Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Renal protective effects in diabetic patients. Blocking the renin-angiotensin system slows the progression of nephropathy and end-stage renal disease in diabetes mellitus. While substantial evidence exists for the renal protective effects of angiotensin converting enzyme (ACE) inhibitors in patients with insulin-dependent diabetes mellitus (IDDM), the role of renin-angiotensin system blockade in non-insulin-dependent diabetes mellitus (NIDDM) is less clear. The evidence regarding ACE inhibitors has been attained through the traditional channels of evidence-based medicine: observational studies, trials in animal models, preliminary human analyses, and large, randomized trials. While a sound approach, these pathways to elucidating therapeutic effects require the expenditure of substantial time and resources. Accelerated trials with angiotensin II receptor antagonists have relied on the proven effects of ACE inhibitors in the diabetic patient, as well as on pharmacologic principles dictating that renin-angiotensin blockade is more complete when the system is interrupted at the rate-limiting or receptor level. Irbesartan and creatinine clearance in NIDDM patients. The Collaborative Study pilot trial has already shown that the angiotensin II receptor antagonist irbesartan is significantly more effective than the calcium antagonist amlodipine on creatinine clearance in hypertensive NIDDM patients. Subsequent to this trial, a large, randomized study of over 1600 hypertensive patients with NIDDM has been initiated. Other trials have indicated that the response to blocking angiotensin II receptors with irbesartan in patients with NIDDM is substantially larger than it is in healthy humans.
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PMID:Non-insulin-dependent diabetes mellitus, nephropathy, and the renin system. 953 15

Angiotensin II receptor antagonists lower blood pressure by blocking the final step in the renin pathway, whereas ACE inhibitors reduce angiotensin II production. ACE inhibitors also block kinin degradation, which may alter both efficacy and side-effects. Irbesartan, one of the newer receptor antagonists, has confirmed their tolerability and shown similar dose-related efficacy to other major classes.
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PMID:Irbesartan treatment in hypertension. 985 Mar 1

A lot of evidence points to the important role of the renin-angiotensin system in the physiopathology of hypertension and the progression of chronic renal failure. In this review, the authors report the data concerning the protective effects of antagonists of angiotensin II AT1 receptors (AT1ra). The AT1 ra have been shown to have beneficial effects in most experimental models of nephropathy in which they have been tested (renal ischaemia, essential or induced hypertension, glomerulonephritis, 5/6 nephrectomy, renal transplantation, induced diabetes, toxic and radiotherapy-induced nephropathy). Clinical trials confirm these beneficial effects. In healthy subjects and hypertensive patients, the AT1 ra have identical effects to those of angiotensin converting enzyme (ACE) inhibitors on renal haemodynamics. In hypertensives, Candesartan and Irbesartan increase renal blood flow and the glomerular filtration rate and decrease the filtration fraction. Two studies have also shown that Candesartan and Irbesartan reduce proteinuria in diabetic patients. Similar results have been reported in essential hypertension with renal failure. These data suggest that AT1 ra have beneficial effects on the progression of experimental kidney disease and on proteinuria in the clinical setting. Of the pharmacological agents available for use in this class, it is essential to propose molecules whose efficacy in antagonising the effects of angiotensin II lasts throughout the 24 hour period. Clinical trials are under way to evaluate the effects of AT1 ra on renal function in man over a long period.
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PMID:[Are the antagonists of angiotensin II AT1 receptors protectors of the kidney?]. 1044 11

