ramipril and candesartan

Angiotensin-receptor blockers (ARBs) offer superior tolerability to angiotensin-converting enzyme inhibitors, and are increasingly used in patient management. ARBs vary in their pharmacological profiles, which results in efficacy differences. Therefore, deciding between ARBs should be evidence-based and related to the specific requirements of the individual patient. For patients with hypertension but at low additional risk, an ARB that provides sustained, powerful 24-h reductions in blood pressure is suitable. For patients at very high additional risk (with heart failure), an ARB with demonstrated efficacy in this patient population is the preferred option. For patients at increased risk, telmisartan should be the ARB of choice based on the results from the Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial (ONTARGET), which demonstrated for the first time that an ARB has equivalent protection to the reference angiotensin-converting enzyme inhibitor in a broad cross-section of at-risk patients but a better side-effect profile.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Biphenyl Compounds; Blood Pressure; Cardiovascular Diseases; Humans; Hypertension; Losartan; Ramipril; Risk Factors; Telmisartan; Tetrazoles

Recent meta-analyses have examined the relationship between lowering blood pressure (BP) and reducing the risk for stroke and dementia. Studies have shown that drug therapy that successfully reduces systolic BP by only 10 mm Hg results in significant protection against stroke. Controversy exists regarding the most effective regimen, with supporters for the standards of diuretics and beta-blockers, or angiotensin-converting enzyme inhibitors and calcium-channel blockers, pitted against the increasing evidence of the effectiveness of angiotensin-receptor blockers or statins. Additionally, the most effective strategy for delivery of BP-reducing therapy is being examined, with some studies supporting use of standards for primary prevention of stroke and reserving the newer drugs for secondary prevention. Ultimately, however, all agree that for patients with the highest risk for cardiovascular and cerebrovascular complications, the strategy of intervention is immaterial, and drug therapy, including low-dose aspirin, is vital.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Cognition; Dementia; Hydrochlorothiazide; Ramipril; Stroke; Tetrazoles; Verapamil

Several cardiac biomarkers, especially brain natriuretic peptide (BNP) and N-terminal (NT)-proBNP, have been used as predictors of prognosis and negative remodeling in DCM. In the present study, we aimed to evaluate the prognostic value of tenascin-C in dilated cardiomyopathy (DCM) and whether it can be used to determine reverse remodeling in patients with DCM.. Sixty-six patients with DCM were followed up for 12 months after initiation of medical treatment including carvedilol, ramipril (candesartan if ramipril was not tolerated), spironolactone, and furosemide. Tenascin-C and NT-proBNP measurements and transthoracic echocardiography were performed at baseline and at 12 months.. At 12 months, a significant improvement in New York Heart Association class (2.57 ± 0.6 vs. 1.87 ± 0.5; P < 0.0001), left ventricular end-diastolic volume (217 ± 47 vs 203 ± 48; P < 0.0001), left ventricular ejection fraction (29.1 ± 5.5 vs 30.9 ± 3.8; P < 0.0001), NT-proBNP (2019 ± 558 vs 1462 ± 805; P < 0.0001), and tenascin-C (76 ± 19 vs 48 ± 28; P < 0.0001) values were observed, compared with baseline. Importantly, decrease in tenascin-C values were correlated with increase in left ventricular ejection fraction. Tenascin-C (odds ratio [OR], 1.896; <95% confidence interval [CI], 1.543-2.670; P = 0.02), diabetes mellitus (OR, 2.456; G95% CI, 1.987-3.234; P = 0.01) and hypertension (OR: 2.106, <95% CI, 1.876-2.897; P = 0.03) were independent predictors of mortality in patients with DCM.. Reverse ventricular remodeling obtained with carvedilol, ramipril/candesartan, and spironolacton is associated with decreases in left ventricular end-diastolic volume, left ventricular end-systolic volume, tenascin-C levels, and NT-proBNP levels. Consequently, tenascin-C may be used to evaluate reverse remodeling in patients with DCM.

Topics: Aged; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Carbazoles; Cardiomyopathy, Dilated; Carvedilol; Drug Therapy, Combination; Echocardiography; Female; Furosemide; Heart Function Tests; Hong Kong; Humans; Male; Predictive Value of Tests; Prognosis; Propanolamines; Ramipril; Spironolactone; Survival Rate; Tenascin; Tetrazoles; Turkey; Ventricular Remodeling

Dietary sodium, the main determinant of the pharmacodynamic response to renin-angiotensin system blockade, influences the pharmacokinetics of various cardiovascular drugs. We compared the effect of contrasted sodium diets on the pharmacokinetics of single oral doses of 8 mg candesartan cilexetil, 160 mg valsartan, 10 mg ramipril, and 50 mg atenolol administered to 64 (16 per group) normotensive male subjects randomly assigned to sodium depletion (SD) or sodium repletion (SR) in a crossover study. Pharmacodynamic response was assessed as the increase in plasma renin concentration for renin-angiotensin system blockers and electrocardiographic changes in PR interval duration for atenolol. The area under the curve (AUC) for plasma candesartan and atenolol concentrations was significantly lower for SR than for SD (respective ratios of AUC0-∞: 0.74; [90% CI, 0.66-0.82] and 0.69 [90% CI, 0.54-0.88], respectively), indicating a lack of bioequivalence between SR and SD. SR did not affect the pharmacokinetics of valsartan or ramipril. The increase in plasma renin concentration with the 3 renin-angiotensin system blockers was 10 times lower during the SR than the SD period. In the multiple regression analysis, the AUC0-24 of plasma drug concentration explained <1% and 21% of the variance of the AUC0-24 of delta plasma renin concentration for candesartan (P=0.8882/P=0.0368) during the SR and SD periods, respectively. The atenolol-induced lengthening of PR interval was fully reversed by SR. Thus, sodium balance modulates the pharmacokinetics of candesartan cilexetil and atenolol, with measurable effects on the selected pharmacodynamic end points.

