ramipril and Cardiomegaly

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

The renin-angiotensin system (RAS) has long been perceived as basically humoral. Since recent findings in molecular biology extended this view to local, possibly independent, tissue-RAS, both the RAS and the kallikrein-kinin cascade are understood as mixed local-systemic interacting systems, which explains local and systemic effects of converting enzyme (CE) inhibitors well. The key enzyme of both systems, CE, catalyzes the activation of the vasopressor and possibly trophic peptide, angiotensin II, and also inactivates the vasodilatory and, according to our observations, cardioprotective bradykinin. Thus, it is consistent that CE-inhibitors lower blood pressure, reduce cardiac hypertrophy, improve metabolic state and attenuate arrhythmias, particularly in ischemic hearts. It is evident from animal experiments that the tight binding favours new oral CE inhibitors, such as ramipril, not only for prevention but also for treatment of tissue injuries due to hypertension or ischemia.

Topics: Animals; Bradykinin; Bridged Bicyclo Compounds; Cardiomegaly; Coronary Disease; Heart Failure; Humans; Hypertension; Muscle, Smooth, Vascular; Peptidyl-Dipeptidase A; Ramipril; Vascular Resistance

Patients with reduced left ventricular function and ventricular enlargement after myocardial infarction are at significantly greater risk for congestive heart failure and death. Nevertheless, recovery of ventricular function occurs in a significant proportion of patients after myocardial infarction, and modern reperfusion strategies have been associated with increased recovery of function.. To determine the extent and predictors of recovery of ventricular function after anterior Q-wave myocardial infarction in the reperfusion era.. Subgroup analysis of the Healing and Early Afterload Reducing Therapy study.. 35 medical centers in the United States and Canada.. 352 patients with Q-wave anterior myocardial infarction.. Placebo for 14 days, followed by full-dose (10 mg) ramipril until day 90; low-dose (0.625 mg) ramipril for 90 days; or full-dose ramipril for 90 days. All patients underwent reperfusion therapy.. Echocardiography was performed on day 1 (before randomization), day 14, and day 90 after myocardial infarction. Left ventricular volume and ejection fraction were measured and wall-motion analyses were performed at all three time points in 249 patients and at baseline in an additional 12 patients who died during follow-up. Echocardiographic and nonechocardiographic predictors of ventricular recovery were examined.. By day 90, 55 of 252 (22%) patients who had abnormal ejection fraction and wall-motion abnormalities on day 1 demonstrated complete recovery of function (ejection fraction in the normal range and infarct segment length of 0%), and an additional 36% (91 of 252 patients) demonstrated partial recovery of function. At 90 days, 53% (132 of 249) of patients had greater than 5% improvement in ejection fraction, whereas only 16% (39 of 249) had a decrease in ejection fraction of more than 5%. The majority of functional improvement occurred by day 14 after infarction. Of various clinical and echocardiographic measures obtained on day 1, peak creatine kinase level was the strongest independent predictor of subsequent recovery of ventricular function in multivariate analysis. Each 100-unit increase in peak creatine kinase was associated with a 4.3% decreased odds of recovery (P < 0.001) after adjustment for ejection fraction on day 1, extent of akinesis or dyskinesis, treatment regimen, Killip class, age, and sex.. Significant myocardial stunning with subsequent improvement of ventricular function occurred in the majority of patients after Q-wave anterior myocardial infarction. A lower peak level of creatine kinase, an estimate of the extent of necrosis, is independently predictive of recovery of function. Early functional assessment (day 1 after acute myocardial infarction) had limited ability to predict recovery of ventricular function.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiomegaly; Creatine Kinase; Double-Blind Method; Echocardiography; Female; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Ramipril; Recovery of Function; Risk Factors; Stroke Volume; Ventricular Dysfunction, Left

Danon disease is a rare X-linked genetic disease resulting from LAMP2 mutations leading to defective lysosomal function. Heart failure is the main causes of morbidity and mortality. Mice with an LAMP2-exon-6-deletion (L2

Topics: Angiotensin II; Animals; Cardiomegaly; Fibrosis; Genetic Therapy; Glycogen Storage Disease Type IIb; Heart Failure; Humans; Mice; Ramipril; Reactive Oxygen Species; Spironolactone

