartan-cilexetil (0.1-30 mg/kg per day), ramipril (0.03-10 mg/kg per day), the calcium-antagonist mibefradil (1-150 mg/kg per day) or combinations thereof. Systolic blood pressure (SBP), left ventricular weight (LVW) and the cardiac activity/mRNA levels of ACE were determined.. SBP was decreased by candesartan-cilexetil [inhibitory concentration (IC50) (mg/kg): 2.47], ramipril (1.97), mibefradil (4.41), candesartan-cilexetil/ramipril (0.68), and candesartan-cilexetil/mibefradil (5.68). Combining candesartan-cilexetil with ramipril increased SBP reduction synergistically rather than additively, since the dose-response curve was shifted 6.6-fold leftwards compared to a hypothetically generated additive curve, calculated by summing up the doses and corresponding effects of the ramipril and candesartan-cilexetil monotreatment regimes. A total threshold dose < 5.14 mg/kg (derived from dose-response curves) was found to exert synergistic effects when candesartan-cilexetil was combined with ramipril. Antihypertensive effects of mibefradil can not be increased when combined with candesartan-cilexetil. When LVW was correlated with SBP reduction, regression lines of candesartan-cilexetil, ramipril and their combination were congruent, while that for mibefradil was significantly flatter and became steeper under candesartan-cilexetil co-administration. Cardiac ACE activity was greatly reduced by ramipril independently of SBP reduction and dosage. With SBP-ineffective doses of ramipril, cardiac ACE mRNA levels were doubled, indicating a positive feedback mechanism. The increase in ACE mRNA was renormalized when SPB-effective ramipril doses were applied, suggesting a blood pressure-dependent regulation of cardiac ACE expression.. Since synergy was observed only after combining low doses of ramipril and candesartan-cilexetil, prospective clinical trials should be performed on a low-dose combination, revealing the antihypertensive/antiproliferative benefits.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Drug Synergism; Drug Therapy, Combination; Hypertension; Hypertrophy, Left Ventricular; Male; Organ Size; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Inbred SHR; RNA, Messenger; Tetrazoles

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Ramipril; Risk Factors; Stroke Volume; Ventricular Dysfunction, Left

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

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

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

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

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

It is well established that angiotensin-converting enzyme (ACE) inhibitors (ACEI) reduce blood pressure (BP) and hypertrophy of the left ventricle and vessels. The aim of our study was to compare chemically different ACEIs regarding their ability to modulate left ventricular and media hypertrophy, ACE activity and plasma endothelin-1 concentrations in spontaneously hypertensive rats (SHRs).. After establishing equi-effective dose regimes, SHRs were treated (3 months) with captopril, enalapril, fosinopril or ramipril (2 x 25, 10, 20 or 1 mg/kg per day or corresponding 1% doses for studying blood pressure-independent effects).. Systolic blood pressure was reduced in SHRs receiving high doses of captopril, enalapril, fosinopril or ramipril (-61, -54, -35 and -47 mmHg), whereas low doses were ineffective. Left ventricular weight was decreased in animals treated with high doses (captopril/enalapril/fosinopril/ramipril: -17/-19/-17/-19%), but not low doses of agents. Media thickness of thoracal aorta was reduced by administering high doses (captopril/enalapril/fosinopril/ramipril: -31/-32/-27/-26%) and low doses (-16/-22/-22/-19%) of agents. ACE activity was reduced in heart, aorta and kidney of rats treated with high and low doses of all ACE inhibitors, whereby high doses showed more pronounced effects. Plasma endothelin-1 concentrations were not altered. A blood-pressure-ineffective treatment with an AT -antagonist revealed similar effects on cardiovascular hypertrophy.. ACEIs reduce cardiovascular hypertrophy uniformly via an AT -receptor- mediated mechanism, reinforcing the opinion that ACEI effects are indeed class effects. The significance of local renin-angiotensin systems was confirmed by antihypertrophic effects in the aorta that were apparent in the absence of any blood pressure reduction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Blood Pressure; Body Weight; Captopril; Circadian Rhythm; Dose-Response Relationship, Drug; Enalapril; Endothelin-1; Fosinopril; Hypertrophy, Left Ventricular; Male; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Inbred SHR

The circulation in the left and right coronary beds in pressure overload-induced left ventricular (LV) hypertrophy was studied in Wistar male rats (n=6/group) that were subjected to abdominal aortic constriction or to sham-operation. From 3 to 6 weeks after surgery, the animals with aortic constriction received vehicle or 0.01, 0.1, or 1 mg/kg per day po of the angiotensin converting enzyme (ACE) inhibitor, ramipril. At 6 weeks, after measuring blood pressure in the carotid artery in vivo, the hearts were isolated and the left and right coronary beds subjected to independent perfusion. Minimum coronary vascular resistance per unit heart weight (MCVR/g) was determined in both beds during simultaneous infusion of 10 micromol/L adenosine. Aortic constriction resulted in a significant increase in blood pressure, LV weight/body weight ratio, and bilateral MCVR/g. Ramipril lowered arterial pressure in a dose-dependent manner and reversed the increased right MCVR/g at the anti-hypertensive dose, but it did not affect LV mass or left MCVR/g. These results suggest that both coronary hypertension and myocardial hypertrophy contribute to the global impairment of coronary circulation in LV hypertrophy. ACE inhibitors may improve coronary circulation in LV hypertrophy when administrated at an appropriate dose and for a sufficient period.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Coronary Circulation; Dose-Response Relationship, Drug; Hypertrophy, Left Ventricular; Male; Myocardium; Organ Size; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Wistar; Vascular Resistance

Topics: Angiotensin-Converting Enzyme Inhibitors; Heart Failure; Humans; Hypertrophy, Left Ventricular; Myocardial Infarction; Ramipril; Stroke

Activation of cytokines such as interleukin-6 (IL-6) has been implicated in the pathogenesis of left ventricular dysfunction and hypertrophy since they have been shown to mediate cell proliferation, negative inotropic effects and myocardial hypertrophy. However, the effects of immunosuppressive therapy on cytokines in the treatment of heart failure and hypertrophy are unclear.. To test the hypothesis that systemic immunosuppresion may influence serum and myocardial IL-6 and, thereby, may affect progression of myocardial hypertrophy. We studied the effects of chronic treatment with methotrexate (MTx) and with the ACE inhibitor ramipril on IL-6 in rats with pressure overload left ventricular hypertrophy (LVH) due to aortic banding.. Animals were treated with either vehicle (n = 6) or methotrexate (MTx 1: 0.3 mg/kg BW/week; MTx 2: 0.9 mg/kg BW/week; i.p.; n = 6 each group) once a week during weeks 4-12 after aortic banding; sham-operated rats served as controls (CTRL; n = 8). During the development of LVH, serum IL-6 was determined by rat-specific ELISA and 12 weeks after aortic banding myocardial IL-6 was measured using a tissue superfusion technique or determining of protein concentration.. Aortic banding significantly lowered blood pressure, increased left ventricular weight and resulted in elevated serum IL-6 levels (27.6 +/- 5.1 vs 19.1 +/- 2.3 pg/ml, p < 0.05) compared to CTRL. MTx treatment normalised the initially elevated serum IL-6 levels after 8 weeks of treatment. The significant increase in IL-6 concentration in the superfusate of all aortic banding groups compared to CTRL (< 30%, p < 0.05) was not altered by prior MTx therapy. Accordingly, both doses of MTx failed to prevent LVH progression (1.67 +/- 0.23 g vs. 2.32 +/- 0.31 g, p < 0.05). In contrast, chronic inhibition of the RAAS not only prevents LVH but also reduces myocardial IL-6 concentration (6898 +/- 355 vs. 3073 +/- 366 pg/mg protein, p < 0.05).. Pressure overload LVH in rats is characterized by an increase in serum levels of IL-6 as well as myocardial IL-6. Chronic immunosuppressive therapy normalized systemic IL-6 levels, but failed to reduce cardiac IL-6 expression and the progression of LVH, while ACE inhibition is sufficient to modify LVH and thereby normalises myocardial IL-6 expression.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Hemodynamics; Hypertrophy, Left Ventricular; Immunosuppression Therapy; Immunosuppressive Agents; Interleukin-6; Male; Methotrexate; Ramipril; Rats; Rats, Wistar