Topics: Adolescent; Adrenergic beta-1 Receptor Antagonists; Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Atenolol; Benzimidazoles; Biphenyl Compounds; Cardiovascular Diseases; Chromatography, Liquid; Cross-Over Studies; Diet, Sodium-Restricted; Dose-Response Relationship, Drug; Electrocardiography; Humans; Immunoradiometric Assay; Male; Ramipril; Reference Values; Renin; Renin-Angiotensin System; Sodium, Dietary; Tetrazoles; Treatment Outcome; Young Adult

The effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor blockade (ARB) on fibrinolysis and inflammation after cardiopulmonary bypass (CPB) are uncertain. This study tested the hypothesis that ACE inhibition enhances fibrinolysis and inflammation to a greater extent than ARB in patients undergoing CPB. One week to 5 days before surgery, patients were randomized to ramipril 5 mg/day, candesartan 16 mg/day, or placebo. ACE inhibition increased intraoperative bradykinin and tissue-type plasminogen activator (t-PA ) concentrations as compared to AR B. Both ACE inhibition and AR B decreased the need for plasma transfusion relative to placebo, but only ACE inhibition decreased the duration of hospital stay. Neither ACE inhibition nor AR B significantly affected concentrations of plasminogen activator inhibitor-1 (PAI -1), interleukin (IL )-6, IL -8, or IL -10. ACE inhibition enhanced intraoperative fibrinolysis without increasing the likelihood of red-cell transfusion. By contrast, neither ACE inhibition nor ARB affected the inflammatory response. ACE inhibitors and ARBs may be safely continued until the day of surgery.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Transfusion; Bradykinin; Cardiopulmonary Bypass; Endpoint Determination; Female; Fibrinolysis; Hematocrit; Hospital Mortality; Humans; Inflammation; Interleukins; Length of Stay; Male; Middle Aged; Monitoring, Intraoperative; Perioperative Care; Postoperative Complications; Ramipril; Tetrazoles; Treatment Outcome

ASCOT-BPLA study demonstrates that in hypertensive subjects, atenolol+bendroflumethiazide therapy is associated with higher incidence of adverse cardiovascular outcomes and developing diabetes than an amlodipine+perindopril regimen. This is not explained by changes in blood pressure alone. We hypothesized that distinct vascular and metabolic effects of anti-hypertensive drugs may explain these differential effects.. Either placebo or one class of anti-hypertensive drug (atenolol 100 mg, amlodipine 10 mg, hydrochlorothiazide 50 mg, ramipril 10 mg, or candesartan 16 mg) was given daily during 8 weeks to 31 patients in each of 6 arms of a randomized, single-blind, placebo-controlled, parallel study.. Atenolol, amlodipine, and candesartan therapies significantly reduced systolic blood pressure when compared with ramipril (P<0.05 by ANOVA). Atenolol and thiazide therapies increased triglycerides levels greater than ramipril or candesartan (P=0.005 by ANOVA). Amlodipine significantly increased HDL cholesterol levels greater than atenolol (P=0.011 by ANOVA). Ramipril and candesartan therapies improved FMD and increased adiponectin levels and insulin sensitivity to a greater extent than atenolol or thiazide therapies (P<0.001 and P<0.015 by ANOVA). Amlodipine therapy increased adiponectin levels greater than atenolol therapy (P<0.05 by ANOVA). Ramipril, candesartan, and amlodipine therapies significantly decreased leptin levels to a greater extent when compared with atenolol or thiazide therapies (P<0.001 by ANOVA). Amlodipine therapies significantly decreased resistin levels greater than ramipril or candesartan therapies (P=0.001 by ANOVA).. We observed differential effects of anti-hypertensive drugs on endothelial dysfunction and plasma adipocytokines.

Topics: Adipokines; Adiponectin; Adult; Aged; Amlodipine; Antihypertensive Agents; Atenolol; Benzimidazoles; Biphenyl Compounds; Cholesterol, HDL; Comorbidity; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Ramipril; Single-Blind Method; Tetrazoles; Triglycerides