This study was conducted to investigate whether the novel orally active nonpeptide angiotensin II (Ang II) AT(1) receptor antagonist irbesartan interacts with the thromboxane A(2)/prostaglandin endoperoxide H(2) (TxA(2)/PGH(2)) receptor in canine coronary arteries and human platelets. Coronary artery rings were isolated from male dog hearts (n = 18) and isometric tension of vascular rings was measured continuously at optimal basal tension in organ chambers. Autoradiographic binding of [(3)H]SQ29,548, a TxA(2) receptor antagonist, in canine coronary sections was determined. Blood for platelet aggregation studies was collected by venous puncture from healthy human volunteers (n = 6) who were free of aspirin-like agents for at least 2 weeks. Vascular reactivity and platelet aggregation in response to the TxA(2) analogs U46619 and autoradioagraphic receptor binding to the TxA(2) receptor antagonist [(3)H]SQ29,548 were studied with and without irbesartan. The TxA(2) analog U46619 produced dose-dependent vasoconstriction in coronary rings (EC(50) = 11.6 +/- 1.5 nM). Pretreatment with irbesartan inhibited U46619-induced vasoconstriction, and the dose-response curve was shifted to the right in a dose-dependent manner. The EC(50) of U46619 was increased 6- and 35-fold in the presence of 1 and 10 microM of irbesartan without a change of maximal contraction. At 1 microM, irbesartan is 2-fold more potent than the AT(1) receptor antagonist losartan in the inhibition of U46619-induced vasoconstriction in canine coronary arteries. In contrast, neither AT(1) receptor antagonists (CV11974 and valsartan), the AT(2) receptor antagonist PD123319, nor the angiotensin converting enzyme inhibitor lisinopril had any effect on U46619-induced coronary vasoconstriction. Irbesartan did not change potassium chloride-induced vasoconstriction; however, irbesartan did inhibit the vasoconstriction mediated by another TxA(2)/PGH(2) receptor agonist prostaglandin F(2alpha) (PGF(2alpha)). Neither the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester nor the cyclooxygenase inhibitor indomethacin had any effect on irbesartan's attenuation of U46619-induced vasoconstriction. Irbesartan specifically reversed U46619-preconstricted coronary artery rings with and without endothelium in a dose-dependent manner. Irbesartan at high concentrations significantly competed for [(3)H]SQ29,548 binding in canine coronary sections. U46619 stimulated dose-dependent human platelet aggregation of platelet-rich plasma. Preincubation with irbesartan significantly inhibited platelet aggregation in a concentration-dependent manner. In conclusion, the dual antagonistic actions of irbesartan by acting at both the AT(1) and TxA(2) receptors in blood vessels and platelets may overall enhance its therapeutic profile in the treatment of hypertension, atherosclerosis, and arterial thrombosis.
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PMID:Novel angiotensin II AT(1) receptor antagonist irbesartan prevents thromboxane A(2)-induced vasoconstriction in canine coronary arteries and human platelet aggregation. 1060 53

The rising incidence of stroke, congestive heart failure (CHF) and end stage renal disease (ESRD) has signalled a need to increase awareness, treatment and control of hypertension. There continues to be a need for effective antihypertensive medications since hypertension is a major precursor to various forms of cardiovascular disease. The renin-angiotensin (AT) aldosterone system (RAAS) is a key component to the development of hypertension and can be one target of drug therapy. Angotensin II (ATII) receptor blockers (ARBs) are the most recent class of agents available to treat hypertension, which work by by inhibiting ATII at the receptor level. Currently, national consensus guidelines recommend that ARBs should be reserved for hypertensive patients who cannot tolerate angiotensin converting enzyme (ACE) inhibitors (ACEIs). ARBs, however, are moving to the forefront of therapy with a promising role in the area of renoprotection and CHF. Recent trials such as the The Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes Trial (IDNT), the Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes (IRMA2), and The Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy (RENAAL) study have demonstrated the renoprotective effects of ARBs in patients with Type 2 diabetes. The Valsartan Heart Failure Trial (Val-HeFT) adds to the growing body of evidence that ARBs may improve morbidity and mortality in CHF patients. As a class, ARBs are well tolerated and have a lower incidence of cough and angioedema compared to ACEIs. This article reviews the differences among the ARBs, existing efficacy data in hypertension, and explores the role of ARBs in CHF and renal disease.
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PMID:Angiotensin II receptor blockers for the treatment of hypertension. 1182 17