Topics: Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Electrocardiography; Humans; Hypertrophy, Left Ventricular; Ramipril; Risk

We previously reported that inhibition of angiotensin-converting enzyme (ACE) prevented the hypertension and left ventricular hypertrophy induced by deoxycorticosterone acetate-salt (DOCA-salt) in 129/SvEvTac mice, which have 2 renin genes (Ren-1 and Ren-2). In the present study, we induced hypertension by uninephrectomy and DOCA-salt in mice having only the Ren-1 gene (C57BL/6J) and investigated the effect of an ACE inhibitor (ramipril, 4 mg. kg(-)(1). d(-)(1)) and an angiotensin type 1 (AT(1)) receptor antagonist (L-158809, 4 mg. kg(-)(1). d(-)(1)) on the development of hypertension, cardiac hypertrophy, and renal injury. After 4 weeks of treatment, systolic blood pressure in DOCA-salt mice was significantly increased (128+/-2 mm Hg) compared with controls (109+/-2 mm Hg) (P:<0.001), while plasma renin concentration was decreased by 97% (P:<0.001). DOCA-salt also induced left ventricular and renal hypertrophy and renal damage as manifested by proteinuria. Collagen content in the left ventricle and kidney was significantly higher in DOCA-salt mice (P:<0.001). Urinary albumin (P:<0.05) and proliferating cell nucleic antigen-positive cells in the tubules and interstitium of the renal cortex (P:<0.001) were significantly increased in the DOCA-salt group. Neither the ACE inhibitor nor the AT(1) antagonist had any antihypertensive effect; however, they partially prevented cardiac hypertrophy and completely inhibited left ventricular collagen deposition. In the kidney, both the ACE inhibitor and AT(1) antagonist partially reduced the increase in collagen but had no effect on hypertrophy. They also significantly prevented the effect of DOCA-salt on urinary albumin and proliferating cell nucleic antigen expression in the kidney. Despite the lack of an antihypertensive effect, both ACE inhibitor and AT(1) antagonist prevented cardiac remodeling and renal damage. Our results indicate that ACE inhibitors and AT(1) antagonists exert beneficial effects on the heart and kidney in DOCA-salt hypertensive mice independently of their effects on blood pressure.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Collagen; Desoxycorticosterone; Hypertension; Hypertrophy, Left Ventricular; Imidazoles; Immunohistochemistry; Kidney Cortex; Kidney Tubules; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephrectomy; Organ Size; Proliferating Cell Nuclear Antigen; Ramipril; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Sodium Chloride; Tetrazoles

It is admitted that low dose of angiotensin converting enzyme (ACE) inhibitors allows the regression of left ventricular hypertrophy (HVG) in experimental models where plasma renin activity (PRA) is high. The use of low dose of ramipril, an ACE inhibitor, make it possible to explore the place of cardiac renin-angiotensin system (RAS) in the regression of HVG independently of blood pressure (BP). Twenty rats TGR (mRen2) 27, heterozygous male, 10 weeks old were treated by daily oral gavage during 6 weeks by 10 micrograms/kg/jour ramipril or distilled water and compared to 10 normotensive Sprague Dawley (SD) rats. BP was measured. After the period of treatment, plasma, left kidney and the ventricles were removed. On each tissue samples and plasma, angiotensinogen (Aogen), the renin activity, angiotensins I (Ang I) and II (Ang II) were determined by radioimmuno assay and the activity of ACE was measured by fluorimetry. BP does not differ between treated and untreated groups during 6 weeks of treatment but is significantly higher compared to SD rats. PRA of untreated rats is high (36 +/- 5 ng Ang I/mL/h). However, treatment did not make it possible to decrease HVG. In plasma and kidney treatment's effect on SRA is confirmed by the increase in renin activity (plasma: 63 +/- 9 vs 36 +/- 5 ng Ang I/mL/h; kidney: 127 +/- 11 vs 92 +/- 7 micrograms Ang I/g/h) which is accompanied by an increase of Ang I rates (plasma: 297 +/- 31 vs 15 +/- 10 fmol/mL; kidney: 241 +/- 37 vs 160 +/- 12 fmol/g) and of the reduction in Aogen. An inhibition of ACE is perceptible with low dose of ramipril in heart (left ventricle: 1.7 +/- 0.1 vs 2.5 +/- 0.3 nmol HisLeu/min/mg protein), but it does not appear significant modifications of the other elements of the RAS in this tissue. The Ang II cardiac rates are probably not solely defined by cardiac ACE activity, other ways of synthesis being described. The absence of regression of the HVG in TGR (mRen2) 27 rat with low dose of ramipril could be related to the absence of effect on cardiac Ang II rates. In addition, the relation between high PRA rates and the effectiveness of low dose of ACE inhibitor in the HVG are not confirmed.

Topics: Animals; Antihypertensive Agents; Dose-Response Relationship, Drug; Hypertrophy, Left Ventricular; Ramipril; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

Elevated systemic arterial blood pressure is associated with left ventricular hypertrophy and fibrosis. It has been suggested that both circulating and local myocardial renin-angiotensin systems play a role in mediating these responses. Here we describe the natural history of ventricular hypertrophy and fibrosis in the transgenic (mRen2)27 rat--a monogenetic model--which has a high tissue expression of the murine renin transgene, and suffers severe hypertension. We further explored the relative contribution of both hypertensive burden and circulating and tissue renin-angiotensin systems to the fibrotic process.. The transgenic rats were treated from 28 days old with (1) a hypotensive dose of the ACE inhibitor ramipril which inhibited both tissue and circulating ACE activity, (2) the calcium antagonist amlodipine, or (3) a non-hypotensive dose of ramipril which inhibited about 60% of tissue ACE activity with little effect on circulating ACE. Normotensive Sprague-Dawley rats were used as controls.. The transgenics developed left ventricular hypertrophy along with perivascular and interstitial fibrosis which became progressively worse up to 24 weeks of age. Both the high dose of ramipril and amlodipine prevented the hypertrophy and fibrosis, whereas tissue ACE inhibition without lowering blood pressure had no effect, and actually led to a worsening of the fibrosis by 24 weeks.. These results suggest that the development of left ventricular hypertrophy and fibrosis in the transgenic (mRen2)27 rat are regulated by blood pressure and not activity of the renin-angiotensin systems and that progression of fibrosis at 24 weeks involves a mechanism unrelated to local renin-angiotensin activity.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Antihypertensive Agents; Collagen; Fibrosis; Hypertension; Hypertrophy, Left Ventricular; Male; Mice; Myocardium; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Time Factors