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

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

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

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

We aimed to characterize different cellular effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin 1 (AT1) receptor blockers (ARBs) as mono- or combination therapy in cardiac pressure overload. Methods and. C57B1/6 mice received either the ACEI ramipril (2.5 mg/kg body weight), the ARB telmisartan (20 mg/kg body weight), or the combination. In all groups, pressure overload was induced by transverse aortic constriction (TAC). Cardiac hypertrophy (heart weight/tibia length) induced by TAC was reduced in all 3 treatment groups, with the most pronounced effect in the telmisartan group. The cardiomyocyte short-axis diameter and cardiac fibrosis were increased by TAC and similarly reduced by ACEI, ARB, and the combination therapy. The TAC-induced increase in the number of proliferating Ki67(pos) cardiomyocytes and noncardiomyocytes was reduced more potently by ACEI than by ARB. Four days of drug treatment induced a significant increase in Scal(pos)/VEGFR1(pos) endothelial progenitor cells (EPCs) in all animals in the treated SHAM groups. After 1 day of aortic constriction, only ramipril increased EPC numbers; after 5 weeks, telmisartan monotherapy did not change the EPC levels compared to vehicle or the combination therapy but raised it compared to ramipril. Neither TAC nor one of the therapies changed the number of cardiac capillaries per cardiomyocytes.. ACE inhibition and AT1 receptor blockade have beneficial effects in remodeling processes during cardiac pressure overload. There are small differences between the 2 therapeutical approaches, but the combination therapy has no additional benefit.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Benzoates; Blood Pressure; Cardiomegaly; Drug Therapy, Combination; Endothelial Cells; Fibrosis; Male; Mice; Mice, Inbred C57BL; Myocardium; Ramipril; Stem Cells; Telmisartan

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

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

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

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

Hypertension causes cardiac hypertrophy characterized by low-grade inflammation. Toll-like receptors (TLRs), members of the innate immune system, contribute to cardiac failure. We hypothesized that hypertension is accompanied by enhanced TLR4 expression and activity. Cardiac TLR4 expression was determined in untreated spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY; 4, 8, 16 weeks). Besides, hearts of 8-week-old rats were stimulated with the endogenous TLR4 ligand heparansulfate (HS); the proinflammatory mRNA pattern was assessed (tumor necrosis factor-α (TNF-α), interleukin (IL)-6, monocyte chemotactic protein (MCP)-1). Additionally, we induced hypertension in WKY by L-NAME (N(ω)-nitro-L-arginine-methylester hydrochloride). In both hypertension models the effect of ramipril on TLR4 density was assessed. Cardiac TLR4 distribution was investigated by fluorescence-activated cell sorting analysis. Blood pressure (BP) and heart weight/body weight ratio (HW/BW) were elevated in SHR. Constitutive TLR4 expression was augmented in adolescent and adult, but not young SHR compared with WKY. TLR4 staining was pronounced in cardiomyocytes. HS entailed an aggravated TNF-α and IL-6 mRNA response in cardiac tissue, which was significantly pronounced in SHR. Ramipril (10 mg kg(-1) per day) reduced BP, HW/BW and TLR4 expression in SHR. L-NAME also augmented TLR4 expression in WKY. Ramipril (1 mg kg(-1) per day) lowered BP but TLR4 expression remained unaffected. High-dose ramipril (10 mg kg(-1) per day) however decreased TLR4 expression. Starting from adolescence SHR demonstrated enhanced cardiac TLR4 expression. TLR4 was also upregulated in L-NAME induced hypertension. Thus, enhanced TLR4 expression might be linked to the development and maintenance of hypertension. Finally, the antihypertensive, anti-inflammatory action of angiotensin-converting-enzyme inhibition had no effect on TLR4 expression in therapeutic doses but in a high-dose model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiomegaly; Chemokine CCL2; Heparitin Sulfate; Hypertension; Interleukin-6; Myocardium; NG-Nitroarginine Methyl Ester; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Up-Regulation

Recent studies suggest that expression of the transforming growth factor-beta (TGF-beta)-inducible gene-h3 (betaig-h3) and its anti-lysosomal activity may be responsible for the development of albuminuria and cardiovascular disease associated with hypertension.. We evaluated the proposed linkage using the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat models. The kidney and left ventricular weight/body weight ratios were measured and cardiac collagen deposition was analyzed by Masson's trichrome stain. Renal and cardiac TGF-beta(1) and betaig-h3 expression were determined by real-time reverse transcription-polymerase chain reaction, and renal and cardiac cathepsin B and L activities were measured as an indicator of lysosomal proteolytic activity.. SHR exhibited increased levels of intact urinary albumin without significant change in total albumin (intact plus albumin-derived material) excretion. This was accompanied by renal hypertrophy, increased renal betaig-h3 expression, and reduced renal cathepsin B and L activities. At the same time, increased cardiac TGF-beta(1) and betaig-h3 expression and reduced cardiac cathepsin B activity was identified in SHR in addition to cardiac hypertrophy and increased collagen deposition. All these changes could be ameliorated with ramipril treatment.. These findings implicate for the first time betaig-h3 expression and lysosomal activity as a key factor in the induction of albuminuria and cardiovascular disease associated with hypertension.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiomegaly; Cathepsins; Extracellular Matrix Proteins; Fibrosis; Hypertension; Kidney; Lysosomes; Male; Myocardium; Ramipril; Random Allocation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