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

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

Ramipril and candesartan have distinct mechanisms of action to improve endothelial function. Therefore, we hypothesized that combination therapy has additive beneficial effects to simultaneously improve endothelial dysfunction and adipocytokine profiles in patients with hypertension.. Thirty-four patients were given ramipril 10 mg and placebo, ramipril 10 mg and candesartan 16 mg, or candesartan 16 mg and placebo daily in a randomized, double-blind, placebo-controlled cross-over trial with three treatment arms and two washout periods (each 2 months). Ramipril, candesartan, or combination therapy reduced blood pressure, improved flow-mediated dilation, and increased plasma adiponectin levels when compared with baseline values. However, combination therapy improved these outcome measures to a greater extent than either ramipril or candesartan alone (P < 0.001 and P = 0.016 for systolic and diastolic blood pressure, P < 0.001 and P = 0.048 for flow-mediated dilation and adiponectin levels by ANOVA). In addition, combination therapy reduced plasma leptin levels to a greater extent than either ramipril or candesartan alone (P = 0.042 by ANOVA). There were correlations between percent changes in adiponectin levels and percent changes in insulin sensitivity (determined by QUICKI) (r = 0.319, P = 0.066) following ramipril therapy, percent changes in QUICKI (r = 0.374, P = 0.029) following combination therapy, and percent changes in QUICKI (r = 0.607, P < 0.001) following candesartan therapy.. Ramipril in combination with candesartan improves blood pressure, endothelial function, and adipocytokine profiles to a greater extent than monotherapy with either drug in hypertensive patients.

Topics: Adiponectin; Adult; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Double-Blind Method; Drug Therapy, Combination; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Ramipril; Tetrazoles; Treatment Outcome

We evaluated the renoprotective effects of dual blockade of renin-angiotensin system (RAS) by using a low-dose combination of ACE inhibiter and angiotensin II receptor blocker in type 2 diabetic patients with advanced kidney disease. The amount of proteinuria and the urinary levels of bioassayable TGF-beta1 were used as surrogate markers of renal injury and sclerosis.. We performed a prospective double-blinded randomized crossover trial consisting of three 16-week treatment periods with ramipril alone (10 mg/day), candesartan alone (16 mg/day), and ramipril (5 mg/day) plus candesartan (8 mg/day) combination therapy. Twenty-one type 2 diabetic patients with overt nephropathy with a 24 h urinary protein excretion rate (UPER) of > 1.0 g/24 h and creatinine clearance (Ccr) of 30 to 59 ml/min/1.73 m2 completed the entire study.. Subjects consisted of 10 female and 11 male patients with a mean age of 49 +/- 8 years and duration of diabetes ranging from 4 to 13 years. At baseline, 24-h blood pressures (BPs) were 133 +/- 6/81 +/- 7 mmHg, Ccr 40.6 +/- 4.1 ml/min/1.73 m2, 24-h UPER 4.1 +/- 1.9 g/24 h, and urinary TGF-beta1 level 28.4 +/- 16.1 pg/mg creatinine (cr). Although there was no comparable change in BP and plasma/urinary biochemical parameters, 24-h UPER was significantly reduced by the combination therapy (2.9 +/- 1.4 g/24 h) compared with that of ramipril (3.5 +/- 1.8 g/24 h) and of candesartan (3.3 +/- 2.0 g/24 h) single therapy (P < 0.05). Urinary TGF-beta1 level was reduced in all three therapies compared with that of the control (28.4 +/- 16.1 pg/mg cr) (P < 0.05). However, the combination therapy showed the most significant change (combination 19.6 +/- 10.6 pg/mg cr; ramipril 24.7 +/- 13.3 pg/mg cr; candesartan; 23.4 +/- 11.7 pg/mg cr). No significant or irreversible adverse effect was observed in the 21 patients who completed the entire study.. The dual blockade of RAS with low-dose ramipril plus candesartan was found to be safe and offered additive benefits with respect to reducing proteinuria and urinary TGF-beta1 excretion in diabetic patients with advanced kidney disease. These benefits were evident as compared with single ramipril and candesartan therapies at doses two-fold greater. Further study on the dose-titration is mandatory in terms of safety and especially for maximizing renoprotection in this patient population.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biomarkers; Biphenyl Compounds; Creatinine; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Ramipril; Renin-Angiotensin System; Tetrazoles; Transforming Growth Factor beta; Treatment Outcome

Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, used alone or in combination, have been shown to improve outcomes in certain populations, primarily when administered in high doses. For stable coronary atherosclerotic disease, however, the relative physiologic effect of these therapies is unclear. Furthermore, because of the notorious subtarget dosing of such agents in clinical practice, we explored the influence of a modest dosing of an angiotensin-converting enzyme inhibitor, angiotensin II type 1 receptor blockers, and the combination on common biologic markers of coronary atherosclerotic disease.. This randomized, cross-over study enrolled stable coronary atherosclerotic disease patients (n=20), each receiving three treatments: candesartan 16 mg daily, ramipril 5 mg daily, and candesartan 8 mg plus ramipril 2.5 mg daily. Treatments were administered for 2 weeks with a 2-week washout. Blood samples were collected before and after each treatment. Markers of endothelial function, fibrinolytic balance, and vascular inflammation were measured.. No significant differences were observed in the pretreatment concentrations of angiotensin-converting enzyme or of any measured biologic marker. Relative to pretreatment levels, candesartan alone was the only therapy to exhibit an action on any measured biomarker--a trend toward increased nitric oxide concentrations (P=0.054). Otherwise, no effects on biologic markers were observed with the treatments.. This study of various methods of the renin-angiotensin system inhibition in stable coronary atherosclerotic disease patients demonstrates negligible effects of a modest dosing of ramipril and the combination of ramipril plus candesartan on common biologic markers of coronary atherosclerotic disease. Candesartan at modest doses may favorably influence endothelial function. Overall, however, the results indicate that the commonly practiced subtarget dosing of such treatments provides little, if any, benefit pertaining to key physiologic components of coronary atherosclerotic disease.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biomarkers; Biphenyl Compounds; Coronary Artery Disease; Cross-Over Studies; Drug Therapy, Combination; Endothelium, Vascular; Female; Fibrinolysis; Humans; Inflammation; Male; Middle Aged; Ramipril; Tetrazoles