Despite normal indices of left ventricular (LV) chamber function, patients with LV hypertrophy (LVH) due to hypertension are thought to have depressed midwall systolic shortening compared with normotensives. The aims of the present study were (1) to confirm this observation and (2) to assess the effects of antihypertensive therapy that cause regression of LVH on LV systolic function assessed at both the midwall and endocardium. Thirty-eight previously untreated hypertensive subjects with LVH underwent echocardiography and were compared with 38 normotensive control subjects. Comparisons between the group with LVH and the control group revealed no significant differences in cardiac output (4. 32+/-0.23 versus 4.55+/-0.21 L/min), ejection fraction (62.5+/-2% versus 66.4+/-1.07%), or endocardial fractional shortening (34.5+/-1.45% versus 37.0+/-0.82%), but shortening assessed at the midwall was significantly less in the group with LVH (17.9+/-1.11% versus 21.6+/-0.63%, P<0.01). Subsequently, 32 patients with uncontrolled hypertension (24 previously untreated and 8 on existing antihypertensive therapy) underwent treatment with ramipril, with the addition of felodipine and bendrofluazide if required, to reduce blood pressure to <140/90 mm Hg. These 32 patients underwent echocardiography at baseline, after blood pressure control, and after an additional 6 months of tight blood pressure control. Good blood pressure control was achieved after 6 months compared with baseline (143/86+/-2.8/1.4 versus 174/103+/-4.1/1.9 mm Hg; P<0.01) with significant regression of LV mass index (124+/-3.4 versus 145+/-3.8 g/m(2), P<0.01). LV fractional shortening assessed at the midwall improved with regression of LVH (21.9+/-0.84 and 18.7+/-1. 19%, P<0.05), with posttreatment midwall shortening being similar to that of the normal control subjects evaluated in the first study. Hypertensive patients with LVH have depressed midwall systolic shortening despite normal indices of LV chamber function. Regression of LVH after good blood pressure control improved midwall shortening to normal levels.

Topics: Adult; Antihypertensive Agents; Bendroflumethiazide; Blood Pressure; Cardiac Output; Echocardiography; Endocardium; Felodipine; Female; Heart; Heart Septum; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Myocardial Contraction; Ramipril; Ventricular Function, Left

We tested the hypothesis that activation of protein kinase C (PKC) isoforms in pressure-overload heart failure was prevented by angiotensin-converting enzyme (ACE) inhibition, resulting in normalization of cardiac sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA) 2a and phospholamban protein levels and improvement in intracellular Ca2+ handling. Aortic-banded and control guinea pigs were given ramipril (5 mg. kg-1. day-1) or placebo for 8 wk. Ramipril-treated banded animals had lower left ventricular (LV) and lung weight, improved survival, increased isovolumic LV mechanics, and improved cardiomyocyte Ca2+ transients compared with placebo-treated banded animals. This was associated with maintenance of SERCA2a and phospholamban protein expression. Translocation of PKC-alpha and -epsilon was increased in placebo-treated banded guinea pigs compared with controls and was attenuated significantly by treatment with ramipril. We conclude that ACE inhibition attenuates PKC translocation and prevents downregulation of Ca2+ cycling protein expression in pressure-overload hypertrophy. This represents a mechanism for the beneficial effects of this therapy on LV function and survival in heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Body Fluids; Calcium; Calcium-Binding Proteins; Calcium-Transporting ATPases; Guinea Pigs; Heart; Heart Failure; Hypertrophy, Left Ventricular; Lung; Male; Muscle Proteins; Myocardium; Protein Kinase C; Ramipril; Sarcoplasmic Reticulum; Survival Analysis

We studied the interaction of the central renin-angiotensin system (RAS) and vasopressin system in rats with left ventricular hypertrophy (LVH) due to aortic banding. In these animals plasma vasopressin is elevated and vasopressin content is increased in specific brain areas. Chronic blockade of the RAS by angiotensin-converting enzyme (ACE) inhibition (ramipril) and AT1 receptor antagonism (losartan) significantly attenuated circulating and central vasopressin in rats with LVH. Given the antidiuretic, vasoconstrictive, and growth-promoting effects, vasopressin may participate in the cardiovascular alterations in LVH. Blockade of the RAS strongly ameliorates central and peripheral-vasopressin. Therefore, central modulatory effects on vasopressin might contribute to the therapeutic efficacy of ACE inhibitors and AT1 antagonists.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Brain Chemistry; Hypertrophy, Left Ventricular; Losartan; Ramipril; Rats; Rats, Wistar; Renin-Angiotensin System; Vasopressins

In renovascular hypertensive rats, low doses of angiotensin converting enzyme (ACE) inhibitors have been found to prevent myocardial hypertrophy independent of blood pressure level. This finding would suggest humoral rather than mechanical control of myocyte growth. The aim of this study was to examine the effect of nonantihypertensive doses of ACE inhibitor on myocardial hypertrophy and necrosis in hypertensive rats. Renovascular hypertension (RHT) was induced in four-week-old Wistar rats. Twenty-eight animals were treated for four weeks with three doses of ramipril (0.01, 0.1 or 1. 0 mg/kg/day, which are unable to lower blood pressure. Fourteen animals were not treated (RHT group). A sham operated, age/sex-matched group was used as control (n = 10). Myocardial histology was analysed in 3 microm thick sections of the ventricle stained with either haematoxylin-eosin, reticulin silver stain or Masson's trichrome. There was a significant correlation between systolic blood pressure and left ventricular to body weight ratio in both sets of animals: untreated plus controls and ramipril-treated rats. ACE inhibition prevented myocyte and perivascular necrosis and fibrosis in a dose-dependent manner. We conclude that myocardial hypertrophy in rats with renovascular hypertension is directly related to arterial pressure, and that this relationship is not affected by nonantihypertensive doses of ACE inhibitor. Myocardial necrosis/fibrosis and coronary artery damage induced by angiotensin II are prevented by ACE inhibitor in a dose-dependent manner, despite the presence of arterial hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiomegaly; Dose-Response Relationship, Drug; Hypertension, Renovascular; Hypertrophy, Left Ventricular; Male; Necrosis; Organ Size; Ramipril; Rats; Rats, Wistar

1 In spontaneously hypertensive rat (SHR) we examined over a 4-week period the influence of control low sodium diet, common salt-enriched diet (sodium chloride 6% of the dry weight of the chow) and a novel mineral salt-enriched diet (potassium-, magnesium-, and l-lysine-enriched mineral salt added at a 75% higher level of 10.5% to produce the same sodium chloride concentration of 6%) on the cardiovascular effects produced by a low-dose combination of an angiotensin converting enzyme inhibitor ramipril (0.25 mg kg(-1) day(-1) in the food) and a calcium channel blocker felodipine (0.4 mg kg(-1) day(-1) subcutaneously via an osmotic minipump). 2 Common salt, but not the mineral salt, accelerated the development of hypertension and induced left ventricular and renal hypertrophy in SHR. Neither common salt nor mineral salt significantly affected heart rate. 3 The combination of ramipril and felodipine decreased systolic blood pressure and prevented the development of left ventricular hypertrophy effectively during the common salt diet without any significant effect on the heart rate. The cardiovascular effects of the drug combination were improved by the low sodium diet or by replacement of high common salt in the diet by mineral salt. 4 Responses of endothelium-intact mesenteric arterial rings in vitro were examined at the end of the four-week study. The combination of ramipril and felodipine markedly improved the endothelium-dependent vascular relaxation responses to acetylcholine and enhanced the endothelium-independent vascular relaxation responses to sodium nitroprusside in SHR on control and common salt diets. Replacement of common salt in the diet by mineral salt improved the endothelium-dependent vascular relaxation responses to acetylcholine. The drug combination attenuated the alpha-adrenoceptor-mediated vascular contractile responses to noradrenaline during the common salt diet. 5 Ramipril and felodipine in combination increased plasma renin activity by 1.9-3.2 fold without affecting serum aldosterone levels. 6 Our findings suggest that the cardiovascular effect of the low-dose combination of ramipril and felodipine was maintained during high salt intake. However, salt restriction or replacement of common salt in the diet by the potassium- and magnesium-enriched mineral salt improved the cardiovascular effects of the drug combination. In the face of a high intake of sodium, a part of the beneficial cardiovascular effects of the drug combination is a