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

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

The antihypertrophic action of angiotensin (Ang)-converting enzyme (ACE) inhibitors in the heart is attributed in part to potentiation of bradykinin. Bradykinin prevents hypertrophy of cultured cardiomyocytes by releasing nitric oxide (NO) from endothelial cells, which increases cardiomyocyte guanosine 3'5'-cyclic monophosphate (cyclic GMP). It is unknown whether cyclic GMP is essential for the action of bradykinin, or whether findings in isolated cardiomyocytes apply in whole hearts, in the presence of other cell types and mechanical/dynamic activity. We now examine the contribution of cyclic GMP to the antihypertrophic action of bradykinin in cardiomyocytes and perfused hearts. In adult rat isolated cardiomyocytes cocultured with bovine aortic endothelial cells, the inhibitory action of bradykinin (10 micromol/L) against Ang II (1 micromol/L)-induced [3H]phenylalanine incorporation was abolished by the soluble guanylyl cyclase inhibitor [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (10 micromol/L). In Langendorff-perfused rat hearts, Ang II (10 nmol/L)-induced increases in [3H]phenylalanine incorporation and atrial natriuretic peptide mRNA expression were prevented by bradykinin (100 nmol/L), the NO donor sodium nitroprusside (3 micromol/L), and the ACE inhibitor ramiprilat (100 nmol/L). The acute antihypertrophic action of bradykinin was accompanied by increased left ventricular cyclic GMP, and the ramiprilat effect was attenuated by HOE 140 (1 micromol/L, a B2-kinin receptor antagonist) or [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (100 nmol/L). In conclusion, bradykinin exerts a direct inhibitory action against the acute hypertrophic response to Ang II in rat isolated hearts, and elevation of cardiomyocyte cyclic GMP may be an important antihypertrophic mechanism used by bradykinin and ramiprilat in the heart.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Cardiomegaly; Cattle; Cells, Cultured; Coronary Circulation; Cyclic GMP; Heart; Heart Rate; Male; Myocardium; Nitric Oxide Donors; Organ Culture Techniques; Phenylalanine; Ramipril; Rats; Rats, Sprague-Dawley

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

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

Rapid cooling contractures were used in this study to test whether low-dose ramipril improves sarcoplasmic reticulum (SR) Ca(2+) uptake and Na(+)/Ca(2+) exchanger function in isolated hypertrophied rat myocytes. Compensated cardiac hypertrophy was induced by abdominal aortic constriction for 5 wk followed by administration of ramipril (50 microg x kg(-1) x day(-1)) or vehicle for 4 wk. Myocyte cell length and cell width were significantly (P < 0.05) increased in both hypertrophied groups (+/-ramipril). Myocytes were loaded with indo 1, and relaxation was investigated after rapid cooling. Hypertrophied myocyte relaxation in Na(+)-free/Ca(2+)-free solution was 63% slower (P < 0.01) and the fall in intracellular Ca(2+) was 60% slower (P < 0.05) than the relaxation of control cells. After ramipril treatment both relaxation and the decline in intracellular Ca(2+) returned to control rates through improved SR Ca(2+)-ATPase function. Relaxation in caffeine showed no change after hypertrophy; however, after ramipril treatment the time to 50% relaxation in caffeine decreased by 30% (P < 0.05). The improvement in Ca(2+) extrusion across the sarcolemmal membrane occurred independently of changes in Na(+)/Ca(2+) exchanger mRNA and protein abundance. These data demonstrate that ramipril improves both SR-dependent and non-SR-dependent calcium cycling after established cardiac hypertrophy. However, the improvements in function are independent of transcriptional activation and likely to involve altered intracellular ion concentrations.

Topics: Animals; Antihypertensive Agents; Caffeine; Calcium; Calcium-Transporting ATPases; Cardiomegaly; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Male; Muscle Fibers, Skeletal; Muscle Relaxation; Myocardial Contraction; Phosphodiesterase Inhibitors; Ramipril; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sarcoplasmic Reticulum; Sodium; Sodium-Calcium Exchanger; Transcriptional Activation

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

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

Beneficial effects of monotherapy with ACE inhibitors or beta-blockers on hemodynamic function after myocardial infarction are well known. Until now, the effects of combined treatment on cardiac function and energy metabolism have been poorly described. This study examines the effects of combined ramipril and metoprolol treatment on the creatine kinase (CK) system and hemodynamic function in rats after infarction. Wistar rats with experimental infarction were randomized for treatment with ramipril (R), metoprolol (M), combined treatment (MR), or placebo (P). Sham-operated (SO) animals served as controls. After 6 weeks, we assayed for CK isoenzymes and performed hemodynamic measurements. In P versus SO, left ventricular systolic pressures (dp/dt(max) and dp/dt(min)) diminished, whereas left ventricular end-diastolic pressure (LVEDP) increased. Decreased total CK activity and mitochondrial CK isoenzyme, increased CK-MB, and increased CK-BB isoenzymes were measured in P versus SO. With infarct size < or =45%, mitochondrial CK increased in M and R versus P. Combined treatment had an additional enhancing effect on mitochondrial CK isoenzyme level versus M and R, decreased LVEDP versus P, as well as increased dp/dt(max) and dp/dt(min) versus R. These results provide evidence of an interaction between normalization of energy metabolism and improvement in cardiac function due to a combination of ACE inhibition and beta blockade after myocardial infarction.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomegaly; Creatine Kinase; Drug Therapy, Combination; Hemodynamics; L-Lactate Dehydrogenase; Male; Metoprolol; Myocardial Infarction; Ramipril; Rats; Rats, Wistar; Ventricular Function, Left

