Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ramipril is a long-acting, lipophylic angiotensin converting enzyme inhibitor, its principle action is to inhibit the conversion of angiotensin I to the active angiotensin II. Ramipril is indicated in the treatment of hypertension, congestive cardiac failure (including that following acute myocardial infarction), nephropathy (with and without diabetes mellitus) and now, following the findings of the HOPE study, in the prevention of cardiovascular events (including myocardial infarction) in high risk individuals. This article concentrates on reviewing the evidence supporting ramipril's use in these indications.
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PMID:Ramipril. 1091 16

The non-insulin-dependent DIABetes, HYpertension, microalbuminuria or proteinuria, CARdiovascular events, and Ramipril (DIABHYCAR) study is a randomized, prospective, double-blind, placebo-controlled, multicenter international trial of the ACE inhibitor ramipril (1.25 mg/day) in patients with type II diabetes and micro- or macroalbuminuria. The main outcome of the study is the time to first occurrence of either death from a cardiovascular origin, including sudden death, nonfatal myocardial infarction, stroke, or congestive heart failure, or requirement of hemodialysis or renal transplantation. The study was launched in France in early 1995 with the participation of general practitioners only, but had to be extended to 15 other countries in 1997 due to difficulties in recruitment. Since 2.5 years after the beginning of the trial the observed event rate was much less than anticipated, it was decided to increase recruitment and follow-up duration and to include congestive heart failure in the definition of the main outcome to keep the study power at a satisfactory level. Recruitment ended on April 1, 1998 with 4937 randomized patients. Following the early discontinuation for efficacy of another study of ramipril in high cardiovascular risk patients, the Heart Outcomes Prevention Evaluation study (HOPE), the second interim analysis of DIABHYCAR was performed early (when 406 instead of 500 patients presented a main outcome) and the Data Safety and Monitoring Board recommended that the study continue. Follow-up is planned to end on March 31, 2001.
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PMID:The non-insulin-dependent diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular events, and ramipril (DIABHYCAR) study: design, organization, and patient recruitment. DIABHYCAR Study Group. 1091 14

Most chronic nephropathies are characterized by a progressive decline in glomerular filtration rate (GFR) that may lead to renal function replacement by dialysis or transplant. Hypertension has an extremely important role among the various mechanisms contributing to renal function deterioration. High blood pressure levels are associated with increased urinary excretion of proteins and the decrease of systemic and glomerular hypertension reduces urinary excretion of proteins and preserves renal function deterioration. Moreover, recent studies found that an intensified blood pressure control (less than 130/80 mmHg) can slow the progression of diabetic and non diabetic renal disease even more than conventional blood pressure control. The Ramipril Efficacy in Nephropathy (REIN) Study showed that ramipril, an ACE-inhibitor, slowed the rate of GFR decline and halved the combined risk of doubling serum creatinine or end stage renal failure (ESRF) in patients with nephrotic range proteinuria as compared to conventional antihypertensive therapy, at comparable levels of blood pressure control. In these patients, prolonged enough treatment (at least 36 months) with ramipril, lowered the velocity of GFR decline and reduced the risk of dialysis. Thus, both tight blood pressure control and ACE-inhibitors may have a renoprotective effect. It will be interesting to evaluate whether the two combined approaches may have sinergistic effects.
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PMID:How much must blood pressure be reduced in order to obtain the remission of chronic renal disease? 1092 1