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Cardiovascular System; Drug Interactions; Felodipine; Heart Rate; Hypertension; Hypertrophy; Hypertrophy, Left Ventricular; Insulin; Kidney; Lysine; Magnesium Chloride; Male; Mesenteric Arteries; Muscle Relaxation; Potassium Chloride; Ramipril; Rats; Rats, Inbred SHR; Sodium, Dietary

We examined the effects of icatibant, a specific bradykinin B2-receptor antagonist, on the regression of left ventricular mass (LVM) induced by angiotensin converting enzyme (ACE) inhibitors, ramipril and imidapril, in spontaneously hypertensive rats. Both ramipril and imidapril lowered blood pressure equally, which were not influenced by icatibant. Icatibant did not alter the regressive effect of imidapril, while it showed a tendency to increase LVM in the ramipril-treated rats. The changes of LVM induced by icatibant were significantly different between the ramipril- and the imidapril-treated rats, suggesting that the role of bradykinin in the antihypertrophic effect might differ among ACE inhibitors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Hypertrophy, Left Ventricular; Imidazoles; Imidazolidines; Ramipril; Rats; Rats, Inbred SHR

Left ventricular hypertrophy (LVH) is characterized by remodeling of both myocyte and interstitial compartments of the heart. The aim of this investigation was to study the effects of angiotensin converting enzyme (ACE) inhibition on alterations in the composition of the interstitium in chronic pressure-overload hypertrophy.. LVH was induced in weanling rats by banding the ascending aorta. Animals with aortic banding received either vehicle (n = 20), hydralazine (20 mg/kg per day, n = 20), or the ACE inhibitor ramipril (10 mg/kg per day, n = 20) during weeks 6-12 after banding.. Compared with sham-operated, untreated rats (n = 20), aortic-banded vehicle and hydralazine-treated rats displayed substantially increased left ventricular weights and myocyte diameters whereas ramipril significantly blunted the hypertrophic response at the myocyte level (each P < 0.001) as well as the increase in left ventricular weight (each P < 0.01). In addition, image analysis revealed a significant induction of perivascular and interstitial tissue accumulation in vehicle- and hydralazine-treated rats (2.5-fold, each P < 0.0001). In contrast, ramipril-treated rats displayed attenuated interstitial and perivascular fibrosis, both being significantly diminished compared with vehicle- and hydralazine-treated rats (each P< 0.001). Further, vehicle- and hydralazine-treated rats were characterized by elevated steady-state messenger (m)RNA levels of fibronectin (2.7- and 2.8-fold, P< 0.005), collagen I (2.0- and 1.8-fold, P < 0.0005), collagen III (both 2.2-fold, P < 0.001) and laminin B (1.6- and 1.6-fold, P < 0.005). In parallel, the corresponding immunohistochemical signals were markedly enhanced in these groups. In comparison, ramipril significantly blunted the induction of collagen I and III, laminin B and fibronectin at both the mRNA and protein levels. These morphological and molecular differences between the hydralazine and ramipril groups could not be attributed to differences in left ventricular-pressures, which were markedly elevated in all aortic stenosis rats (1.9-fold, each P < 0.001 versus sham). In fact, given that ramipril but not hydralazine blunted the hypertrophic response to pressure overload, the echocardiographic measurements revealed that left ventricular systolic wall stress was higher in the ramipril group (70 +/- 1 versus 34 +/- 0.7 kdyn/cm2; P < 0.02).. ACE inhibition may limit both myocyte and interstitial remodeling despite ongoing cardiac pressure overload.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Extracellular Matrix Proteins; Fibronectins; Gene Expression; Hydralazine; Hypertension; Hypertrophy, Left Ventricular; Laminin; Male; Procollagen; Ramipril; Rats; Rats, Wistar; RNA, Messenger; Transforming Growth Factor beta

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

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

The aim of this study was to investigate the possible link between the regression of the left ventricular mass induced by ACE-inhibition and L-type calcium channels. For this purpose, an evaluation of both L-type calcium channels and AT1 receptor patterns in the left ventricular tissue of adult spontaneously hypertensive rats (SHR) was made before and after long-term treatment with ramipril. An abnormal density of both dihydropyridine and AT1 receptors was observed in SHR at 24 weeks, compared to age-matched control Wistar-Kyoto (WKY) rats (dihydropyridine receptor Bmax: 1. 30+/-0.09 vs 1.14+/-0.06 pmol mg-1 proteins, P<0.001; AT1 receptor Bmax: 1.35+/-0.07 vs 2.62+/-0.08, P<0.001 pmol mg-1 proteins). A treatment for 10 weeks with ramipril induced a significant decrease in the left ventricular mass index of SHR, as well as a significant decrease in dihydropyridine receptor density (Bmax: 0.96+/-0.01 vs 1. 39+/-0.08 pmol mg-1 proteins, P<0.001) and a significant increase in AT1 receptor density (Bmax: 3.08+/-0.26 vs 2.78+/-0.09 pmol mg-1 proteins, ramipril-treated SHR vs vehicle-treated SHR, P<0.001). These results suggest that the decrease in left ventricular mass after treatment with ramipril may be dependent on changes in L-type calcium channels other than the direct effect on circulating and tissue angiotensin II (ang II) levels: involvement of calcium channels and subsequent calcium influx into cardiac cells could be proposed as an additional mechanism for the regression of left ventricular mass after ACE-inhibition.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Calcium Channels; Calcium Channels, L-Type; Heart Ventricles; Hypertension; Hypertrophy, Left Ventricular; Male; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Species Specificity; Systole; Ventricular Function, Left