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

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

Spontaneously hypertensive rats (SHR) begin to die from cardiovascular complications at approximately 15 months of age. We tested whether chronic ACE-inhibitor treatment would extend the lifespan of such old animals. We also studied cardiac hypertrophy and function, endothelial function and expression, and activity of NO synthase (eNOS). One hundred 15-month-old SHR were randomized into 3 groups, control (n=10), placebo-treated (n=45), and ramipril-treated with an antihypertensive dose of 1 mg. kg(-1). d(-1) in drinking water (n=45). Ex vivo experiments were performed after 15 months (control) and 21 months, when approximately 80% of the placebo group had died. Late treatment with ramipril significantly extended lifespan of the animals from 21 to 30 months. Fully established cardiac hypertrophy, observed in placebo-treated animals and in controls, was significantly reversed by ramipril treatment. In isolated working hearts, a significantly improved function associated with increased cardiac eNOS expression was seen versus placebo and control hearts. Endothelial dysfunction in isolated aortic rings from control and placebo-treated SHR was significantly improved by ACE inhibition and associated with enhanced NO release. Late treatment of SHR with the ACE inhibitor ramipril extended lifespan from 21 to 30 months, which is comparable to the lifespan of untreated normotensive Wistar-Kyoto rats. This lifespan extension, probably due to blood pressure reduction, correlated with increased eNOS expression and activity followed by a regression of left ventricular hypertrophy and cardiac and vascular dysfunction.

Topics: Age Factors; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta, Thoracic; Blood Pressure; Blotting, Western; Body Weight; Cardiomegaly; Data Interpretation, Statistical; Endothelium, Vascular; Heart; Heart Ventricles; Hypertension; In Vitro Techniques; Luminescent Measurements; Male; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Placebos; Ramipril; Random Allocation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Superoxides; Time Factors

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

The effects of a nonpeptide, orally active mixed endothelin (ET) ETA/ETB receptor antagonist, SB 217242, and an angiotensin-converting enzyme (ACE) inhibitor, ramipril, were evaluated after inter-renal aortic banding in the rat. Separate sham, vehicle, and treatment groups were compared in each study. In vehicle-treated animals in the ramipril group, aortic banding for 4 weeks produced significant cardiac hypertrophy (247 +/- 5 mg/100 g bw vs. 305 +/- 11 mg/100 g bw; p < 0.001), right (upstream) renal hypertrophy (380 +/- 6 mg/100 g bw vs. 559 +/- 28 mg/100 g bw; p < 0.001), and significant left (downstream) renal atrophy (405 +/- 4 mg/100 g bw vs. 192 +/- 25 mg/100 g bw; p < 0.001). Continuous ramipril treatment (1 mg/kg p.o. once daily), begun 3 days before aortic banding, inhibited cardiac hypertrophy (305 +/- 11 mg/100 g bw vs. 266 +/- 7 mg/100 g bw; p < 0.05) but did not alter renal hypertrophy or atrophy. In a similarly designed study, SB 217242 (30 mg/kg p.o. b.i.d.) had no effect on the development of cardiac hypertrophy (298 +/- 7 mg/100 g bw vs. 310 +/- 12 mg/100 g bw) or renal hypertrophy (561 +/- 15 mg/100 g bw vs. 575 +/- 19 mg/100 g bw), but abolished the development of renal atrophy (158 +/- 16 mg/100 g bw vs. 395 +/- 19 mg/100 g bw; p < 0.001). [125I]ET-1 radioligand binding experiments indicated that the density of both ETA and ETB receptors was increased dramatically (three- to fourfold) in the atrophic kidney cortex compared to sham or hypertrophic kidneys. In situ hybridization studies indicate an upregulation of ETB receptor mRNA in the glomeruli of atrophic kidneys within 5 days of aortic banding. In conclusion, an angiotensin-dependent mechanism may mediate cardiac hypertrophy associated with aortic banding, whereas ET-dependent mechanisms may mediate an atrophic response in the hypoperfused kidney, perhaps through an interaction with upregulated ETA and/or ETB receptors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomegaly; Endothelin Receptor Antagonists; Hypertrophy; In Situ Hybridization; Kidney; Kidney Cortex; Male; Radioligand Assay; Ramipril; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

We examined the hypothesis that the angiotensin converting enzyme inhibitor ramipril at sub-antihypertensive concentrations could improve sarcoplasmic reticulum (SR) CaATPase expression and function in compensated hypertrophied rat hearts. Five weeks after abdominal aortic constriction, rats received a daily dose (50 micrograms/kg/day) of ramipril or vehicle for 4 weeks. Cardiac angiotensin-converting enzyme (ACE) activity increased with cardiac hypertrophy (CH) but returned to normal following ramipril treatment. SR CaATPase protein levels and activity decreased with CH (P < 0.05) and were normalized following ramipril treatment (P < 0.05 for protein and activity). No change in phospholamban (PLB) protein levels could be demonstrated between any of the groups. In contrast, ramipril treatment specifically increased control SR CaATPase and PLB mRNA levels by > 60% (P < 0.01) and > 30%, respectively. In the hypertrophied group, SR CaATPase increased by 35% (P < 0.05 n = 6) after ramipril treatment. Calsequestrin mRNA levels were unaffected by ramipril administration. In conclusion, ramipril normalizes SR CaATPase protein expression and function in pressure-overloaded and compensated CH. The effects of ramipril are however multifaceted, affecting RNA and protein expression differentially.

