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)

Nonpeptide angiotensin AT-1 and AT-2 receptor antagonists were administered cerebroventricularly to rats and their effects on various types of angiotensin II (AII)-stimulated water and NaCl intakes examined. The AT-1 receptor blocker, losartan potassium (DUP 753), inhibited water intake evoked by central administration of AII, with the 50% inhibitory dose being less than 0.1 microgram. The functional inhibition by higher doses lasted at least 1 h. The AT-2 receptor antagonist PD 123319 also inhibited AII-induced water intake, but at doses about tenfold higher than losartan. Central, but not peripheral, administration of losartan partially inhibited NaCl intake induced by either sodium depletion, treatment with angiotensin converting enzyme inhibitors (CEIs), or adrenalectomy. PD 123319 partially inhibited NaCl intake induced by both sodium depletion and administration of CEI, but not after adrenalectomy. Another AT-2 receptor antagonist, CGP 42112A, likewise inhibited NaCl intake after sodium deprivation. These data suggest that both AT-1 and AT-2 receptor subtypes in the brain are involved in angiotensin-related water and NaCl intakes.
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PMID:Effect of nonpeptide angiotensin receptor antagonists on water intake and salt appetite in rats. 139 12

While the bulk of the existing data are in diabetic renal disease, there are some animal and clinical studies that compare the effects of angiotensin I (AT-1) receptor antagonists to angiotensin converting enzyme (ACE) inhibitors in renal disease of nondiabetic origin. Based on these data, preservation of renal function and morphology occurs with AT-1 receptor antagonists in animal models where renal injury is hemodynamically mediated such as in the remnant kidney. Conversely, in non-hemodynamically mediated renal injury such as in puromycin nephrosis, AT-1 receptor antagonists have not consistently protected against declines in glomerular filtration rate or development of interstitial fibrosis. This may, however, be related to dosage, since high doses of AT-1 receptor antagonists show some protection against progression in these models. It is too early, however, to make judgments regarding the clinical impact of the AT-1 receptor antagonists on progression of nondiabetic renal disease. The result of the ELITE trial support the concept that progression of renal dysfunction associated with heart failure is ameliorated to a similar extent between ACE inhibitors and the AT-1 receptor antagonist, losartan. The AT-1 receptor antagonist group also had fewer side effects including the absence of cough as well as a lower, albeit not statistically significant, incidence of hyperkalemia. Thus, the emerging database supports the concept that AT-1 receptor antagonists have an efficacy similar to ACE inhibitors for preserving renal function and morphology in hemodynamically mediated renal injury. It is unclear, however, whether this drug class will reduce immunologically-mediated renal injury.
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PMID:Angiotensin II receptor blockade and progression of nondiabetic-mediated renal disease. 940 25

Many of the pathophysiologic events associated with kidney disease are driven by angiotensin II. Irrespective of the etiology, many kidney diseases lead to tubulointerstitial inflammation, fibrosis and loss of renal function. Contributors to the process of tubulointerstitial fibrosis include monocyte/macrophage infiltration, the synthesis of profibrotic cytokines such as transforming growth factor beta 1 (TGF-beta 1), interstitial myofibroblast proliferation, and clusterin expression. These processes are ameliorated by angiotensin converting enzyme (ACE) inhibition. Blockade of the angiotensin II receptor (AT-1) impaired fibroblast proliferation, consequent differentiation into myofibroblasts, and the synthesis of TGF-beta 1, but did not prevent monocyte infiltration. TGF-beta 1 synthesis or fibroblast proliferation but prevented the differentiation of fibroblasts into myofibroblasts and blocked clusterin expression. The nuclear factor-kappa B (NF-kappa B) family of transcription factors regulates genes involved in inflammation, proliferation and differentiation. ACE inhibition, AT-1 and AT-2 receptor blockade each differentially attenuated NF-kappa B isotype activation. The changes in NF-kappa B isotype may account for the variation seen in the pharmacologic effect of angiotensin II formation or action on the fibrotic process. When considering therapeutic options to prevent renal disease progression, one must be aware of the impact of transcription factors on the injured kidney and the consequent changes in cell infiltration, proliferation and differentiation.
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PMID:Comparative study of ACE inhibitors and angiotensin II receptor antagonists in interstitial scarring. 940 36

