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)

Recent data suggest that there is interaction between peripheral angiotensin II and nitric oxide. However, sparse information is available on the mutual interaction of these two compounds in the brain. The potential intercourse of nitric oxide with brain neuropeptides needs to be substantiated by assessing its local production and gene expression of the synthesizing enzymes involved. The aim of the present study was to evaluate whether the gene expression of brain nitric oxide synthase (bNOS) is related to the sites of gene expression of different components of the rat brain renin angiotensin system (renin, angiotensin converting enzyme (ACE) or angiotensin receptors of AT1 and AT2 subtypes). The levels of corresponding mRNAs were measured and correlated in nine structures of adult rat brain (hippocampus, amygdala, septum, thalamus, hypothalamus, cortex, pons, medulla and cerebellum). As was expected, positive correlation was observed between renin and angiotensin-converting enzyme mRNAs. Moreover, a significant correlation was found between brain NO synthase and AT1 receptor mRNAs, but not with mRNA of the AT2 receptor, ACE and renin. Parallel distribution of mRNAs coding for bNOS and AT1 receptors in several rat brain structures suggests a possible interaction between brain angiotensin 11 and nitric oxide, which remains to be definitely demonstrated by other approaches.
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PMID:Nitric oxide synthase mRNA levels correlate with gene expression of angiotensin II type-1 but not type-2 receptors, renin or angiotensin converting enzyme in selected brain areas. 1170 51

An accumulating body of evidence strongly indicates a local tissue renin-angiotensin system in the pancreas of a various species. In contrast to the majority of tissues that primarily express the angiotensin type 1 (AT1) receptor, the pancreas is one of the few tissues that contain a significant proportion of the AT2 subtype. Moreover, our findings indicate a greater distribution angiotensin II binding sites in the exocrine pancreas. Although the physiological aspects of a local pancreatic renin-angiotensin system remain largely unexplored, recent studies in our laboratory utilizing an acinar cell model demonstrate both functional AT1 and AT2 receptors. Indeed, we show that the AR42J cell line expresses all components of an angiotensin system including the mRNA for renin, angiotensinogen, angiotensin converting enzyme (ACE), AT1a, AT1b and AT2 receptors. Thus, these cells may be of particular value to study the interplay of the AT1 and AT2 receptors to regulate cell growth and potentially exocrine function.
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PMID:The renin-angiotensin system and the exocrine pancreas. 1186 20

Aldosterone breakthrough during ACE inhibitor therapy has been reported. This study investigates changes in plasma aldosterone concentration (PAC) and its mechanism and effects on target organ damage during long-term angiotensin II type 1 (AT1) receptor antagonist (AT1A) therapy in hypertensive rats. An AT1A (candesartan, 1 mg/kg per day PO) was administered in stroke-prone spontaneously hypertensive rats from 4 weeks of age for 34 weeks. PAC was significantly decreased during the first 4 weeks but showed aldosterone breakthrough after 8 weeks of AT1A administration. Plasma angiotensin II concentration was significantly elevated, whereas no change was seen in plasma ACTH or serum potassium. The mechanism(s) of aldosterone breakthrough were investigated by giving high doses of candesartan (3 mg/kg per day PO), dexamethasone (200 microg/kg per day IP), or the AT2 antagonist (PD123319, 10 mg/kg per day SC) during the last week of the 24-week AT1A treatment period. Dexamethasone and AT2 antagonist but not high-dose AT1A produced a significant decrease in PAC, with a larger decrease produced by the AT2 antagonist. To clarify the effects of the residual aldosterone, effects of coadministration of low-dose spironolactone (10 mg/kg per day SC), an aldosterone antagonist, on left ventricular hypertrophy and expression of brain natriuretic peptide mRNA were determined. Low-dose spironolactone further improved left ventricular hypertrophy and brain natriuretic peptide mRNA expression despite no additional depressor effect. These results suggest that aldosterone breakthrough occurs during long-term AT1A therapy, mainly by an AT2-dependent mechanism. Residual aldosterone may attenuate the cardioprotective effects of AT1A.
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PMID:Aldosterone breakthrough during angiotensin II receptor antagonist therapy in stroke-prone spontaneously hypertensive rats. 1210 34

Angiotensin II (Ang II) acts mainly on two receptor subtypes: AT1 and AT2. Most of the known biological actions of Ang II are mediated by AT1 receptors; however, the role of AT2 receptors remains unclear. We tested the hypothesis that the cardioprotective effects of AT1 receptor antagonists (AT1-ant) after myocardial infarction (MI) are partially mediated by activation of AT2 receptors; thus in AT2 receptor gene knockout mice (AT2-/Y), the effect of AT1-ant will be diminished or absent. MI was induced by ligating the left anterior descending coronary artery. Four weeks later, AT2-/Y and their wild-type littermates (AT2+/Y) were started on vehicle, AT1-ant (valsartan, 50 mg/kg per day), or ACE inhibitor (enalapril, 20 mg/kg per day) for 20 weeks. Basal blood pressure and cardiac function as well as remodeling after MI did not differ between AT2+/Y and AT2-/Y. AT1-ant increased ejection fraction and cardiac output and decreased left ventricular diastolic dimension, myocyte cross-sectional area, and interstitial collagen deposition in AT2+/Y, and these effects were significantly diminished in AT2-/Y. ACE inhibitors improved cardiac function and remodeling similarly in both strains. We concluded that (1) activation of AT2 during AT1 blockade plays an important role in the therapeutic effect of AT1-ant and (2) the AT2 receptor may not play an important role in regulation of cardiac function, either under basal conditions after MI remodeling or in the therapeutic effect of ACE inhibitors.
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PMID:Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. 1221 61