Diabetes mellitus has reached epidemic proportions in many countries and is the most common cause of end stage renal disease (ESRD). The angiotensin II receptor-1 (AT(1)) antagonists losartan and irbesartan have recently been evaluated as renoprotective agents in large clinical trials of patients with Type 2 diabetes and nephropathy. In the Reduction of End points in Non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist (RENAAL) study, losartan decreased the number of patients reaching the primary end point of a composite of measures of neuropathy. The relative risk reduction was approximately 15% with losartan and this was due to a reduction in both the doubling of creatinine concentration (25%) and of ESRD (28%) but not in death. In the Irbesartan Diabetic Nephropathy Trial (IDNT), the beneficial effect of irbesartan was mainly against the doubling of the baseline creatinine concentration (37% risk reduction) but there was also a 20% reduction in the onset of ESRD. Irbesartan had no effect on mortality. Beneficial effects occurred in addition to blood pressure being controlled by agents other than the AT(1) antagonists. These clinical trials suggest that there may be a class renoprotective action with AT(1) antagonists, although the mechanism is not clear. Patients with Type 2 diabetes and nephropathy should receive either an AT(1) antagonist or the angiotensin converting enzyme inhibitor ramipril to ensure renoprotection.
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PMID:Class benefits of AT(1) antagonists in Type 2 diabetes with nephropathy. 1199 40

ACE-inhibitors and AT, receptor antagonists play an important role in the treatment of cardiovascular and renal diseases. The criteria of evidence-based medicine indicate that ACE-inhibitors (in appropriate combinations with other cardiovascular agents) continue to represent the treatment of first choice in chronic heart failure, post-myocardial infarction with compromised ventricular function, high cardiovascular risk, and diabetic (type 1) nephropathy. It is here that the AT1 antagonists should be used--in particular when ACE-inhibitors are not tolerated. The AT1 antagonists, Irbesartan and Losartan, are applied, at appropriately high doses, primarily in hypertensives with diabetic (type 2) nephropathy. With the current exception of chronic heart failure, no confirmed data are yet available on the value of combination treatment. The LIFE study has shown that an AT1 antagonist is superior to an established beta blocker in hypertensives with an increased risk (left-ventricular hypertrophy), in particular when diabetes mellitus is impending or already present.
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PMID:[ACE inhibitor or AT1 antagonist. Is there a differential therapy?]. 1213 23

Diabetes mellitus is the most common cause of end-stage renal disease in the United States, accounting for about 50% of all new cases. Although we previously established the renoprotective benefits of angiotensin converting enzyme (ACE) inhibitors in patients with coexisting hypertension and type 1 diabetes, evidence of the renoprotective effect of ACE inhibitors in patients with type 2 diabetes is less clear. We conducted the Irbesartan Diabetic Nephropathy Trial (IDNT) to determine whether the angiotensin II receptor blocker (ARB) irbesartan slows the progression of nephropathy in patients with type 2 diabetes independently of its blood pressure (BP)-lowering effect. In this randomized, controlled trial, we found that irbesartan was associated with a 20% reduction in the risk for the primary composite end point (doubling of the baseline serum creatinine concentration, development of end-stage renal disease, or death from any cause) compared with placebo (P =.02) and a 23% reduction compared with amlodipine therapy (P =.006). These results were not explained by differences in the BP that was achieved. In a separate study, losartan was shown to reduce the risk for progression of renal disease in patients with type 2 diabetic nephropathy. Angiotensin II receptor blocker therapy has also been demonstrated to slow the progression to overt nephropathy when initiated early in the course of type 2 diabetic renal disease (ie, in patients with microalbuminuria). Based on these studies, ARBs are clearly effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of their BP-lowering effect. Preclinical studies with the newest ARB, olmesartan medoxomil, suggest that this agent may provide renoprotective benefits as well.
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PMID:The role of angiotensin II receptor blockers in preventing the progression of renal disease in patients with type 2 diabetes. 1238 93