Recent studies have provided evidence of angiotensin converting enzyme (ACE)-independent angiotensin (Ang) II formation in tissue renin-angiotensin systems. We studied the effects of Ang II generated by ACE-independent pathways on renal hemodynamics. We used a synthetic peptide, [Pro11, D-Ala12]-Ang I (S), which yields Ang II by chymase, but not by ACE. Infusion of Ang I into a renal artery caused a decrease in renal blood flow, and reciprocally an increase in mean arterial pressure. Infusion of S (1 nmol/kg) caused a decrease in renal blood flow (-20%), but a larger dose was needed to increase mean arterial pressure. Studies with an intravital needle-probe CCD camera revealed that the Ang I infusion induced dose-dependent vasoconstriction of afferent and efferent arterioles (49% and 54%, respectively at 1 nmol/kg). In contrast, infusion of S elicited only 30% constriction of these vessels at a dose of 1 nmol/kg and induced no further constriction at higher doses, indicating that different segments of renal vessels responded in different fashions to Ang II formed via ACE-independent pathways. These vasoconstrictions were abolished by an angiotensin II receptor (AT-1) antagonist. Enzymatic assays using reverse-phase HPLC revealed that the ACE-dependent pathway was predominant in the rena1 cortex (approximately 80%). We also determined Ang II concentrations in renal cortex specimens obtained by needle biopsy. Intrarenal S infusion (10 nmol/kg) increased plasma and renal Ang II concentrations to 160% and 710% of the respective baseline levels. This study provides in vivo evidence of ACE-independent Ang II formation in renal tissue and suggests that this locally-formed Ang II influences the renal circulation in a paracrine fashion.
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PMID:Role of angiotensin II generated by angiotensin converting enzyme-independent pathways in canine kidney. 940 41

The renin-angiotensin system (RAS) has been implicated in the development of hypertensive glomerulosclerosis. However, there are no experimental findings clearly demonstrating activation of glomerular RAS in hypertensive nephropathy. Using the stroke-prone spontaneously hypertensive rat (SHRSP) as an animal model of hypertensive glomerulosclerosis, we examined the relationship between the sequential changes in urinary albumin excretion (UAE), renal morphology, and glomerular mRNA expression for transforming growth factor-beta (TGF-beta) and fibronectin (FN) and glomerular mRNA levels for RAS components, and determined the effects of the angiotensin II (Ang II) type 1 (AT-1) receptor antagonist (candesartan) and equihypotensive hydralazine on these parameters. In SHRSP, UAE was normal at nine weeks of age and increased by 12 weeks. Plasma renin activity, plasma Ang II concentration, and angiotensin converting enzyme (ACE) activity were not higher in 9- and 12-week-old SHRSP than in WKY. RNase protection assay revealed higher glomerular mRNA levels for angiotensinogen, ACE, and AT-1a and AT-1b receptors in 9-, 12-, and 14-week-old SHRSP than in WKY. The glomerular mRNA levels for TGF-beta and FN in SHRSP were increased from nine weeks of age. SHRSP had a greater glomerulosclerosis index (GSI) at 24 weeks of age than did WKY. Administration of candesartan for two weeks, but not of hydralazine, markedly reduced UAE and normalized mRNA levels for TGF-beta, FN, and RAS components. Candesartan administration for 12 weeks virtually prevented the progression of glomerulosclerosis in rats. We conclude that in SHRSP, RAS activation and increased sensitivity to Ang II in glomeruli play important roles in the progression of glomerulosclerosis.
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PMID:Candesartan prevents the progression of glomerulosclerosis in genetic hypertensive rats. 940 67

Angiotensin II, a potent vasoconstrictor, has a key role in renal injury and in the progression of chronic renal disease of diverse causes. In vascular smooth muscle cells, angiotensin II modulates growth, which may lead to hypertrophy and also may inhibit mitogen-stimulated DNA synthesis. The effects of angiotensin II on responsive cells are mediated by two classes of receptors, AT-1 and AT-2. Information obtained in the last decade indicates that angiotensin II increases the production of several autocrine factors, including transforming growth factor beta1 (TGF-beta1), tumor necrosis factor-alpha (TNF-alpha), and platelet-derived growth factor A chain (PDGF). Angiotensin also increases the release of other growth factors such as endothelin, platelet-activating factor (PAF), and interleukin 6. In addition, it increases the "activity" of nuclear factor-kappaB (NF-kappaB) and the synthesis of angiotensinogen. The emerging picture indicates that the actions of angiotensin II may be related to factors that are released or upregulated by angiotensin II, possibly through NF-kappaB activation. It appears likely that many of the effects of angiotensin II on renal disease may be mediated by TGF-beta1, TNF-alpha, and changes in the activity of NF-kappaB. The use of ACE inhibitors or antagonists of AT-1 or AT-2 receptors in experimental animals decreases the levels of angiotensin II or limits its action, thereby interfering with the production and effects of the factors described.
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PMID:Angiotensin II and gene expression in the kidney. 942 70