Extracellular signal-regulated kinase 1/2 (ERK1/2) may play a central signaling role in vascular remodeling. We investigated a possible combined role for the renin-angiotensin system and platelet-derived growth factor beta-receptor (PDGF-beta-R) in pressure-induced ERK1/2 activation in intact rat mesenteric small arteries. In an organ culture model, vessels were pressurized (70 mm Hg) for 1 hour plus a 5-minute intervention period. The intervention was either a rise in intraluminal pressure (up to 140 mm Hg) or challenge with angiotensin II (Ang II, 0.1 micromol/L) or PDGF-BB (30 microg/L). ERK1/2 activation was determined by Western blotting as formation of phosphorylated ERK1/2. All interventions caused ERK1/2 activation that was inhibited by the MEK inhibitor PD98059. The response to pressure was inhibited by an ACE inhibitor (perindoprilat), an Ang II receptor type 1 (R-AT1) antagonist (candesartan), and tyrosine kinase inhibitors (genistein, herbimycin A). An R-AT2 antagonist (PD123319) had no significant effect. Both a PDGF-receptor tyrosine kinase inhibitor (RPR101511A) and a neutralizing PDGF-beta-R antibody (AF385) inhibited the activation of ERK1/2 caused by PDGF-BB, Ang II, and pressure. That the latter interventions could indeed inhibit the PDGF-beta-R was supported by experiments with unmounted vessels in which PDGF-beta-R activation was measured by Western blot; both PDGF-BB and Ang II-mediated PDGF-beta-R activation were inhibited by RPR101511A and AF385. Immunohistochemistry showed that ERK1/2 and PDGF-beta-R was located in the adventitia, tunica media, and intima. The results suggest that pressure in rat mesenteric small arteries causes acute activation of ERK1/2 through pathways involving Ang II and PDGF-beta-R.
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PMID:Pressure-induced activation of extracellular signal-regulated kinase 1/2 in small arteries. 1262 63

To examine the possible role of the bradykinin-NO system in the action of ACE inhibitors, we studied the effects of imidapril, an ACE inhibitor, on inflammatory vascular injury by using AT1a-receptor-deficient (AT1aKO) mice. A polyethylene cuff was placed around the femoral artery of AT1aKO mice and wild-type (WT; C57BL/6J) mice. Neointimal area in cross sections of the artery was measured 14 days after cuff placement. A low dose of imidapril (1 mg/kg per day), which did not affect blood pressure, was administered by gavage. Expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR) 7 days after the operation. Neointimal formation, vascular smooth muscle cell proliferation, and expression of MCP-1 and TNF-alpha were attenuated in the injured artery in AT1aKO mice compared with those in WT mice. Imidapril inhibited neointimal formation, DNA synthesis of vascular smooth muscle cells, and expression of MCP-1 and TNF-alpha in AT1aKO mice as well as in WT mice. In addition, imidapril increased tissue cGMP content after cuff placement. These inhibitory effects of imidapril were significantly reduced or abolished by a bradykinin receptor antagonist, Hoechst 140, or an NO synthase inhibitor, L-NAME, both in WT and AT1aKO mice. Treatment with imidapril did not change AT2 receptor and ACE expression detected by RT-PCR in the injured artery. These results indicate that not only blockade of angiotensin II production but also activation of the bradykinin-NO system plays an important role in the beneficial effects of imidapril on vascular remodeling.
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PMID:Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. 1296 79

Reducing the effects of angiotensin II by blockade of AT1-receptors may be superior to inhibition of angiotensin II formation by angiotensin converting enzyme (ACE) inhibitors in chronic heart failure (CHF) patients. However, the results of several trials did not fulfil this expectation. In both ELITE II with symptomatic CHF patients and in OPTIMAAL involving high risk patients after acute myocardial infarction, angiotensin II type I (AT1) receptor blocker (ARB) losartan did not prove to be superior to captopril. There are several potential reasons, why ARBs did not fare better than ACE inhibitors. Although AT1-receptor blockade may block the effects of non-ACE pathways of tissue angiotensin II formation, no clinical evidence is available that a more powerful inhibition of the tissue renin-angiotensin system brings improved survival. The choice of patients for clinical trials of HF therapy is not based on the level of neurohumoral activation. Thus, the more effective attenuation of angiotensin II action with ARBs may not bring additional benefits. The potential antiremodeling effect of ARBs through the stimulation of AT2 receptors by angiotensin II could be counterbalanced by a failure of AT1-receptor blockers to enhance bradykinin, nitric oxide and prostacyclin formation with antigrowth properties. Although ACE-inhibitors seem to have slightly better results at present than AT1 blockers in the battle on heart failure patient, future trials will decide which is the definitive winner.
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PMID:ACE-inhibition and angiotensin II receptor blockers in chronic heart failure: pathophysiological consideration of the unresolved battle. 1466 46