The therapeutic benefits of dual blockade of the renin-angiotensin system (RAS) have been inconsistent on renal function and proteinuria. To know the contribution of the heterogeneity of study subjects to such inconsistency, we evaluated the effects of dual blockade of RAS in 2 groups of selected renal diseases, IgA and diabetic nephropathy. To avoid confounding by the blood pressure-reducing effects, angiotensin II receptor antagonists (ATRAs) were added on the patients with long-term, optimally controlled blood pressure taking ACE inhibitors. Twenty-four-hour urinary protein excretion rate and urinary TGF-beta1 level were measured as surrogate markers of renal injury.. We conducted a prospective crossover trial with 14 IgA and 18 type-2-diabetic nephropathy patients showing moderate degree of proteinuria (> or = 1.0 g/day) and renal dysfunction (creatinine clearance 25 - 75/ml/min). Four to 8 mg once-daily dose of candesartan and placebo were alternatively added on ramipril dose of 5 - 7.5 mg/day for 16 weeks.. All baseline data except for the age factor were statistically the same between the 2 disease groups. Twenty-four-hour mean arterial blood pressures were 91.2 +/- 1.6 and 92.3 +/- 1.8 mmHg in IgA and diabetic nephropathy patients respectively at baseline (p = NS). Mean arterial pressure did not change by the addition of candesartan or placebo in both groups. The addition of candesartan (combination) reduced 24-hour urinary protein excretion rate in IgA nephropathy patients with a mean change of -12.3 +/- 4.5%, which is significantly greater compared to a mean change of -0.1 +/- 3.3% after the addition of placebo (placebo) (mean difference 12.4 +/- 5.0, 95% CI 1.2 - 23.5; p < 0.05). Urinary TGF-beta1 level was reduced considerably by the combination therapy, with a -28.9 +/- 6.0% decrease, which was significantly different to that by the placebo, with +4.3 +/- 12.4% (33.3 +/- 13.5, 3.2 - 63.3; p < 0.05). In diabetic nephropathy patients, the addition of candesartan did not reduce 24-hour urinary protein excretion rate. Mean changes of 24-hour urinary protein excretion rate were -0.8 +/- 4.7% by the combination therapy and +0.5 +/- 6.1% by placebo (mean difference 1.3 +/- 4.7, 95% CI -6.8 - 13.5; p < NS). The level of urinary TGF-beta1 was reduced by the combination therapy, with -14.3 +/- 9.5% decrease, but it did not reach statistical significance compared to placebo of +0.7 +/- 15.5% (15.0 +/- 13.5, -14.4 - 44.5; p < NS). The changes in 24-hour urinary protein excretion rate and urinary TGF-beta1 level were neither correlated with each other, nor with the change in mean arterial pressure. Significant changes in the renal function were not detected during the study period.. Definite beneficial effects of dual blockade of RAS on proteinuria and TGF-beta1 excretion were found in IgA nephropathy patients, which was independent of blood pressure-reducing effect. With our 16-week trial, such benefits were not observed in type 2 diabetic nephropathy. The reduction in urinary TGF-beta1 level suggests that the combination therapy may provide additional renoprotection through the antisclerosing effects. Based on our results, for a proper interpretation the therapeutic effects of the combination therapy should be evaluated separately according to the underlying renal disease.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Cross-Over Studies; Diabetic Nephropathies; Female; Glomerulonephritis, IGA; Humans; Male; Middle Aged; Prospective Studies; Proteinuria; Ramipril; Renin-Angiotensin System; Tetrazoles; Transforming Growth Factor beta

The article presents the results of a preclinical study of ramipril and candesartan in an experimental group of hypertensive rats of different sexes. Antihypertensive therapy was performed for 21 days. The drugs were administered daily in moderate therapeutic doses calculated for rats using the coefficient of species sensitivity. It was found that the course of experimental hypertension has gender differences, and in males, according to blood pressure, the level of NO metabolites is more pronounced. The use of ramipril from the group of ACE inhibitors and candesartan from the ARBs group in experimental hypertension in rats has gender differences. Ramipril is likely to be more effective in normalizing blood pressure and endothelial function in males than females. The use of candesartan did not show significant gender differences, but there was a tendency for females to be slightly more effective than males. Established gender differences in hypertension pharmacotherapy should be considered to optimize treatment.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Female; Hypertension; Male; Ramipril; Rats; Tetrazoles