Hypertensive patients with left ventricular hypertrophy (LVH) have been found to have greater peri-infarction and postinfarction mortality. In this study, we evaluated the postinfarction survival, susceptibility to ventricular arrhythmias, and degree of LVH and cardiac fibrosis in the spontaneously hypertensive rat (SHR) and the effects of the ACE inhibitor ramipril and the direct vasodilator hydralazine on these characteristics.. An acute myocardial infarction (MI) was produced by ligation of the left anterior descending coronary artery. Rats were randomized to either control (n=50), hydralazine (n=41), or ramipril (n=45). Treatments were started 4 hours after infarction and continued for 8 weeks. Ramipril and hydralazine reduced arterial pressure similarly. Medications were stopped 72 hours before euthanasia, at which time hemodynamic, programmed electrophysiological stimulation (PES), and morphological studies were performed. Mortality was decreased in ramipril (56%) compared with hydralazine (78%) and control (82%) SHRs (P=0.008). This was accompanied by a decrease in myocardial hypertrophy and fibrosis and a decrease in inducibility of ventricular arrhythmias by PES in the ramipril group regardless of MI size. Treatment with hydralazine had little or no effect on LVH and cardiac fibrosis and did not modify inducibility of ventricular arrhythmias by PES. Ramipril but not hydralazine prevented the increase in LV end-diastolic pressure in rats with large MIs.. In the SHR, the ACE inhibitor ramipril reduces LVH, cardiac fibrosis, and susceptibility to ventricular arrhythmias by PES and improves survival and LV function. Despite a similar decrease in arterial pressure, hydralazine does not have these beneficial effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arrhythmias, Cardiac; Blood Pressure; Cardiac Pacing, Artificial; Fibrosis; Heart Rate; Hemodynamics; Hydralazine; Hypertrophy, Left Ventricular; Male; Myocardial Infarction; Myocardium; Ramipril; Rats; Rats, Inbred SHR; Survival Analysis; Vasodilator Agents

We investigated the mechanism of action of the ACE inhibitor-induced increase in cardiac capillary length density. Stroke-prone spontaneously hypertensive rats were treated prenatally and up to the age of 20 weeks with the ACE inhibitor ramipril (0.01 and 1 mg/kg per day PO) and the AT1 receptor antagonist losartan (30 mg/kg per day PO). The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment with the bradykinin B2-receptor antagonist Icatibant (0.5 mg/kg per day, SC via osmotic minipumps) from 6 to 20 weeks of age. At the end of the treatment period, cardiac capillary length density was measured stereologically using the orientator method. The development of hypertension and left ventricular hypertrophy was prevented by high- but not low-dose ramipril and was not affected by chronic bradykinin B2-receptor blockade. Low- and high-dose ramipril significantly increased cardiac capillary length density (3577 +/- 279, n = 11 and 3988 +/- 300 mm/mm3; n = 10; P < .05) compared with vehicle-treated animals (2935 +/- 137 mm/mm3; n = 13). These effects were abolished by chronic bradykinin B2-receptor blockade. The bradykinin antagonist alone was without effect on cardiac capillary length density. Losartan prevented hypertension and left ventricular hypertrophy but did not significantly alter cardiac capillary length density (3429 +/- 309 mm/mm3; n = 7). Our results demonstrate that chronic ACE inhibitor treatment can increase cardiac capillary length density in stroke-prone spontaneously hypertensive rats independently of a reduction in blood pressure or left ventricular hypertrophy. This effect is related to the ACE inhibitor-induced potentiation of endogenous bradykinin since it was prevented by chronic bradykinin B2-receptor blockade and was not observed following antihypertensive treatment with the AT1-receptor antagonist losartan.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Bradykinin; Bradykinin Receptor Antagonists; Capillaries; Coronary Vessels; Hypertension; Hypertrophy, Left Ventricular; Imidazoles; Losartan; Male; Neovascularization, Pathologic; Ramipril; Rats; Rats, Inbred SHR; Receptor, Bradykinin B2; Tetrazoles

1. Cardiovascular effects of submaximal antihypertensive doses of the angiotensin converting enzyme inhibitor, ramipril (0.25 mg kg-1 day-1 in the food), and the calcium channel blocker, felodipine (0.4 mg kg-1 day-1 subcutaneously by osmotic minipump), both alone and in combination, were examined in spontaneously hypertensive rats (SHR) in a four-week study. 2. Both ramipril and felodipine as monotherapy decreased systolic blood pressure. The antihypertensive effect of the drug combination was more than that of ramipril treatment alone, but not significantly better than that of felodipine monotherapy. Ramipril or felodipine treatments did not significantly affect the heart rate, either alone or in combination. 3. The beneficial effect of ramipril monotherapy on left ventricular hypertrophy was more prominent than that of felodipine. The cardioprotective effect of felodipine was improved when combined to ramipril. The systolic blood pressure at the end of the experimental period correlated only weakly with left ventricular hypertrophy. 4. Responses of mesenteric arterial rings in vitro were examined at the end of the four-week study. Ramipril and felodipine monotherapies as well as their combination markedly improved the endothelium-dependent vascular relaxation responses to acetylcholine. The combination of ramipril and felodipine slightly enhanced the endothelium-independent vascular relaxation responses to sodium nitroprusside. Ramipril treatment alone slightly diminished the vascular contractile responses to noradrenaline. Neither ramipril nor felodipine alone or in combination affected the vascular contractile responses to potassium chloride. 5. Ramipril treatment, both alone and in combination with felodipine, caused a three fold increase in plasma renin activity. Serum aldosterone, fasting blood glucose level, serum insulin and the 24 hour urinary excretions of sodium, potassium, magnesium, calcium, phosphorus or protein were not significantly affected by the drug treatments. 6. Our findings suggest that a better overall control of hypertension and end-organ damages, without an increase in adverse effects, can be achieved by the combination of submaximal antihypertensive doses of felodipine and ramipril than by monotherapy with either drug alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Calcium Channel Blockers; Drug Therapy, Combination; Felodipine; Heart Rate; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; In Vitro Techniques; Male; Mesenteric Arteries; Ramipril; Rats; Rats, Inbred SHR

To evaluate factors of action of ramipril, an inhibitor of angiotensin-converting enzyme, which may induce a decrease in left ventricular hypertrophy (LVH), 45 LVH patients aged 21-53 years with mild and moderate essential hypertension have underwent echo-CG determination of left ventricular mass and 24-h monitoring of arterial pressure (AP). Multiple regression was used to examine prognostic significance of such parameters as age, sex, height, weight, duration of the disease, mean 24-h AP, its variability and the degree of nocturnal fall. It was found that ramipril reduced LVH irrespective of the hypotensive effect.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Drug Evaluation; Echocardiography; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Ramipril; Time Factors

Systemic and regional (including coronary) hemodynamics were studied in spontaneously hypertensive and normotensive Wistar Kyoto rats after 3 weeks of treatment with one of the three doses of the angiotensin converting enzyme inhibitor, ramipril. The effects of respective treatments on cardiovascular mass and systemic, coronary, and regional hemodynamics (at rest, during maximal treadmill exercise, and during dipyridamole infusion) then were evaluated in conscious rats using radiomicrosphere techniques. Low-dose ramipril (10 micrograms/kg/day by gavage) neither decreased arterial pressure nor reduced cardiac mass. However, medium (100 micrograms/kg/day) and high (1 mg/kg/day) doses reduced total cardiac and left ventricular masses to the same extent in spontaneously hypertensive rats, despite a much greater fall in arterial pressure with a high dose. Resting cardiac index, and myocardial and all other organ blood flows remained unchanged in both strains. When compared with Wistar Kyoto rats, coronary circulation was impaired in untreated spontaneously hypertensive rats (ie, reduced coronary flow and flow reserve and increased minimal coronary vascular resistance during dipyridamole infusion). This remained unchanged by ramipril. Furthermore, significant (and comparable) increases in cardiac index and myocardial blood flow and decreases in coronary vascular resistance were produced by maximal treadmill exercise in both strains. This also was unaffected by ramipril. These data showed that angiotensin converting enzyme inhibition with suboptimal and optimal hypotensive doses of ramipril reversed left ventricular hypertrophy in spontaneously hypertensive rats, but coronary flow, flow reserve, and minimal coronary vascular resistance remained unchanged despite left ventricular hypertrophy reversal.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Coronary Circulation; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Male; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vascular Resistance