Insulin resistance and hyperinsulinaemia are presumed to participate in the pathogenesis of essential hypertension (EH). Insulin resistance is characterised by an impaired insulin-mediated glucose uptake. Participation of the renin-angiotensin system in the development of hyperinsulinaemia in EH patients has not been unanimously proven. The present study aimed to asses the influence of antihypertensive therapy with angiotensin converting enzyme inhibitor (ACEI, enalapril = 10 mg/day) (9 male patients) or angiotensin II AT-1 receptor blocker (A II RB = losartan 50 mg/day) (9 male patients) respectively on insulin sensitivity in patients with EH. 3-hours euglycaemic clamp test with constant infusion of insulin (50 mU/m2/min) was performed twice: before and after 8 weeks of therapy with ACEI or A II RB respectively. The control group (CG) consisted of 12 healthy males (clamp test was performed once). Serum insulin concentration (I) was estimated by radioimmunoassay. Glucose disposal rate (M-value = mg/kg/min) and tissue insulin sensitivity (M/I value = mg/kg/min per mU/l) were calculated in subjects of the CG and in patients with EH before and after antihypertensive therapy with ACEI or A II RB, respectively. In CG the M-value (7.38 +/- 0.13) and tissue insulin sensitivity (M/I = = 6.76 +/- 0.19) were significantly higher than in EH before treatment with ACEI (M-value = 5.44 +/- 0.16; M/I = = 4.57 +/- 0.18) or A II RB (M-value = 5.75 +/- 0.21; M/I = 4.77 +/- 0.31), respectively. ACEI therapy was followed by a significant increase of both M (6.82 +/- 0.25) and M/I (5.68 +/- 0.25) values. In contrast to ACEI, treatment with A II RB did not influence neither M (5.75 +/- 0.21) nor M/I (4.79 +/- 0.21) values respectively. In contrast to A II RB, ACEI shows a beneficial effect on insulin sensitivity in EH patients. This effect does not seem to be mediated by an influence on the AT-1 receptor.
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PMID:[The effect of treatment with enalapril versus losartan on levels of insulin resistance in patients with essential hypertension]. 1123 38

Authors describe pharmacotherapy used in the end stage of heart failure (EF 20.5 +/- 4.1%) in routine cardiologic practice in Slovakia, and compare it with pharmacotherapy after the discharge from specialized centers. Medical records of 107 (11 females) were evaluated. At admission vs. discharge, digoxin was prescribed in 94 vs. 91, ACE inhibitors in 86 vs. 94, loop diuretics in 90 vs. 94, AT-1 antagonists in 0 vs. 4, beta blockers in 23 vs. 55. The dosage of ACE inhibitors used in routine practice was rather low.
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PMID:[Pharmacologic therapy of heart failure]. 1172 66

For the treatment of different forms of systemic sclerosis (SSc), drugs play a predominant role. Depending on disease activity as well as type and severity of cutaneous, vascular and internal organ manifestations, different systemic (antiinflammatory, immunosuppressive, antifibrotic) or organ-specific therapies are used. The scientific basis of most treatment modalities is insufficient and incomplete. There is sufficient evidence for an antiinflammatory and antiproliferative efficacy of glucocorticosteroids, methotrexate, cyclophosphamide and cyclosporine A in the treatment of diffuse cutaneous systemic sclerosis. Vasoactive therapies play an important role in treating Raynaud's phenomenon (nifedipine or other dihydropyridines, prostaglandin analogs, losartan, prazosine), and arterial (ACE blockers, AT-1 antagonists) or pulmonary (epoprostenol) hypertension. Cyclophosphamide is effective in fibrosing alveolitis, prokinetic substances (metoclopramid, domperidone) in gastroesophageal dysmotility or octreotide in intestinal pseudoobstruction. Physical therapies (e.g., massage) are poorly studied. In particular cases, surgical measures (e.g., removal of calcifications) are necessary.
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PMID:[Evidence-based therapy of systemic sclerosis]. 1182 42

Type 2 diabetes is a worldwide increasing disease resulting from the interaction between a subject's genetic makeup and lifestyle. In genetically predisposed subjects, the combination of excess caloric intake and reduced physical activity induces a state of insulin resistance. When beta cells are no longer able to compensate for insulin resistance by adequately increasing insulin production, impaired glucose tolerance appears, characterized by excessive postprandial hyperglycemia. Impaired glucose tolerance may evolve into overt diabetes. These 3 conditions, ie, insulin resistance, impaired glucose tolerance, and overt diabetes, are associated with an increased risk of cardiovascular disease. Because all these conditions are also accompanied by the presence of an oxidative stress, this article proposes oxidative stress as the pathogenic mechanism linking insulin resistance with dysfunction of both beta cells and endothelium, eventually leading to overt diabetes and cardiovascular disease. This hypothesis, moreover, may also contribute to explaining why treating cardiovascular risk with drugs, such as calcium channel blockers, ACE inhibitors, AT-1 receptor antagonists, and statins, all compounds showing intracellular preventive antioxidant activity, results in the onset of new cases of diabetes possibly being reduced.
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PMID:Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. 1497 2


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