Topics: Animals; Blotting, Northern; Blotting, Western; Calcium; Calcium-Binding Proteins; Calcium-Transporting ATPases; Calsequestrin; Cardiomegaly; Carotid Arteries; Dose-Response Relationship, Drug; Guanosine Monophosphate; Immunoblotting; Male; Oxalates; Peptidyl-Dipeptidase A; Pressure; Ramipril; Rats; Rats, Sprague-Dawley; Sarcoplasmic Reticulum

The aim of this study was to compare the effects of angiotensin converting enzyme (ACE) inhibition, angiotensin II (AII) AT1-receptor blockade, and dihydropyridine calcium antagonism on hypertrophy and on vascular albumin permeability in kidney, heart, and mesenteric artery in a model combining genetic hypertension and diabetes mellitus. Diabetes mellitus was induced by streptozotocin in 8-week-old spontaneously hypertensive rats. The animals were randomized to receive no treatment, the angiotensin converting enzyme inhibitor ramipril, the AII AT1-receptor blocker valsartan, or the dihydropyridine calcium antagonist lacidipine for 3 weeks. Vascular albumin permeability was measured as the tissue content of intravenously injected Evans blue dye (EB) in kidney, heart, and mesenteric artery and the tissue/plasma EB ratio was calculated. Systolic blood pressure was reduced by all three antihypertensive regimens. Glycemic control was similar in all diabetic groups. Kidney hypertrophy was not affected by any of the antihypertensive drugs. Hypertrophy of the mesenteric artery was enhanced by lacidipine but was not affected by ramipril or valsartan. Relative heart weight was also increased by lacidipine. Vascular albumin permeability, expressed as EB content in micrograms/gram dry weight or as tissue/plasma EB ratio, was higher in the kidneys of lacidipine-treated rats than in any other group of diabetic rats. There was a positive correlation between kidney weight/body weight and kidney/plasma EB ratio in the diabetic rats. These findings indicate that the dihydropyridine calcium antagonist lacidipine is associated with an unfavorable effect on vascular hypertrophy and on vascular albumin permeability in the kidneys in rats with hypertension and diabetes mellitus. Furthermore, there seems to be a coupling in the diabetic kidney between hypertrophy and increased vascular albumin permeability.

Topics: Analysis of Variance; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Capillary Permeability; Cardiomegaly; Coloring Agents; Coronary Vessels; Diabetes Mellitus, Experimental; Dihydropyridines; Evans Blue; Hypertension; Hypertrophy; Kidney; Male; Mesenteric Arteries; Ramipril; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Serum Albumin; Tetrazoles; Valine; Valsartan

The renin-angiotensin system (RAS) has been proposed to play a major role in causing the heart to hypertrophy during pressure overload. We examined whether blockade of this system by the angiotensin-converting enzyme (ACE) inhibitors enalapril (0.5 to 20 mg/kg p.o.) or ramipril (1.0 mg/kg p.o.) or the angiotensin receptor (AT1) antagonist losartan (3.0 mg/kg p.o.) could prevent pressure overload-induced hypertrophy. Pressure overload was produced by abdominal aortic constriction in rats. Cardiac hypertrophy was assessed by an increase in the ratio of left ventricular (LV) weight to body weight and total protein content of the left ventricle. Treatment with enalapril or ramipril, initiated 3 weeks after aortic banding and continued for 3 more weeks, failed to prevent the progression or cause regression of cardiac hypertrophy. Treatment for 6 weeks with ramipril initiated immediately after aortic banding also failed to prevent cardiac hypertrophy. Losartan treatment initiated 3 weeks after aortic banding and continued for 3 more weeks resulted in a slight but significant reduction in the extent of cardiac hypertrophy (45.6% hypertrophy in controls and 35.6% hypertrophy in losartan-treated animals, p < 0.05, n = 11 and 10, respectively). Surgical removal of bands 3 weeks after placement reduced cardiac hypertrophy to a greater extent than that observed in losartan-treated animals. These results suggest that angiotensin may not play a major role in causing pressure overload-induced hypertrophy or in maintaining such hypertrophy.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Abdominal; Biphenyl Compounds; Blood Pressure; Body Weight; Cardiomegaly; Enalapril; Heart Ventricles; Imidazoles; Losartan; Male; Organ Size; Ramipril; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Tetrazoles; Ventricular Function