To investigate mechanisms by which angiotensin converting enzyme (ACE)-inhibition increases insulin sensitivity, spontaneously hypertensive (SH) rats were treated with or without ramipril (1 mg/kg per day) for 12 weeks. Insulin binding and protein levels of insulin receptor substrate-1 (IRS-1), p85-subunit of phosphatidylinositol 3'-kinase (p85) and Src homology 2 domain-containing phosphatase-2 (SHP2) were then determined in hindlimb muscle and liver. Additionally, protein tyrosine phosphatase (PTPase) activities towards immobilized phosphorylated insulin receptor or phosphorylated IRS-1 of membrane (MF) and cytosolic fractions (CF) of these tissues were measured. Ramipril treatment increased IRS-1-protein content in muscle by 31+/-9% (P<0.05). No effects were observed on IRS-1 content in liver or on insulin binding or protein expression of p85 or SHP2 in both tissues. Ramipril treatment also increased dephosphorylation of insulin receptor by muscle CF (22.0+/-1.0%/60 min compared to 16.8+/-1.5%/60 min; P<0.05), and of IRS-1 by liver MF (37.2+/-1.7%/7.5 min compared to 33.8+/-1.7%/7.5 min; P<0.05) and CF (36.8+/-1.0%/7.5 min compared to 33.2+/-1.0%/7.5 min; P<0.05). We conclude that the observed effects of ACE-inhibition by ramipril on the protein expression of IRS-1 and on PTPase activity might contribute to its effect on insulin sensitivity.
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PMID:Ramipril increases the protein level of skeletal muscle IRS-1 and alters protein tyrosine phosphatase activity in spontaneously hypertensive rats. 1093 26

1. Recent studies demonstrated that the cardiac calpain system is activated during ischaemic events and is involved in cardiomyocyte injury. The aim of this study was to investigate the contribution of AT(1) and AT(2) receptors in the regulation of calpain-mediated myocardial damage following myocardial infarction (MI). 2. Infarcted animals were treated either with placebo, the ACE inhibitor ramipril (1 mg kg(-1) d(-1)), the AT(1) receptor antagonist valsartan (10 mg kg(-1) d(-1)) or the AT(2) receptor antagonist PD 123319 (30 mg kg(-1) d(-1)). Treatment was started 7 days prior to surgery. On day 1, 3, 7 and 14 after MI, gene expression and protein levels of calpain I, II and calpastatin were determined in left ventricular free wall (LVFW) and interventricular septum (IS). At day 3 and 14 post MI, morphological investigations were performed. 3. Calpain I mRNA expression and protein levels were increased in IS 14 days post MI, whereas mRNA expression and protein levels of calpain II were maximally increased in LVFW 3 days post MI. Ramipril and valsartan decreased mRNA and protein up-regulation of calpain I and II, and reduced infarct size and interstitial fibrosis. PD 123319 did not affect calpain I or II up-regulation in the infarcted myocardium, but decreased interstitial fibrosis. Calpastatin expression and translation were not affected by AT receptor antagonists or ACE inhibitor. 4. Our data demonstrate a distinct, temporary-spatial up-regulation of calpain I and II following MI confer with the hypothesis of calpain I being involved in cardiac remodelling in the late and calpain II contributing to cardiac tissue damage in the early phase of MI. The up-regulation of calpain I and II is partly mediated via the AT(1) receptor and can be reduced by ACE inhibitors and AT(1) receptor antagonists.
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PMID:Transcriptional and translational regulation of calpain in the rat heart after myocardial infarction--effects of AT(1) and AT(2) receptor antagonists and ACE inhibitor. 1115 30

Over a 4.5 year follow-up period, the HOPE (Heart Outcomes Prevention Evaluation) trial, and the MICRO-HOPE (Microalbuminuria, Cardiovascular, and Renal Outcomes) and SECURE (Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E) substudies have all demonstrated a large benefit of ramipril versus placebo in patients over 55 years at high risk (by reason of a prior vascular event), or by being diabetic subjects with one additional risk factor. The baseline blood pressure on average was normal, at 139/79 mmHg, and was modestly reduced by 3.3/1.4 mmHg. Patients with known left ventricular dysfunction were excluded, as were those with uncontrolled hypertension. The incidence of stroke was reduced by 32%, myocardial infarction by 20% and cardiovascular death by 25%. The benefits conferred were in addition to, and largely independent of, other conventional treatments such as aspirin, lipid-lowering agents, beta-blockers, diuretics and calcium channel blockers. The relative risk reduction was very similar whether or not the patient was a known hypertensive at baseline. High dose ACE inhibition with ramipril is applicable to a far wider population of patients at high risk of cardiovascular events than the current indications of hypertension and left ventricular dysfunction.
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PMID:Future perspectives and implications. 1171 55