The number of patients who has a daily intake of antihypertensive drugs is rising, due to an also rising prevalence of lifestyle diseases. Interestingly, knowledge about effects of these drugs in terms of wound healing is low.. Based on a few differing studies, the idea arose that antihypertensives may have side effects on wound healing.. Five antihypertensive drugs from different substance classes (metoprolol, amlodipine, ramipril, hydrochlorothiazide, candesartan) were investigated, in terms of possible impacts on cell metabolism and migration of human skin fibroblasts and keratinocytes. Additionally, histological and immunohistochemical analyses were performed in a 3-dimensional (3D) wound model addressing the influence on regeneration processes, such as cell migration, metabolic activity, apoptosis and epidermal thickness.. Hydrochlorothiazide and ramipril exerted inhibiting effects in nearly all analyses, interestingly, in serum equivalent doses. In contrast, candesartan and amlodipine induced slight positive effects in 2D as well as in 3D models. The previously described positive effects of β-blockers could only partially be confirmed by metoprolol. Antihypertensive drugs affected fibroblasts more than keratinocytes - whether positively or negatively.. Antihypertensive drugs have an influence on keratinocytes and fibroblasts; they are not neutral. Candesartan has the most positive effects on skin cells. For angiotensin-converting enzyme inhibitors and thiazide diuretics, wound healing in a 3D model is delayed. β-Receptor blockers seem to improve wound healing to a small extent just like calcium channel blockers. These results should be evaluated in a clinical trial to verify their clinical relevance.

Topics: Amlodipine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Calcium Channel Blockers; Cell Line; Cell Movement; Diuretics; Fibroblasts; Humans; Hydrochlorothiazide; Keratinocytes; Metoprolol; Ramipril; Tetrazoles; Wound Healing

Fixed-dose combinations (FDC) have been developed to reduce the pill burden for hypertensive patients. Data on fixed-dose or free-dose (freeDC) ramipril/amlodipine (R/A) or candesartan/amlodipine (C/A) combination treatment initiation were assessed. 71 463 patients were prescribed R/A and 10 495 C/A. For both R/A and C/A, FDC patients were younger (both P < .001) and less comorbid. Prior MI (OR: 0.61 and 0.60), prior stroke (OR: 0.68 and 0.70) and CHD (OR: 0.68 and 0.64) were negatively associated with FDC use, whereas hyperlipidemia was positively associated (OR: 1.26 and 1.19). Use of antihypertensive comedication (OR: 0.78; OR: 0.55) and treatment discontinuation within 12 months (HR: 0.65 and 0.82) were less likely in FDC patients, who also showed superior adherence (mean MPR; both P < .001). Cost of the combination was higher for FDCs (both P < .001). FDCs improve persistence and adherence, although they are more commonly prescribed in patients with less cardiovascular disease.

Topics: Age Factors; Aged; Aged, 80 and over; Amlodipine; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Comorbidity; Drug Combinations; Female; Humans; Hypertension; Male; Middle Aged; Patient Compliance; Ramipril; Tetrazoles

Choosing a method of treating arterial hypertension remains an urgent problem today. For effective therapy, it is necessary to select hypotensive drugs that not only effectively reduce the pressure, but also contribute to the restoration of the structure of tissues sensitive to oscillations of arterial pressure. The purpose of this study was to conduct a comparative analysis of the effect of angiotensin 2-candesartan receptor antagonist and angiotensin converting factor ramipril on pathomorphological changes in the myocardium, kidney, and liver in SHR lines that received treatment for 7 days (short) and 21 days (prolonged therapy ) The study was conducted on 20 spontaneously hypertensive rats with a mass of 248.0-441.0 g. The rabbit was administered at a dose of 5 mg / kg and candesartan 4 mg / kg, respectively. The period of short-term therapy was 7 days and long-term-21 days. For the evaluation of morphological changes in the heart, kidney, liver, frozen cross sections were stained using Ramonovsky-Giemsa method (H and E). The data obtained indicate a more significant effect of candesartan on myocardium and kidney. Ramipril had a negative effect on the renal tubules, increasing the degree of atrophy. Treatment with ramipril and candesartan, especially with long-term use, reduced the hydropic swelling of hepatocytes.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Hypertension; Kidney; Liver; Myocardium; Ramipril; Rats, Inbred SHR; Tetrazoles; Time Factors

Sensory defects associated with small-fiber neuropathy (SFN) can lead to profound disabilities. The relationship between the sensory nervous system and modulation of the renin-angiotensin system (RAS) has been described and focused on pain and neurodegeneration in several animal models. We have recently developed an experimental model of functional sensory neuropathy showing thermal hypoalgesia and neuropeptide depletion without nerve fiber degeneration. Here, we aimed to determine whether the modulation of angiotensin II (Ang II) activity could prevent sensory neuropathy induced by RTX. Control and RTX mice received ramipril, an Ang II converting enzyme (ACE) inhibitor, (0.5 mg/kg/day) or candesartan, an Ang II type 1 receptor (AT1R) blocker (0.5 mg/kg/day), one day before vehicle or RTX administration, and each day for the next seven days. Ramipril did not have a beneficial effect in RTX mice, whereas candesartan prevented thermal hypoalgesia and reduced neuropeptide depletion in intraepidermal nerve fibers and dorsal root ganglion neurons. The preventive effect of candesartan was not observed in mice deficient for the Ang II type 2 receptor (AT2R) and was counteracted in wild type mice by EMA200, an AT2R antagonist (3 mg/kg/day). Thus, candesartan may promote AT2R activation by blocking AT1R and increasing Ang II production and enhance its mechanisms of neuroprotection in our RTX model. Our finding that candesartan prevents nociception deficits and neuropeptide depletion encourages the evaluation of its therapeutic potential in patients presenting SFN, particularly those who experience chemotherapy-induced SFN.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Calcitonin Gene-Related Peptide; Diterpenes; Ganglia, Spinal; Imidazoles; Male; Mice; Mice, Knockout; Neuroprotective Agents; Pyridines; Ramipril; Receptor, Angiotensin, Type 2; Sensory Receptor Cells; Small Fiber Neuropathy; Substance P; Tetrazoles