We examined the effect of non-antihypertensive doses of the angiotensin-converting enzyme inhibitor ramipril, kinins, and/or nitric oxide on left ventricular hypertrophy in rats with aortic coarctation. We investigated the effect of either HOE 140, a specific B2 receptor antagonist, or NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, on the antihypertrophic effect of ramipril at non-antihypertensive doses (10 micrograms/kg per day) failed to alter left ventricular hypertrophy significantly, although a small decrease was obtained. Given at a dose of 1 mg/kg per day for 6 weeks, ramipril prevented increased blood pressure and left ventricular hypertrophy after aortic coarctation. Neither of these effects was blocked by simultaneous administration of HOE 140 (500 micrograms/kg per day). In rats with aortic coarctation treated with L-NAME, blood pressure increased further but left ventricular weight did not. Ramipril (1 mg/kg per day) significantly reduced left ventricular hypertrophy, although blood pressure was still higher than in rats given water alone. The slope of the correlation between left ventricular weight and blood pressure in rats that received L-NAME was significantly lower than in rats that did not (0.52 versus 1.29; P = .008). This suggests that for each 1 mm Hg that the blood pressure increased, the increase in left ventricular weight was less in the L-NAME groups. Thus, only antihypertensive doses of ramipril possessed antihypertrophic activity. Kinins did not participate in the chronic antihypertensive and antihypertrophic effects of ramipril. In hypertension induced or aggravated by chronic nitric oxide synthase, L-NAME partially impaired development of left ventricular hypertrophy for reasons that are unclear.

Topics: Amino Acid Oxidoreductases; Animals; Aortic Coarctation; Arginine; Blood Pressure; Cardiomegaly; Dose-Response Relationship, Drug; Heart Ventricles; Hypertension; Kinins; Male; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Organ Size; Ramipril; Rats

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

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

To evaluate the role of bradykinin in the antihypertrophic effect of the angiotensin-converting enzyme (ACE) inhibitor, ramipril, we investigated the influence of HOE 140, a specific B2-receptor antagonist, on the effects of ramipril on left ventricular hypertrophy (LVH) in rats with aortic banding. Ramipril at a dose of 1 mg kg-1 day-1 for 6 weeks prevented the increase in blood pressure and development of LVH after aortic banding; plasma ACE activity was significantly inhibited. A lower 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 prevented LVH after aortic banding. The antihypertrophic effects of the higher and the lower dose ramipril, as well as the antihypertensive action of the higher dose of ramipril were abolished by the coadministration of HOE 140 (500 micrograms kg-1 day-1). The present data show for the first time that the beneficial effects of an ACE-inhibitor on LVH in rats with hypertension caused by aortic banding can be prevented by a specific B2-receptor antagonist.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Bridged Bicyclo Compounds; Cardiomegaly; Heart; Hypertension; Male; Oligopeptides; Organ Size; Ramipril; Rats; Rats, Inbred Strains; Receptors, Bradykinin; Receptors, Neurotransmitter

1. Angiotensin converting enzyme (ACE)-inhibitors have been demonstrated to be effective in the treatment of cardiac hypertrophy when used in antihypertensive doses. The aim of our one year study with an ACE-inhibitor in rats was to separate local cardiac effects produced by a non-antihypertensive dose from those on systemic blood pressure when an antihypertensive dose was used. 2. Rats made hypertensive by aortic banding were subjected to chronic oral treatment for one year with an antihypertensive dose of the ACE inhibitor, ramipril 1 mg kg-1 daily, (RA 1 mg) or received a low dose of 10 micrograms kg-1 daily (RA 10 micrograms) which did not affect high blood pressure. 3. Chronic treatment with the ACE-inhibitor prevented left ventricular hypertrophy in the antihypertensive rats as did the low dose which had no effects on blood pressure. Similar effects were observed on myocardial fibrosis. Plasma ACE activity was inhibited in the RA 1 mg but not in the RA 10 micrograms group although conversion of angiotensin (Ang) I to Ang II in isolated aortic strips was suppressed in both treated groups. Plasma catecholamines were increased in the untreated control group, but treatment with either dose of ramipril normalized the values. The myocardial phosphocreatine to ATP ratio (an indicator of the energy state in the heart) was reduced in the vehicle control group whereas the hearts from treated animals showed a normal ratio comparable to hearts from sham-operated animals. 4. After one year, five animals were separated from each group, treatment withdrawn, and housed for additional six months. In the RA 1 mg group, blood pressure did not reach the value of the control vehicle group and surprisingly, left ventricular hypertrophy and myocardial fibrosis did not recur in animals during withdrawal of treatment.5. These data show that long term ACE inhibitor treatment with ramipril in antihypertensive and non-antihypertensive doses prevented cardiac hypertrophy and myocardial fibrosis. This protective effect was still present after 6 months treatment withdrawal.