Diabetes is a major risk factor for cardiovascular events. Indeed, people with diabetes are 2-4 times more likely to die from cardiovascular causes than individuals without diabetes. Despite evidence to suggest that the burden of cardiovascular disease may be decreasing in Western populations, this trend has not been repeated in diabetic populations. Diabetes is also the most common cause of new-onset end-stage renal disease, blindness and amputations. The growing incidence of diabetes throughout the world, particularly in developing nations, suggests that diabetes-related cardiovascular disease and other chronic cardiovascular diseases will constitute a serious global threat to health and well-being. The HOPE (Heart Outcomes Prevention Evaluation) study was designed to determine if the angiotensin converting enzyme (ACE) inhibitor, ramipril, prevents cardiovascular events in high risk patients. As people with diabetes have a high risk of such events, this group was specified for inclusion and analysis in the HOPE study. The HOPE study was designed to include up to 4,000 people with diabetes and was designed with high power to detect an 18% risk reduction in the diabetic sub group alone. A total of 3,577 individuals with diabetes were randomised to receive either 10 mg of ramipril or placebo. After a period of 4.5 years of follow-up, the group of patients receiving ramipril had a statistically and clinically significant risk reduction of 25% in the primary outcome of myocardial infarction (MI), stroke or cardiovascular (CV) death. This comprises a 37% risk reduction in CV death, a 22% risk reduction in MI, a 33% reduction in stroke and a 24% reduction in all-cause mortality. The MICRO-HOPE (Microalbuminuria, Cardiovascular, and Renal Outcomes) sub study assessed the effect of ramipril on diabetic nephropathy. This was detected by a centrally measured urine albumin:creatinine ratio and confirmed by timed urine collection. Ramipril significantly reduced the risk of overt nephropathy by 22% (P = 0.045), and overt nephropathy, laser therapy or dialysis by 15% (P = 0.05). ACE inhibition with ramipril represents a new macrovascular and microvascular preventive therapy for people with diabetes.
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PMID:Diabetes and the HOPE study: implications for macrovascular and microvascular disease. 1171 57

The aim of this study was to compare the mechanical and intrinsic effects of an angiotensin converting enzyme inhibitor, vs a beta-blocker, on brachial arterial compliance. In a double blind study, 34 essential hypertensive patients were treated for 3 months with either ramipril 2.5-5.0 mg daily (n = 17, age 57 +/- 7 y, 11 males) or atenolol 50-100 mg daily (n = 17, age 53 +/- 8 y, 11 males). Blood pressure (BP), brachial artery diameter (D), brachial-radial pulse wave velocity (PWV) and effective compliance (Ceff), were measured before and at the end of the study. Isobaric evaluation (Ciso) was performed in the entire population studied at an average mean BP of 110 mmHg. Ramipril significantly reduced BP from 155 +/- 16/94 +/- 6 mmHg to 140 +/- 15/85 +/- 7 mmHg (p < 0.001) without affecting heart rate (HR; 74 +/- 10 vs. 75 +/- 12 bpm). In addition, it significantly improved both PWV (18%; p < 0.001) and arterial compliance (45%; p < 0.001), from which 35% was related to a pressure independent effect (p < 0.01). Atenolol also induced a reduction in both BP (159 +/- 17/96 +/- 10 to 133 +/- 13/81 +/- 8 mmHg; p < 0.001) and HR (76 +/- 10 to 57 +/- 7 bpm; p < 0.001). In a similar way, PWV (11%; p < 0.05) and Ceff (30%; p < 0.05) were significantly improved without significant change in Ciso. This suggests that blood pressure reduction was responsible for compliance improvement. In conclusion, it is suggested that atenolol induces only hemodynamic changes, mediated mainly by BP reduction. In contrast, the improved brachial buffering function observed after ramipril involves not only hemodynamic changes, but also changes mediated by other mechanisms, such as modification of wall structures.
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PMID:Mechanical vs intrinsic components in the improvement of brachial arterial compliance. Comparison of the effects of atenolol versus ramipril in hypertensive patients. 1172 19