Statins, such as simvastatin, and ACE inhibitors (ACEis), such as ramipril, are standard therapies for the prevention and treatment of cardiovascular diseases. These types of drugs are commonly administered together. More recently, angiotensin II type 1 receptor (AT1R) antagonists, such as candesartan cilexetil (candesartan), have been used in the place of, or in combination with, ACEis. Here, we investigated the effects of simvastatin and ramipril single and combination therapy, and candesartan treatment on the lifespan of isocalorically fed, long-lived, B6C3F1 mice. Males were used for their relative endocrine simplicity and to minimize animal usage. The drugs were administered daily in food. The simvastatin and ramipril combination therapy significantly increased the mean and median lifespan by 9 %. In contrast, simvastatin, ramipril, or candesartan monotherapy was ineffective. All groups consumed the same number of calories. Simvastatin, alone or administered with ramipril, decreased body weight without changing caloric consumption, suggesting it may alter energy utilization in mice. Combination therapy elevated serum triglyceride and glucose levels, consistent with altered energy homeostasis. Few significant or consistent differences were found in mortality-associated pathologies among the groups. Simvastatin treatment did not reduce normal serum cholesterol or lipid levels in these mice, suggesting that the longevity effects may stem from the pleiotropic, non-cholesterol-related, effects of statins. Together, the results suggest that statins and ACEis together may enhance mouse longevity. Statins and ACE inhibitors are generally well-tolerated, and in combination, they have been shown to increase the lifespan of normotensive, normocholesterolemic humans.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Glucose; Cholesterol; Chromatography, Liquid; Cohort Studies; Drug Synergism; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kaplan-Meier Estimate; Longevity; Male; Mice; Mice, Inbred C57BL; Ramipril; Simvastatin; Tandem Mass Spectrometry; Tetrazoles; Triglycerides

Topics: Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Drugs, Generic; Humans; Hydrochlorothiazide; Hypertension; Nifedipine; Prescription Drugs; Ramipril; Tetrazoles

Topics: Adult; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Female; Humans; Hypertension; Male; Middle Aged; Ramipril; Tetrazoles; Vaccines

Flail mitral valve usually causes severe mitral regurgitation, which may lead to left ventricular dysfunction if left uncorrected. The authors present a case of flail posterior mitral valve leaflet and severe mitral regurgitation in which mitral valve adaptation led to enlargement of the anterior mitral valve leaflet, decrease in mitral regurgitation, and reverse left ventricular remodeling without any need for surgery.

Topics: Adult; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Echocardiography; Echocardiography, Doppler, Color; Follow-Up Studies; Hemodynamics; Humans; Male; Mitral Valve; Mitral Valve Insufficiency; Mitral Valve Prolapse; Ramipril; Remission, Spontaneous; Tetrazoles; Ventricular Remodeling

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

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

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

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

Pancreatic stellate cells (PSCs) are involved in pancreatic inflammation and fibrosis. Recent studies have shown that blocking the renin-angiotensin system (RAS) attenuates pancreatic inflammation and fibrosis. However, there are few data about the direct effects of high glucose on extracellular matrix (ECM) protein synthesis and angiotensin II (Ang II) induction in PSCs. PSCs were isolated from male Sprague-Dawley rats and cultured in medium containing 5.5 mM (LG group) or 27 mM D-glucose (HG group). Levels of Ang II and transforming growth factor-beta (TGF-beta) in culture media were measured and Ang II-positive cells were counted. We used real-time polymerase chain reaction (PCR) to detect Ang II receptor expression and Western blot analysis for the expression of ECM proteins such as connective-tissue growth factor (CTGF) and collagen type IV. Cells were also treated with an Ang II-receptor antagonist (candesartan, 10 microM) or angiotensin-converting enzyme (ACE) inhibitor (ramiprilat, 100 nM). Thymidine uptake by PSCs increased fourfold with high glucose treatment. Ang II levels and the proportion of Ang II-positive PSCs were significantly increased after 6 h under high-glucose conditions. TGF-beta concentrations also increased significantly with high glucose. After 72 h, the expression of CTGF and collagen type IV proteins in high-glucose cultures increased significantly and this increase was effectively attenuated by the candesartan or the ramiprilat. All together, high glucose induced PSCs proliferation and ECM protein synthesis, and these effects were attenuated by an Ang II-receptor antagonist. The data suggest that pancreatic inflammation and fibrosis aggravated by hyperglycemia, and Ang II play an important role in this pathogenesis.