Topics: Adenosine Triphosphate; Angiotensins; Animals; Aorta, Thoracic; Blood Pressure; Cardiomegaly; Catecholamines; Cyclic GMP; Endomyocardial Fibrosis; Hypertension; Male; Myocardium; Peptidyl-Dipeptidase A; Phosphocreatine; Radioimmunoassay; Ramipril; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley

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

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

The influence of angiotensin converting enzyme inhibition on the development of left ventricular (LV) hypertrophy due to stenosis of the aortic arch was studied in female Sprague-Dawley rats. The aortic arch was banded to an outer diameter of 1.0 mm. After 14 days, LV and right ventricular functional parameters and transstenotic pressure gradient were measured in anesthetized rats. In addition, regional heart weights were determined, and myocytes of three different heart regions were isolated and subjected to morphometric analysis. To inhibit the angiotensin converting enzyme, ramipril was administered orally by gavage in a single daily dose of 1 mg/kg. Rats with aortic stenosis showed a marked increase in LV systolic pressure, mean prestenotic aortic pressure, and LV stroke work compared with sham-operated rats and demonstrated a systolic transstenotic pressure gradient of 82 mm Hg. This increase in LV hemodynamic load was paralleled by the development of LV hypertrophy as determined by a 37% increase in LV weight and by a 20% increase in cell volume of isolated LV myocytes. Concomitant ramipril treatment did not significantly affect LV functional parameters. The transstenotic pressure gradient was the same as in untreated rats with aortic stenosis. Likewise, the weight gain of the LV as well as the development of cellular hypertrophy of the LV were not influenced. Thus, in this model, angiotensin converting enzyme inhibition did not reduce the development of LV hypertrophy independent of the hemodynamic load.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aortic Valve Stenosis; Biochemical Phenomena; Biochemistry; Bridged Bicyclo Compounds; Cardiomegaly; DNA; Female; Heart; Hemodynamics; Myocardium; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Inbred Strains; RNA

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Abdominal; Biphenyl Compounds; Bridged Bicyclo Compounds; Cardiomegaly; Constriction; Hypertension; Imidazoles; Losartan; Male; Ramipril; Rats; Rats, Inbred Strains; Receptors, Angiotensin; Tetrazoles

The influence of the angiotensin-converting enzyme (ACE) inhibitor ramipril (1 mg/kg orally in a single daily dose) on right ventricular (RV) hypertrophy was studied in Sprague Dawley rats. The pulmonary artery was banded to an outer diameter of 1.7 mm. After 14 days, left (LV) and RV hemodynamic parameters were measured in anesthetized animals. Furthermore, regional heart weights were determined, and myocytes of three different heart regions were isolated and subjected to morphometric analysis. Pulmonary artery stenosis caused a marked increase in RV systolic blood pressure (SBP) without alteration of LV functional parameters as compared with sham-operated animals. Correspondingly, the weight of the RV free wall as well as the RV cell volume were increased to about the same extent, while the LV weight was unchanged. Administration of ramipril to pulmonary artery-constricted animals slightly reduced LV SBP and LVdP/dtmax as compared with banded animals without treatment. The increase in RV SBP and the weight gain of the RV free wall were not affected, however. In contrast, the increase in cell volume of isolated myocytes was less pronounced in this group (+27% as compared with +58% in untreated animals). Because there were no differences in water content of the tissue, interstitial or cellular edema cannot be responsible for this discrepancy. Thus, ACE inhibition with ramipril appears to blunt the cellular hypertrophy in this model without affecting the weight gain of the RV.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bridged Bicyclo Compounds; Cardiomegaly; Constriction, Pathologic; Female; Glucosephosphate Dehydrogenase; Hemodynamics; Pulmonary Artery; Ramipril; Rats; Rats, Inbred Strains; Renin-Angiotensin System

Thirty-two hypertensive subjects with diastolic blood pressure greater than 95 mm Hg were treated with ramipril over a period of 3 months. To determine the effective decrease of blood pressure and for reliable and reproducible demonstration of regression of myocardial hypertrophy during ramipril treatment, we performed parallel measurements with magnetic resonance imaging (MRI) and echocardiography. Measurements were carried out before treatment, 4 h after the first dose, and after 14 days and 3 months of treatment. MRI slices showed a significant decrease of interventricular septal thickness from 19.57 to 15.20 mm, whereas echocardiography demonstrated an equivalent decrease from 18.78 to 14.57 mm. At each measuring point, quantification of wall thickness was performed three times and the means were calculated. The septum and the posterior wall of the left ventricle were also measured at three different points. The values were obtained with negligible scatter and the changes with ramipril treatment were highly significant (p less than 0.001). A concomitant decrease of blood pressure was also observed. The therapeutic aim to reduce diastolic blood pressures below 90 mm Hg was achieved in all patients. In addition to the significant reduction in blood pressure, the angiotensin converting enzyme (ACE) inhibitor ramipril caused a significant regression of pathologic left ventricular hypertrophy demonstrated by magnetic resonance imaging and echocardiography.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Cardiomegaly; Echocardiography; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Ramipril