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

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

Recent studies have shown that increased intake of dietary sodium chloride produces blood pressure-independent increase in cardiac and renal mass even in young normotensive rats. With advancing age the harmful cardiovascular effects of increased dietary sodium are not so well known. In the present study the influence of advancing age on the cardiovascular effects of increased intake of sodium (control diet, 0.3% and high-sodium diet, 2.6% sodium in the chow) were examined in young and aged (3 and 18 months old, respectively, at the beginning of the experiment) male normotensive Wistar rats in a six-week study. Moreover, the potential role of renin-angiotensin system in ageing during normal and a high-sodium intake was studied using a pharmacological tool, angiotensin converting enzyme (ACE) inhibitor ramipril. Ageing did not significantly modify basal systolic blood pressure measured by the tail cuff method. A high intake of sodium chloride increased blood pressure significantly only in aged rats, while in young rats it increased renal weight. Left ventricular weight was not affected by high-sodium diet in either age group. The ACE inhibition during control diet lowered blood pressure and decreased left ventricular weight in young rats only and these effects were completely blocked by a high-sodium diet. The maximal vascular contraction force of mesenteric arterial rings to noradrenaline was decreased with ageing while endothelium-dependent and -independent relaxation responses were unaltered with ageing. The sensitivity to sodium nitroprusside was impaired by the high-sodium diet in young rats. In both age groups the urinary excretion of calcium was increased during the high-sodium diet. In conclusion, the increased intake of sodium produced different changes in cardiovascular function in normotensive rats depending on age. With advancing age, the sensitivity to sodium-induced increase in blood pressure was increased. In aged rats a high intake of dietary sodium elevated blood pressure, while in young rats it increased renal mass without increase in blood pressure. In both age groups sodium did not affect left ventricular hypertrophy. Both high-sodium intake and ageing attenuated or even abolished the cardiovascular effects of ACF inhibition.

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Hemodynamics; Hypertrophy, Left Ventricular; In Vitro Techniques; Kidney; Male; Mesenteric Arteries; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Norepinephrine; Organ Size; Ramipril; Rats; Rats, Wistar; Sodium, Dietary

Hypertrophied and failing myocardium has been shown to undergo creatine kinase (CK) isoform switching, resulting in increased MB and BB components. We tested the hypothesis that chronic volume overload hypertrophy due to mitral regurgitation in the dog causes CK isoenzyme switching and that this could be reversed by angiotensin converting enzyme inhibitor therapy. Thirteen adult mongrel dogs had mitral regurgitation induced by mitral valvular chordal rupture: six were treated with ramipril for 4 months and seven were untreated for 4 months. Twelve dogs were sham-operated: six received ramipril for 3 months and six were untreated. Left ventricular end-diastolic volume increased from 58+/-4 to 104+/-10 ml in untreated (P<0.001) and from 55+/-3 to 91+/-6 ml in treated dogs (P<0.01) as LV mass/volume ratio decreased in both untreated (1. 60+/-0.07 to 1.13+/-0.08 g/ml, P<0.001) and treated dogs (1.44+/-0.06 to 1.20+/-0.08 g/ml, P<0.01). CK-MB isoform was 7.4+/-1.1% in normal shams and increased to 13.5+/-1.9% and 18.1+/-3.0% in both treated and untreated mitral regurgitation dogs; respectively (P<0. 05). Steady state CK-B mRNA increased three-fold in treated and untreated dogs with mitral regurgitation (P<0.003) compared to normals, while CK-M mRNA expression did not differ in all groups. Thus, chronic volume overload hypertrophy of mitral regurgitation induces CK isoform switching by selective induction of the CK-B gene, and ramipril therapy does not affect this isoform switch. This may reflect a response to increased diastolic stress and more efficient energy utilization in the volume overloaded myocardium.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Creatine Kinase; Dogs; Gene Expression Regulation; Heart Ventricles; Hemodynamics; Hypertrophy, Left Ventricular; Isoenzymes; Magnetic Resonance Imaging; Ramipril; RNA, Messenger

The aim of the present study was to investigate the influence of age and an increased intake of dietary sodium on the cardiovascular and renal effects of the angiotensin converting enzyme inhibitor, ramipril. Male spontaneously hypertensive rats (SHR) aged 10 and 60 weeks received either control or a high level of sodium (0.3% vs. 2.6% Na) and ramipril (2 mg/kg/day) mixed in the chow for 6 weeks. Blood pressure was measured weekly by tail-cuff method. Arterial functions were determined by measuring vascular contractile and relaxation responses of mesenteric arterial rings in vitro at the end of the study. An age-related increase in systolic blood pressure, left ventricular (LVH) and renal hypertrophy (RH) as well as proteinuria were found in SHR. The vascular relaxation to nitroprusside was impaired in aged SHR. The high sodium intake accelerated the development of hypertension only in young SHR but increased LVH and RH in both age groups. Ramipril effectively lowered blood pressure in both age groups, but decreased the LVH significantly only in young rats. Ramipril markedly improved the vascular relaxation to acetylcholine and nitroprusside only in young rats. The vascular contractile responses to noradrenaline and potassium chloride were not affected by age, sodium intake or ramipril treatment. The high sodium intake markedly attenuated the cardiovascular effects of ramipril. The high-sodium diet enhanced the urinary excretion of cyclic GMP in both age groups, while it increased urinary excretion of protein in young SHR only. In conclusion, the cardiovascular effects of ramipril were impaired with advanced age even in the presence of a control intake of sodium. A high sodium intake attenuated or even abolished the cardiovascular effects of ramipril in both young and aged SHR.

Topics: Acetylcholine; Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; In Vitro Techniques; Kidney; Male; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth, Vascular; Nitroprusside; Ramipril; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Sodium, Dietary; Vasodilator Agents

In hypertension with cardiac hypertrophy, the specific contributions to increased production of the cardiac natriuretic peptides (NP) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) by load and the hypertrophic process are not known. In the present work we determine ANF and BNP synthesis and secretion in the aortic-banded rat treated with dosage schedules of the ACE inhibitor ramipril that result in the prevention or regression of both hypertension and hypertrophy (high dosage) or in the prevention or regression of hypertrophy alone with persistent hypertension (low dosage). Myosin heavy chain (MHC) isoform switch was studied as an indicator of ventricular cardiocyte hypertrophy as well as the levels of collagen III mRNA as a measure of changes in extracellular matrix.. Ramipril was administered for 6 weeks just after suprarenal aortic banding, or rats were banded for 6 weeks, after which ramipril was administered during the following 6 weeks. Banding caused an increase in blood pressure, left ventricular weight-to-body weight ratio, plasma and ventricular NP, ventricular NP mRNA, collagen III, and beta-MHC mRNA. Ramipril at 1 mg/kg normalized all these parameters while ramipril at 10 micrograms/kg normalized left ventricular weight-to-body weight ratio but not blood pressure. Plasma and ventricular NP content and mRNA levels were partially normalized by ramipril (10 micrograms/kg). Ramipril (10 micrograms/kg) prevented increased collagen III mRNA levels but did not affect beta-MHC mRNA levels.. (1) NP production and secretion in aortic-banded rats are independently related to increased blood pressure and hypertrophy. (2) A load-dependent component is more important than a load-independent component in regulating left ventricular NP production. (3) ANF production is more sensitive than BNP production to the load-independent component. (4) Low-dose ramipril treatment reverses hypertrophy and the increased collagen III expression but does not reverse the increased beta-MHC isoform expression, suggesting that these are independently regulated processes. (5) Aortic banding and ACE inhibition do not affect atrial NP production and content.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta; Atrial Natriuretic Factor; Base Sequence; Body Weight; Constriction; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Male; Molecular Sequence Data; Myocardium; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Organ Size; Ramipril; Rats; Rats, Sprague-Dawley; Renin