Topics: Angiotensin I; Angiotensin II; Animals; Benzimidazoles; Biphenyl Compounds; Collagen; Connective Tissue Growth Factor; Dose-Response Relationship, Drug; Extracellular Matrix; Extracellular Matrix Proteins; Fibronectins; Fibrosis; Glucose; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Male; Pancreas; Pancreatitis; Ramipril; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Tetrazoles; Transforming Growth Factor beta

Angiotensin II type 1 (AT(1)) receptors are expressed within organs of the hypothalamo-pituitary-adrenal (HPA) axis and seem to be important for its stress responsiveness. Secretion of CRH, ACTH, and corticosterone (CORT) is increased by stimulation of AT(1) receptors. In the present study, we tested whether a blockade of the angiotensin II system attenuates the HPA axis reactivity in spontaneously hypertensive rats. Spontaneously hypertensive rats were treated with candesartan (2 mg/kg), ramipril (1 mg/kg), or mibefradil (12 mg/kg) for 5 wk. In addition to baseline levels, CORT and ACTH responses to injection of CRH (100 microg/kg) were monitored over 4 h. mRNA of CRH, proopiomelanocortin, AT(1A), AT(1B), and AT(2) receptors was quantified by real-time PCR. All treatments induced equivalent reductions of blood pressure and had no effect on baseline levels of CORT and ACTH. However, both candesartan and ramipril significantly reduced CRH-stimulated plasma levels of ACTH (-26 and -15%) and CORT (-36 and -18%) and lowered hypothalamic CRH mRNA (-25 and -29%). Mibefradil did not affect any of these parameters. Gene expression of AT(1A), AT(1B), and AT(2) receptors within the HPA axis was not altered by any drug. We show for the first time that antihypertensive treatment by inhibition of AT(1) receptors or angiotensin-converting enzyme attenuates HPA axis reactivity independently of blood pressure reduction. This action is solely evident after CRH stimulation but not under baseline conditions. Both a reduced pituitary sensitivity to CRH and a down-regulation of hypothalamic CRH expression have the potential to reduce HPA axis activity during chronic AT(1) blockade or angiotensin-converting enzyme inhibition.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Corticosterone; Gene Expression Regulation; Hypothalamus; Male; Mibefradil; Pituitary-Adrenal System; Ramipril; Rats; Rats, Inbred SHR; Tetrazoles

Surveys of prescribing patterns in both hospitals and primary care have usually shown delays in translating the evidence from clinical trials of pharmacological agents into clinical practice, thereby denying patients with heart failure (HF) the benefits of drug treatments proven to improve well-being and prolong life. This may be due to unfamiliarity with the evidence-base for these therapies, the clinical guidelines recommending the use of these treatments or both, as well as concerns regarding adverse events. ACE inhibitors have long been the cornerstone of therapy for systolic HF irrespective of aetiology. Recent trials have now shown that treatment with beta-blockers, aldosterone antagonists and angiotensin receptor blockers also leads to substantial improvements in outcome. In order to accelerate the safe uptake of these treatments and to ensure that all eligible patients receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of HF. The objective of these recommendations is to provide practical guidance for non-specialists, in order to increase the use of evidenced based therapy for HF. These practical recommendations are meant to serve as a supplement to, rather than replacement of, existing HF guidelines.

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzopyrans; Biphenyl Compounds; Bisoprolol; Captopril; Carbazoles; Carvedilol; Drug Therapy, Combination; Enalapril; Ethanolamines; Evidence-Based Medicine; Guideline Adherence; Heart Failure; Humans; Indoles; Lisinopril; Metoprolol; Mineralocorticoid Receptor Antagonists; Nebivolol; Practice Guidelines as Topic; Propanolamines; Ramipril; Spironolactone; Stroke Volume; Tetrazoles; Valine; Valsartan

We have investigated the effects of the angiotensin II type 1 receptor antagonist candesartan, and the angiotensin II converting enzyme inhibitor ramipril, on catecholamine release from the anaesthetized dog's adrenal gland. These drugs were given systemically in low and high doses. The gland was stimulated electrically (0.5-12 Hz) and by angiotensin II infusion (40 ng/kg/min). Electrical stimulation resulted in frequency-dependent increases in catecholamine release. Candesartan (0.8, 4.0 mg/kg) and ramipril (0.125, 0.625 mg/kg) increased basal catecholamine release along with decreases in blood pressure. Both drugs diminished direct nerve stimulation-induced catecholamine release. When both drugs were combined, their inhibitory effect was slightly enhanced. Candesartan blocked catecholamine release induced by angiotensin II. Ramipril was not tested in this respect. The percentage of noradrenaline released during electrical stimulation of the gland remained constant and ranged from 14% to 22%. Both drugs appear to act by blocking local modulation of catecholamine release by the chromaffin cells.

Topics: Adrenal Glands; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Catecholamines; Chromatography, High Pressure Liquid; Denervation; Dogs; Electric Stimulation; Homeostasis; Male; Ramipril; Stimulation, Chemical; Tetrazoles