Angiotensin converting enzyme (ACE) inhibitors have offered new perspectives in the treatment of hypertension. The development of new ACE inhibitors such as ramipril provides an opportunity to improve the knowledge on this class of drug, and to optimize the benefit/risk ratio for the patient. Ramipril was selected among several analogs because of its unique physicochemical properties. It is a nonsulfhydryl ACE inhibitor, and after oral absorption it is transformed in the liver into its active metabolite ramiprilat, which is at least 23 times more lipophilic than enalaprilat. Furthermore, the in vitro affinity of ramiprilat for the enzyme is 7 times higher than for enalaprilat and 47 times higher than for captopril. The ramiprilat-ACE complex is therefore very stable and dissociates 6 times more slowly than the enalaprilat-ACE complex and 22 times more slowly than the captopril-ACE complex. Ramipril possesses a favorable pharmacokinetic profile as a consequence of its physicochemical properties: its high potency allows the use of very low doses, and the slow dissociation of the ramipril-ACE complex explains the long duration of its action, permitting a once-daily treatment. Dose-finding studies have confirmed that very low doses of ramipril--2.5 mg once a day--can be used as a first-step treatment of hypertension. This dose can be increased up to 5 mg, and if necessary a low dose of a diuretic can be added. Using this therapeutic scheme, ramipril normalized blood pressure, insuring that each patient receives the smallest effective dose. Inhibition of the tissue renin-angiotensin system by ramipril has been described in recent studies on animal models.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Cardiomegaly; Chemical Phenomena; Chemistry; Humans; Hypertension; Ramipril; Renin-Angiotensin System; Solubility

Antihypertensive agents have been shown to differ markedly in their effects on the development and regression of cardiac hypertrophy. In view of possible trophic properties of angiotensin II (ANG II), we compared the effects of equipotent antihypertensive doses of the converting enzyme (CE) inhibitor ramipril (1 mg/kg), the calcium antagonist nifedipine (30 mg/kg), and the arterial vasodilator dihydralazine (30 mg/kg) on cardiac mass in rats subjected to banding of the abdominal aorta. Treatment was started either immediately after banding ("prevention experiments") or after hypertension and hypertrophy had already developed ("regression experiments"). Groups of untreated animals with aortic constriction and sham-operated animals served as controls. In the prevention experiments heart weight, myocardial protein content and ANG II plasma levels were significantly increased in untreated animals and in those receiving nifedipine and dihydralazine. In contrast, values obtained in animals treated with ramipril were not different from those seen in normotensive, sham operated controls with the exception of plasma ANG II levels which were lower. Similar results were observed in the second series of studies which examined the effect of antihypertensive agents on the "regression" of cardiac hypertrophy. Treatment was started 6 weeks after aortic banding and continued for another 6 weeks. While all three drugs lowered blood pressure equally well, only ramipril induced a significant and complete regression of cardiac hypertrophy to values not different from sham-operated controls. In addition we studied a group of animals treated with a nonantihypertensive low dose of ramipril (10 micrograms/kg). Remarkably, these animals showed the same complete regression of cardiac hypertrophy as seen in the group receiving the antihypertensive dose of CE inhibitor. Our study indicates a selective advantage of CE inhibitors over other antihypertensive drugs in the prevention and regression of hypertensive cardiac hypertrophy. Importantly, the dissociation between effects on blood pressure and cardiac mass demonstrated in the experiments with a low dose of ramipril stresses the role of factors other than blood pressure and afterload on the development of hypertensive cardiac hypertrophy. One such peptide, thus, may be ANG with its known potential as a growth factor.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Bridged Bicyclo Compounds; Cardiomegaly; Dihydralazine; Hypertension; Male; Nifedipine; Ramipril; Rats; Rats, Inbred Strains

Thirty-two patients with arterial hypertension (diastolic blood pressure greater than 95 mm Hg) were treated with ramipril for 3 months. The aim of the study was to achieve an effective decrease in blood pressure and demonstrate reliably and reproducibly that regression of left ventricular hypertrophy takes place with ramipril treatment. Nuclear magnetic resonance images and echocardiographic measurements of the left ventricle were therefore made before treatment started, 4 hours after the first dose, 14 days after the start of treatment and after 3 months of treatment. The thickness of the septum decreased from 19.57 to 15.20 mm on magnetic resonance scans and from 18.78 to 14.57 mm on echocardiograms. The values were reproduced 3 times at the same measuring point and means were calculated. The septum and posterior wall of the left ventricle were also measured at 3 different points. With negligible scatter, the values obtained were reproducible and the differences were highly significant (p = 0.001). A parallel decrease in blood pressure to levels 15% below baseline was also observed. The therapeutic aim of achieving diastolic blood pressure levels of less than or equal to 90 mm Hg was achieved in all patients. In addition to reducing the blood pressure significantly, the angiotensin converting enzyme inhibitor ramipril caused a significant regression of pathologic left ventricular hypertrophy, which was demonstrated clearly using magnetic resonance imaging and echocardiography.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Cardiomegaly; Female; Humans; Hypertension; Magnetic Resonance Spectroscopy; Male; Middle Aged; Ramipril; Stroke Volume