The aim of the present study was to investigate the functional regulation of the myocardial postreceptor adenylyl cyclase (AC) system in compensated left ventricular hypertrophy (LVH) and the effect of long-term angiotensin converting enzyme (ACE) inhibition.. Pressure overload LVH was induced in rats by supravalvular aortic banding for 12 weeks. At 12 weeks left ventricular function and inner diameters were analyzed by echocardiography of anesthetized animals, and responsiveness to forskolin (systolic developed pressure) was determined in isolated perfused hearts. Functional activities of AC and the stimulatory G protein Gs were measured as well as mRNA expression (quantitative slot blot analyses) of AC type V, isoforms of Gs alpha and Gi alpha 2. G protein alpha-subunits were also quantified by immunoblotting. Rats were treated with ramipril (Ram, 10 mg/kg per day p.o.) during weeks 7 to 12 to induce regression of LVH or with vehicle (Veh, tap water).. Pressure overload induced severe LVH (3.2 +/- 0.09 g/kg in Veh vs. 1.8 +/- 0.03 in sham; P < 0.05) which was significantly reduced by ramipril (2.7 +/- 0.09; P < 0.05 vs. Veh). In-vivo left ventricular function and diameters were unchanged in LVH. In contrast, in hearts with LVH, responsiveness of left ventricles to forskolin was attenuated and basal, GTP gamma S and forskolin as well as manganese chloride-stimulated adenylyl cyclase activity was significantly downregulated by approximately 40% (basal 20.8 +/- 1.9 pmol cAMP/mg per min vs. 34.0 +/- 2.2 in sham; P < 0.01). However, no significant changes of AC type V mRNA were found in hypertrophied left ventricles. Functional activity of the stimulatory G protein Gs was reduced in LVH (48 +/- 7 pmol cAMP/mg per min in Veh vs. 68 +/- 3 in sham), whereas mRNA expression of long and short Gs alpha-isoforms was not altered and that of Gi alpha 2 was only slightly increased in ramipril-treated animals. Western analysis showed no significant differences of Gs alpha or Gi alpha 2 subunits. Long-term blockade of the renin-angiotensin system had no effect on the activity of the adenylyl cyclase system.. Functional desensitization of adenylyl cyclase and stimulatory G protein occurred in rat adaptive LVH prior to the onset of severe left ventricular dysfunction which was not restored by ACE-inhibitor treatment. The desensitization seems not to be mediated by significant changes of mRNA expression of AC type V or abundance of regulatory G proteins.

Topics: Adenylyl Cyclases; Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Western; Gene Expression; GTP-Binding Proteins; Hypertrophy, Left Ventricular; Male; Myocardium; Ramipril; Rats; Rats, Wistar

In male Sprague Dawley rats with left ventricular hypertrophy (LVH) and hypertension induced by aortic constriction (AC) and subsequent myocardial infarction (MI) by occlusion of the left coronary artery the effects of ACE inhibition with ramipril (RA 1 mg/kg/day via the drinking water during 6 weeks) on survival as well as cardiac function and metabolism were investigated. Respective groups (sham AC; AC; AC + sham MI; normotensive animals with sham MI; MI; MI + RA) served as comparisons. Following MI hypertensive rats with AC and LVH revealed an increased postoperative mortality (68%) when compared to normotensives without AC (28%). ACE inhibition with ramipril significantly reduced mortality in hypertensive rats by 26%. Untreated hypertensive animals with LVH clearly showed reduced MI size (6.2 +/- 2.3%) in comparison with untreated normotensive animals and MI (31.0 +/- 3.3%). In hypertensive rats with MI which died during the study a significant increase in infarct size was found compared to those which survived MI. In normotensive animals ramipril reduced infarct size by 50%. Due to the quite small infarct size observed in hypertensive rats, ACE inhibition did not further reduce MI in these animals. LVH as well as hydroxyproline/proline ratio was diminished by ACE inhibitor treatment. In the isolated hearts of ramipril treated rats contractility was improved when compared to the respective untreated groups with MI. In the coronary effluent of isolated hearts from rats with AC and MI lactate dehydrogenase and creatine kinase activities as well as lactate levels were increased. Ramipril treatment starting one week before MI normalized these parameters and in addition increased prostacyclin output. Hearts with MI from treated normotensive animals contained increased energy rich phosphates when compared to hearts from untreated rats with MI.. Hypertensive rats with LVH undergoing MI experience increased postoperative mortality probably due to a reduced tolerance to myocardial ischemia and occurrence of arrhythmias. In these animals ACE inhibition with ramipril increased survival. Both, increased survival in hypertensive and reduction in infarct size in normotensive rats by ACE inhibition with ramipril was accompanied by an improved myocardial metabolism.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Constriction, Pathologic; Coronary Vessels; Heart; Hypertension; Hypertrophy, Left Ventricular; Male; Myocardial Infarction; Myocardium; Postoperative Period; Ramipril; Rats; Rats, Sprague-Dawley; Reference Values; Survival Analysis

The effect of chronic oral treatment with the angiotensin converting enzyme (ACE) inhibitor ramipril at antihypertensive and sub-antihypertensive doses, on vascular morphology and function as well as left ventricular hypertrophy (LVH) and cardiac capillary length density was investigated in spontaneously hypertensive rats (SHR). Treatment was commenced before hypertension developed (prevention study) or in adult animals with established hypertension (regression study). In both studies, high-dose ramipril reduced ACE activity in plasma, heart and aorta, normalised blood pressure, and prevented LVH or caused regression of LVH. Low-dose ramipril did not prevent the development of hypertension or LVH, but caused an increase in cardiac capillary length density. In adult hypertensive animals, low-dose ramipril did not reduce blood pressure but caused regression of LVH. In both studies, vascular function as tested in the aortic vessels was improved not only after high- but also after low-dose ACE inhibitor treatment: an inhibition of vascular ACE was associated with attenuated vasoconstrictor responses to norepinephrine and enhanced dilator responses to acetylcholine and bradykinin. A reduction of vascular hypertrophy/hyperplasia in the mesenteric vessels was achieved by the antihypertensive dose of ramipril in the prevention but not the regression study. Our data demonstrate that an improvement of vascular function in SHR can be achieved by chronic ACE inhibition with ramipril independently of structural changes and of the antihypertensive action exerted by the drug. LVH was reduced even at a sub-antihypertensive dose of ramipril in the regression but not the prevention study. In the prevention study, however, low-dose ramipril, like high-dose ramipril, was able to protect the heart by preventing cardiac microvascular rarefaction.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Bradykinin; Hypertension; Hypertrophy, Left Ventricular; In Vitro Techniques; Mesenteric Arteries; Myocardium; Norepinephrine; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Inbred SHR; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

Topics: Echocardiography; Humans; Hypertrophy, Left Ventricular; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic; Ventricular Dysfunction, Left