In the HOPE-trial, the ACE inhibitor ramipril significantly reduced cardiovascular morbidity and mortality in patients at high risk for cardiovascular events. The benefit could only partly be attributed to the modest mean reduction of office blood pressure (OBP) during the study period (3/2 mm Hg). However, because according to the HOPE protocol ramipril was given once daily at bedtime and blood pressure was measured during the day, the 24-hour reduction of blood pressure may be underestimated based on OBP. Thirty-eight patients with peripheral arterial disease enrolled in the HOPE study underwent 24-hour ambulatory blood pressure (ABP) measurement before randomization and after 1 year. OBP was measured in the sitting position immediately before fitting the ABP measuring equipment to the patients. Ramipril did not significantly reduce OBP (8/2 mm Hg, P=NS) or day ABP (6/2 mm Hg, P=NS) after 1 year. Twenty-four-hour ABP was significantly reduced (10/4 mm Hg, P=0.03), mainly because of a more pronounced blood pressure lowering effect during nighttime (17/8 mm Hg, P<0.001). The night/day ratio was also significantly lowered in the ramipril group. ABP shows greater falls, especially at night, than OBP during treatment with ramipril given once daily at bedtime. Although, OBP is the correct comparator when comparing with previous large intervention trials and epidemiological studies, the effects on cardiovascular morbidity and mortality seen with ramipril in the HOPE study may, to a larger extent than previously ascribed, relate to effects on blood pressure patterns over the 24-hour period.
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PMID:Comparative effects of ramipril on ambulatory and office blood pressures: a HOPE Substudy. 1262 66

1. The concept that angiotensin II exerts pro-angiogenic activity is not universally accepted. We evaluated whether inhibition of the renin-angiotensin system (RAS) would influence reparative angiogenesis in a murine model of limb ischaemia. 2. Perfusion recovery following surgical removal of the left femoral artery was analysed by laser Doppler flowmetry in mice given the ACE inhibitor ramipril (1 mg kg(-1) per day), the AT(1) antagonist losartan (15 mg kg(-1) per day), or vehicle. Muscular capillarity was examined at necroscopy. Ramipril-induced effects were also studied under combined blockade of kinin B(1) and B(2) receptors. Furthermore, the effects of ischaemia on AT(1) gene expression and ACE activity were determined. 3. In untreated mice, muscular AT(1a) gene expression was transiently decreased early after induction of limb ischaemia, whereas AT(1b) mRNA was up-regulated. ACE activity was reduced in ischaemic muscles at 1 and 3 days. Gene expression of AT(1) isoforms as well as ACE activity returned to basal values by day 14. Spontaneous neovascularization allowed for complete perfusion recovery of the ischaemic limb after 21 days. 4. Reparative angiogenesis was negatively influenced by either ramipril (P<0.02) or losartan (P<0.01), leading to delayed and impaired post-ischaemic recovery (50 - 70% less compared with controls). Ramipril-induced effects remained unaltered under kinin receptor blockade. 5. The present study indicates that (a) expression of angiotensin II AT(1) receptors and ACE activity are modulated by ischaemia, (b) ACE-inhibition or AT(1) antagonism impairs reparative angiogenesis, and (c) intact AT(1) receptor signalling is essential for post-ischaemic recovery. These results provide new insights into the role of the RAS in vascular biology and suggest cautionary use of ACE inhibitors and AT(1) antagonists in patients at risk for developing peripheral ischaemia.
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PMID:Angiotensin AT(1) receptor signalling modulates reparative angiogenesis induced by limb ischaemia. 1178 83


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