Occlusion of the artery of organs results in ischaemia. The opening of occluded artery results in tissue lesion identified as reperfusion injury (RI). Renin-angiotensin system seems to be involved in the RI. In this study we assessed the effects of different doses of two inhibitors of angiotensin converting enzyme (captopril or enalapril) and an angiotensin receptor type 1 (AT1) receptor blocker (losartan) in the RI of the kidney of rats. Female rats of 200-250 g were anaesthetized and used for RI studies. Different doses of captopril (5, 20 and 80 mg/kg), enalapril (1, 4 and 16 mg/kg) and/or losartan (5, 10 and 20 mg/kg) were used (s.c.) 120 min prior to the initiation of RI. Kidneys were removed and checked histologically for the presence and the grading of ischaemic injury. Appropriate controls were used as well, RI produced lesions comparable with that of ischaemia. Different doses of captopril or enalapril prevented these lesions. This is suggestive of the involvement of renin-angiotensin system in the RI. Different doses of losartan failed to prevent RI lesions which suggest that the effect of captopril or enalapril are not mediated through the AT1 receptors. Further studies on the involvement of AT2 receptor or other independent mechanisms are suggested.
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PMID:The preventive effect of captopril or enalapril on reperfusion injury of the kidney of rats is independent of angiotensin II AT1 receptors. 1470 20

It is generally accepted that regulation of blood pressure and sympathetic neurotransmission by angiotensin (Ang) II is brought about through activation of AT1-receptors. Since recent studies demonstrated a high proportion of AT2-receptors in the human heart, the aim of our study was to investigate whether Ang II modulates noradrenaline release also through activation of AT2-receptors in this tissue. Human atrial appendages were prelabeled with [3H]-noradrenaline and electrically field-stimulated. Stimulation-induced outflow of radioactivity was taken as an index of endogenous noradrenaline release. Ang I and II enhanced noradrenaline release in a dose-dependent manner up to 55 and 72%, respectively. These effects were blocked by the selective AT1-receptor antagonists EXP3174 and irbesartan (10 nmol/L). Moreover, the selective AT2-receptor antagonists PD123319 and CGP42112A (0.1 and 1 micromol/L) also inhibited Ang II-induced facilitation of noradrenaline release. Captopril (5 micromol/L) shifted the dose response curve for Ang I less potent to the right than EXP3174 (10 nmol/L). Ang I and II enhanced the stimulation-induced noradrenaline release significantly more potent in tissues of patients pretreated with ACE inhibitors than without. In conclusion, both AT1- and AT2-receptors seem to play a role in Ang II-mediated facilitation of noradrenaline release in the human heart. Chronic treatment with ACE inhibitors appears to affect cardiac sympathetic neurotransmission possibly by upregulation of presynaptic Ang II receptors.
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PMID:AT1 and AT2-receptor antagonists inhibit Ang II-mediated facilitation of noradrenaline release in human atria. 1471 24

It is suggested that vasoconstriction mediated by angiotensin II cleaved from angiotensin I by angiotensin converting enzyme (ACE) is counterbalanced by concomitant formation of vasodilator angiotensin (1-7) by neutral endopeptidase (NEP). Here, we tested this hypothesis using as a bioassay the isolated rat lung perfused with Krebs-Henseleit (KH) solution and ventilated with negative pressures. Addition of angiotensin I (100 nM) into the isolated lung resulted in an immediate increase in pulmonary arterial pressure (Delta PAP) which was not accompanied by a significant change in respiratory lung function or weight of the lung. The Delta PAP response induced by angiotensin I was abolished by an inhibitor of ACE, perindoprilate (1 microM), or by angiotensin type 1 receptor antagonist (losartan, 1 microM) but not by angiotensin type 2 receptor antagonist (PD 123.319, 10 microM) suggesting the involvement of ACE and AT1 (but not AT2) receptors in this response. On the other hand, antagonist of bradykinin receptor B2 (icatibant, 100 nM) or an inhibitor of neutral endopeptidase, thiorphan (1 microM and 10 microM) did not modify DeltaPAP response induced by angiotensin I. In summary, in the isolated rat lung perfused with KH solution, ACE has a dominant role in the pulmonary conversion of angiotensin I to angiotensin II, while NEP-derived angiotensin 1-7 does not seem to constitute a major counterbalancing mechanism in the pulmonary vasoconstriction induced by endogenously formed angiotensin II.
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PMID:Effect of neutral endopeptidase inhibition on vascular response induced by exogenous angiotensin I in the isolated rat lung. 1473 Jan 3


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