Converting enzyme inhibitor (CEI) therapy, but not angiotensin II subtype I receptor blockade, has been shown to attenuate left ventricular remodeling in the dog after transmyocardial direct current (DC) shock. The purpose of this study was to address the importance of preservation of bradykinin to the antiremodeling effect of CEI treatment in this model.. Twenty-four hours after DC shock, adult mongrel dogs were assigned to one of three groups: a control group; a group treated with ramipril 10 mg BID; and a group treated with ramipril 10 mg BID along with a continuous subcutaneous infusion of HOE 140, a bradykinin antagonist. To assess change in left and right ventricular structure, a magnetic resonance imaging (MRI) study was performed 4 weeks after DC shock and compared with a baseline MRI study performed before DC shock. The increase in left ventricular mass (mean +/- SEM) in the control group was similar to that observed in the CEI-HOE 140 group (+0.73 +/- 0.19 versus +0.75 +/- 0.18 g/kg, P = NS), but both were greater than the change in mass in the ramipril group (-0.48 +/- 0.13 g/kg, P = .004 and P = .0005, respectively). No significant change occurred in left ventricular volume or right ventricular structure in any group. Mean arterial pressure was reduced by ramipril compared with the control group (-8 +/- 2 versus +7 +/- 2 mm Hg, P = .03), and this effect was not blunted by the addition of HOE 140 (-7 +/- 3 mm Hg).. Prevention by ramipril of the early increase in left ventricular mass in the DC shock model appears to be related to the preservation of bradykinin.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Dogs; Electric Injuries; Heart Injuries; Hemodynamics; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Myocardium; Necrosis; Ramipril; Ventricular Function, Left

To delineate the cardioprotective actions of bradykinin (BK) and the contribution of endogenous kinins to the cardiac effects of the ACE inhibitor ramipril, we used the specific B2 kinin receptor antagonist icatibant (HOE 140) during myocardial ischemia and left ventricular hypertrophy (LVH). In isolated working rat hearts, perfusion with ramiprilat (10 nM to 10 microM) reduced the incidence and duration of ventricular fibrillation, and improved cardiodynamics and myocardial metabolism. BK perfusion (0.1 nM to 10 nM) induced comparable cardioprotective effects. In addition, perfusion with ramiprilat (0.1 microM) markedly increased kinin outflow measured by RIA. The beneficial effects of ramiprilat and BK were abolished by the addition of the specific NO synthase inhibitor NG-nitro-L-arginine (L-NNA 1 microM) or icatibant (1 nM). Similar results were obtained in dogs, rabbits and rats with myocardial infarction induced by ligation of the left descending coronary artery. The influence of the icatibant on the antihypertrophic effect of ramipril and BK in the LVH was investigated in rats made hypertensive by aortic banding. Ramipril at the antihypertensive dose of 1 mg kg-1 day-1 for 6 weeks prevented the increase in blood pressure and the development of LVH. The lower non-antihypertensive dose of ramipril (10 micrograms kg-1 day-1 for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity but also prevented LVH after aortic banding. The antihypertrophic effect of the higher and the lower dose of ramipril as well as the antihypertensive action of the higher dose of ramipril were abolished by coadministration of the icatibant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arginine; Bradykinin; Dogs; Endothelium, Vascular; Humans; Hypertrophy, Left Ventricular; Myocardial Ischemia; Nitroarginine; Ramipril; Rats

1. The influence of salt (sodium chloride; NaCl) (an additional 6% in the diet) and that of a novel sodium-reduced, potassium-, magnesium-, and L-lysine-enriched salt alternative on the cardiovascular effects of ramipril was studied in stroke-prone spontaneously hypertensive rats in a 6-week study. The intake of sodium chloride was adjusted to the same level by adding the salt alternative at a 1.75 times higher amount than regular salt. 2. Salt produced a marked rise in blood pressure and induced cardiac hypertrophy and significant mortality, while the salt alternative neither increased blood pressure nor caused any mortality and produced less cardiac hypertrophy than salt. 3. Ramipril treatment at a daily dose of 3 mg kg-1 normalized blood pressure and prevented the development of cardiac hypertrophy of rats on control diet. These effects of ramipril were blocked by the addition of salt but were only slightly attenuated by the addition of the salt alternative. The mortality in the salt group was prevented by ramipril. 4. Responses of mesenteric arterial rings in vitro were examined at the end of the study. Salt, but not the salt alternative, increased vascular contractile responses to noradrenaline. Ramipril treatment improved the arterial relaxation responses to acetylcholine and to sodium nitroprusside. The vascular relaxation enhancing effect of ramipril was blocked by salt but only slightly attenuated by the salt alternative. 5. Ramipril treatment did not significantly increase plasma renin activity in the presence or in the absence of salt supplementation. The salt alternative did not cause hyperkalaemia, either alone or in combination with ramipril treatment. 6. Both salt supplementations, irrespective of ramipril treatment, induced a six to eight fold increase in the urinary excretion of calcium. There was an expected 90 to 140% rise in the urinary excretion of magnesium and 200% rise in the urinary excretion of potassium in the salt alternative group. Salt also produced an approximately 50% increase in magnesuria.7. Our findings suggest that replacement of salt by the potassium-, magnesium- and L-lysine-enriched salt alternative improves the cardiovascular effects of ramipril. In the present study the beneficial effect was related to the increased intakes of potassium and/or magnesium and L-lysine from the salt alternative because the amount of sodium chloride was the same.

Topics: Animals; Blood Pressure; Cardiovascular System; Cerebrovascular Disorders; Electrolytes; Hypertrophy, Left Ventricular; Magnesium; Male; Mesenteric Arteries; Potassium; Ramipril; Rats; Rats, Inbred SHR; Sodium Chloride

The effect of chronic low- and high-dose treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril (0.01 and 1 mg/kg per day) on the development of hypertension and left ventricular hypertrophy as well as on functional and biochemical alterations of the heart was studied in stroke-prone spontaneously hypertensive rats treated prenatally and subsequently up to the age of 20 weeks. The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment of rats with the bradykinin B2-receptor antagonist Hoe 140 (500 micrograms/kg per day SC) from 6 to 20 weeks of age. High- but not low-dose ACE inhibitor treatment prevented the development of hypertension and left ventricular hypertrophy. Chronic bradykinin receptor blockade did not attenuate the antihypertensive and antihypertrophic actions of ramipril. High-dose ramipril treatment improved cardiac function, as demonstrated by an increase in left ventricular pressure (29.9%), dP/dtmax (34.9%), and coronary flow (22.1%), without a change in heart rate. The activities of lactate dehydrogenase and creatine kinase and lactate concentration in the coronary effluent were reduced by 39.3%, 55.5%, and 66.7%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 31.3%, 39.9%, and 73.7%, respectively, whereas lactate was decreased by 20.8%. Chronic low-dose ACE inhibitor treatment led to a pattern of changes in cardiodynamics and cardiac metabolism similar to that observed with the high dose. All ACE inhibitor-induced effects on cardiac function and metabolism were abolished by chronic bradykinin receptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Administration, Oral; Animals; Bradykinin; Cerebrovascular Disorders; Coronary Circulation; Creatine Kinase; Dose-Response Relationship, Drug; Female; Glycogen; Heart; Hypertension; Hypertrophy, Left Ventricular; L-Lactate Dehydrogenase; Lactates; Male; Myocardium; Phosphocreatine; Pregnancy; Ramipril; Rats; Rats, Inbred SHR; Rats, Wistar; Ventricular Pressure