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

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

ACE-inhibitors and AT -receptor antagonists may exert part of their pharmacological actions by interference with angiotensin-and/or bradykinin-mediated prejunctional stimulation of cardiac norepinephrine release. As endogenous formation of angiotensin and bradykinin is increased in ischemia, we investigated the effects of the ACE-inhibitor ramiprilat and the AT -receptor antagonist candesartan on cardiac norepinephrine release in isolated perfused rat hearts, under nonischemic and stop-flow conditions. Exocytotic release of endogenous norepinephrine was induced by electrical field stimulation and measured by HPLC. Paired stimulations were applied in each heart to obtain an intraindividual comparison of the effect of the pharmacological agent on norepinephrine release with the release under baseline conditions. The ACE-inhibitor ramiprilat (0.1-10 nM) and the AT -receptor antagonist candesartan (1-100 nM) were studied during normal flow or in the fourth minute of stop-flow. Under nonischemic conditions, the ACE-inhibitor slightly reduced norepinephrine release at the highest concentration, while the AT -receptor antagonist did not influence norepinephrine release in normoxia. Conversely, both substances significantly increased norepinephrine release during ischemia. Augmentation of norepinephrine release in ischemia by ramiprilat and candesartan was blocked by the bradykinin B -receptor antagonist HOE 140 and, in case of candesartan, by the AT -receptor antagonist PD 123319. The ACE-inhibitor ramiprilat and AT -receptor antagonist candesartan enhance cardiac norepinephrine release selectively in ischemia by stimulating presynaptic bradykinin B -receptors. Regarding the AT -receptor antagonist, AT -receptor activation is also involved in bradykinin-mediated prejunctional stimulation.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Male; Myocardial Ischemia; Myocardium; Norepinephrine; Ramipril; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Tetrazoles

The effects of the angiotensin-converting-enzyme inhibitor (ACEI) ramiprilat, the angiotensin II type 1 receptor antagonist (AT(1)A) candesartan, and the combination of both drugs on infarct size (IS) resulting from regional myocardial ischaemia were studied in pigs. Both ACEI and AT(1)A reduce myocardial IS by a bradykinin-mediated process. It is unclear, however, whether the combination of ACEI and AT(1)A produces a more pronounced IS reduction than each of these drugs alone. Forty-six enflurane-anaesthetized pigs underwent 90 min low-flow ischaemia and 120 min reperfusion. Systemic haemodynamics (micromanometer), subendocardial blood flow (ENDO, microspheres) and IS (TTC-staining) were determined. The decreases in left ventricular peak pressure by ACEI (by 9+/-2 (s.e. mean) mmHg), AT(1)A (by 11+/-2 mmHg) or their combination (by 18+/-3 mmHg, P<0.05 vs ACEI and AT(1)A, respectively) were readjusted by aortic constriction prior to ischaemia. With placebo (n=10), IS averaged 20.0+/-3.3% of the area at risk. IS was reduced to 9.8+/-2.6% with ramiprilat (n=10) and 10.6+/-3.1% with candesartan (n=10). Combined ramiprilat and candesartan (n=10) reduced IS to 6.7+/-2.1%. Blockade of the bradykinin-B(2)-receptor with icatibant prior to ACEI and AT(1)A completely abolished the reduction of IS (n=6, 22.8+/-6.1%). The relationship between IS and ischaemic ENDO with placebo was shifted downwards by each ACEI and AT(1)A and further shifted downwards with their combination (P<0.05 vs all groups); icatibant again abolished such downward shift. The combination of ACEI and AT(1)A enhances the reduction of IS following ischaemia/reperfusion compared to a monotherapy by either drug alone; this effect is mediated by bradykinin.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Drug Therapy, Combination; Hemodynamics; Myocardial Infarction; Ramipril; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Swine; Tetrazoles

This study was designed to explore the mechanisms mediating the expression of the type 1 angiotensin II (AngII) receptor (AT1) in neuronal and renal tissues. Four groups of rats were given 1% NaCl in water and subjected to the renal reduced mass protocol (RRM), RRM + ramipril (Ram, 10 mg/kg per d), RRM + candesartan (Can, 10 mg/kg per d), or sham surgery. After 12 d, mean arterial pressure (MAP) was significantly higher in RRM rats than in RRM + Ram, RRM + Can, and sham-operated rats. Northern blot analysis showed that renal AT1 receptor mRNA levels (AT1 mRNA/18 rRNA) were significantly decreased in RRM (1.08+/-0.05) and RRM + Ram (0.82+/-0.02) compared with sham-operated rats (1.38+/-0.06) and that candesartan treatment caused a further decrease in renal AT1 mRNA content (0.73+/-0.07) compared with RRM. In contrast, dorsal root ganglia AT1 receptor mRNA content was significantly decreased in RRM (0.52+/-0.06) compared with sham-operated rats (1.18+/-0.07), and this decrease was abolished by ramipril (1.40+/-0.13) and candesartan treatment (1.56+/-0.11). RIA showed that levels (ng/mg protein) of calcitonin gene-related peptide (CGRP) in the dorsal root ganglia were significantly increased in RRM (1.60+/-0.11) but not in RRM + Ram (1.14+/-0.20) and RRM + Can (1.18+/-0.09), compared with sham-operated rats (0.94+/-0.05). Thus, RRM-induced downregulation of neuronal AT1 mRNA expression is mediated by AngII activation of the AT1 receptor, whereas an AT1-independent mechanism is operant in mediating renal AT1 gene expression. Furthermore, the inverse relationship between neuronal AT1 expression and CGRP content indicates that activation of the neuronal AT1 receptor inhibits CGRP synthesis in the dorsal root ganglia. The functional implications of these findings are discussed.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Calcitonin Gene-Related Peptide; Hypertension; Kidney; Male; Neurons, Afferent; Ramipril; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Tetrazoles