Blockade of the renin-angiotensin system with angiotensin converting enzyme inhibitors or with angiotensin receptor antagonists confers patients with arterial hypertension (AH) and associated risk factors, target organ lesion or cardiovascular disease with greater protection in morbidity and mortality terms. The objective of the present study was to evaluate the effect of irbesartan, an angiotensin II receptor antagonist, on the absolute cardiovascular risk in a cohort of hypertensive patients with moderate, high, or very high cardiovascular risk. This was a multicenter, prospective, observational, cohort study with 1974 patients (63 11 years; 47% males) with newly diagnosed essential AH or AH non-controlled with anti-hypertensive monotherapy, and moderate to very high cardiovascular risk. Irbesartan therapy at a dosage of 150300 mg was instituted as monotherapy or associated with hydrochlorothiazide, 12.5 mg. The clinical follow-up was 6 months. The evaluated parameters included the absolute cardiovascular risk, measured either quantitatively (Framingham algorithm) or qualitatively (low, moderate, high, and very high risk groups following the WHO/International Hypertension Society guidelines). Irbesartan therapy led to a significant (p = 0.0001) decrease in SBP (from 170.9 18.4 to 138.5 16.5 mmHg) and DBP (from 96.6 11 to 82 9 mmHg). The quantitative absolute cardiovascular risk decreased by 29.8% (from 12.14 8 to 8.65 6.2; p < 0.0001). The percentage of patients with very high cardiovascular risk decreased from 1.52% to 0.51% and that for patients with high cardiovascular risk from 92.77% to 88.32%. The latter patients changed to the moderate risk group. As a result, this moderate risk group increased from 5.71% to 11.17%. The adverse reaction rate was very low as only 2.2% of patients had some adverse reaction. In conclusion, irbesartan as monotherapy or associated with hydrochlorothiazide has been shown to be effective in reducing the absolute cardiovascular risk, which is obtained by a substantial decrease in arterial pressure and a good safety profile on the biochemical parameters. Tolerability was excellent, with a very low rate of adverse reactions.
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PMID:[Effect of anti-hypertensive therapy with irbesartan on the absolute cardiovascular risk]. 1268 Dec 1

Microvascular remodeling contributes to increased cardiovascular risk in hypertension. The dual angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitor omapatrilat improves small artery remodeling in hypertension. The aim of the present study was to compare effects of omapatrilat to the ACE inhibitor fosinopril and the AT(1) antagonist irbesartan on the coronary microvasculature in spontaneously hypertensive rats (SHR). Ten-week-old SHR were treated for 10 weeks with omapatrilat (20 or 40 mg/kg/d), irbesartan (50 mg/kg/d), or fosinopril (20 mg/kg/d). Arterioles and capillaries were identified in the myocardium by immunolabeling. After 10 weeks, systolic blood pressure (BP) was significantly reduced in treated versus untreated SHR (P <.01). Myocardial arteriolar density/mm(2) was higher (P <.05) in untreated SHR versus Wistar-Kyoto (WKY), and was reduced by omapatrilat (at both high and low doses) and by fosinopril (P <.01). Irbesartan decreased only subepicardial arteriolar density (P <.05). Myocardial capillary density/mm(2) was decreased in untreated SHR versus WKY (P <.01), associated with increase in cardiomyocyte cross-sectional area and cardiomyocyte-to-capillary ratio, and a decrease in myocyte density. Omapatrilat (at both high and low doses) resulted in increased capillary density, decreased myocyte hypertrophy and cardiomyocyte to capillary ratio, and increased myocyte density (P <.01). Fosinopril and irbesartan reduced myocyte hypertrophy of SHR, but had no effect on capillary density. Dual ACE/NEP inhibition was more effective than ACE inhibition or AT(1) antagonism in improving microvascular and cardiomyocyte remodeling in the hypertensive heart. This suggests a role for NEP inhibition added to blockade of the renin-angiotensin system that may explain the greater efficacy of omapatrilat.
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PMID:Effect of dual angiotensin converting enzyme/neutral endopeptidase inhibition, angiotensin converting enzyme inhibition, or AT1 antagonism on coronary microvasculature in spontaneously hypertensive rats. 1457 31


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