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)

The endothelium controls vascular smooth muscle tone by secreting relaxing and contracting factors. There is a constant release of endothelium-derived relaxing factors (EDRFs) under basal conditions. In addition, the endothelium can increase the release of EDRFs in response to humoral stimulation by vasoactive substances such as acetylcholine or bradykinin. Under physiological conditions, the most important stimulus to the release of EDRFs is an increase in blood flow leading to increased shear stress on endothelial cells. Recent experimental studies raised the possibility that bradykinin plays an important role in the regulation of vascular tone at rest and during flow-stimulated conditions. Bradykinin is a very potent vasodilator that exerts its vasodilatory actions by causing endothelial release of nitric oxide, prostacyclin and/or a hyperpolarising factor [endothelium-derived hyperpolarising factor (EDHF)]. This concept is also supported by recent studies in humans demonstrating that bradykinin contributes to the regulation of coronary vascular tone under resting and flow-stimulated conditions. This mechanism has now been shown to be important in both human peripheral and coronary arteries. Angiotensin converting enzyme (ACE) inhibitors not only reduce angiotensin II, but also increase bradykinin levels, since the angiotensin converting enzyme is identical to kininase II, an enzyme that degrades bradykinin. This raises the possibility that beneficial vascular effects of ACE inhibitors may be related to increased availability of bradykinin. Indeed, we have recently shown that ACE inhibition improves flow-dependent, endothelium-mediated vasodilation and that this beneficial effect of ACE inhibition is bradykinin dependent. These findings raise the possibility that the beneficial effects of ACE inhibition in heart failure and coronary artery disease might be partly due to improved endothelial function.
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PMID:Endothelial function and bradykinin in humans. 942 44

Bradykinin-induced responses were studied in isolated porcine iliac arteries. Relaxation was endothelium dependent and seen at low concentrations (10(-10)-10(-8) M) of bradykinin. It was inhibited by the bradykinin B2-receptor antagonist icatibant (HOE-140) and by the nitric oxide synthase inhibitor Nomega-nitro-L-arginine. Bradykinin-induced relaxation was significantly potentiated by the kininase I carboxypeptidase inhibitor mergepta (10(-6) M). Bradykinin (>10(-7) M) elicited contraction of preparations with or without endothelium. The contraction was abolished by indomethacin but was not affected by the thromboxane A2/prostaglandin H2-receptor antagonist SQ 29,548. Icatibant and the bradykinin B1-receptor antagonist desArg9[Leu8]bradykinin significantly decreased bradykinin-induced contraction regardless of endothelial function. The contraction also was decreased by treatment with mergepta. The bradykinin B1-receptor agonist desArg9-bradykinin contracted endothelium-denuded arterial strips. This contraction was significantly decreased by desArg9[Leu8]bradykinin but not by icatibant. The desArg9-bradykinin-induced contraction also was inhibited by the protein-synthesis inhibitor cycloheximide. Neither bradykinin-induced relaxation nor contraction was affected by the ACE inhibitors enalaprilat or cilazaprilat. In conclusion, bradykinin-induced relaxation of isolated porcine iliac arteries was mediated by endothelial bradykinin B2 receptors and mainly nitric oxide. Bradykinin-induced contraction was endothelium independent, indomethacin sensitive, and probably mediated by bradykinin B1 (inducible) and B2 receptors located in the vascular smooth-muscle layer. Kininase I carboxypeptidase, and not ACE, is the main enzyme responsible for bradykinin degradation in these vessels.
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PMID:Biphasic response to bradykinin in isolated porcine iliac arteries is mediated by bradykinin B1 and B2 receptors. 947 74

The coronary circulation is controlled by the central nervous system, circulating hormones and local vascular mechanisms. The importance of local regulatory mechanisms has only recently been recognized. The endothelium is in a strategical anatomical position within the blood vessel wall located between the circulating blood and vascular smooth muscle cells. It can respond to mechanical and hormonal signals from the blood; of particular importance is the fact that it is a source of mediators which can modulate the contractile state and proliferative responses of vascular smooth muscle cells, platelet function and coagulation as well as monocyte adhesion. Important relaxing factors are nitric oxide and prostacyclin and a putative hyperpolarizing factor. Nitric oxide also inhibits smooth muscle proliferation and, together with prostacyclin, platelet adhesion and aggregation. Bradykinin-induced nitric oxide production is regulated by angiotensin converting enzyme located on the endothelial cell membrane; indeed, the enzyme not only activates angiotensin I into angiotensin II, but also inactivates bradykinin. Endothelin-1 and thromboxane A2 and prostaglandin H2 are contracting factors produced by the endothelium. In contrast to thromboxane A2 and prostaglandin H2 which activate platelets, endothelin has no direct effects on these cells, but has proliferative properties in vascular smooth muscle. Under physiological conditions, the endothelium plays a protective role as it prevents adhesion of circulating blood cells, keeps the vasculature in a vasodilated state and inhibits vascular smooth muscle proliferation. In disease states, however, endothelial dysfunction contributes to enhanced vasoconstrictor responses, adhesion of platelets and monocytes and proliferation of vascular smooth muscle cells, events all known to occur in coronary artery disease. Nitrates substitute in part for deficient endogenous nitric oxide, while angiotensin converting enzyme inhibitors increase the bradykinin induced nitric oxide and prostacyclin production. The newly developed endothelin antagonists allow specific blocking of the effects of endothelin. Pharmacological correction of endothelial dysfunction may be important to treat coronary artery disease and its complications.
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PMID:The endothelium in acute coronary syndromes. 959 23

The endothelium controls vascular smooth muscle tone by secreting relaxing and contracting factors. There is a constant release of endothelium-derived relaxing factors(s) (EDRF) under basal conditions. In addition, the endothelium can increase the release of EDRF in response to humoral stimulation by vasoactive substances such as acetylcholine or bradykinin. Under physiological conditions the most important stimulus to the release of EDRF is an increase in blood flow, leading to increased shear stress on endothelial cells. Recent experimental studies have raised the possibility that bradykinin plays an important role in the regulation of vascular tone at rest and during flow-stimulated conditions. Bradykinin is a very potent vasodilator that exerts its vasodilatory actions by causing endothelial release of nitric oxide, prostacyclin and/or endothelium-derived hyperpolarizing factor. Recent studies in humans have demonstrated that bradykinin contributes to the regulation of coronary vascular tone under resting and flow-stimulated conditions. This mechanism has been shown to be important in humans in both peripheral and coronary arteries. Angiotensin-converting enzyme (ACE) inhibitors not only decrease angiotensin II but also increase bradykinin levels, since ACE is identical to kininase II, which degrades bradykinin. The beneficial vascular effects of ACE inhibitors may therefore be related to increased availability of bradykinin. Indeed, we have recently shown that ACE inhibition improves flow-dependent, endothelium-mediated vasodilation and that this beneficial effect is bradykinin-dependent. Our preliminary data also indicate that ACE inhibition improves endothelium-mediated vasodilation in patients with heart failure and coronary artery disease due to an enhanced availability of nitric oxide. These findings suggest that the beneficial vascular effects of ACE inhibition in heart failure may be due in part to improved endothelial function.
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PMID:Effect of ACE inhibition on endothelial dysfunction in patients with chronic heart failure. 971 56

Angiotensin II is able to modulate both the presynaptic sympathetic system and the adrenal medulla resulting in an enhanced release of noradrenaline and adrenaline. Consequently, the inhibition of the converting enzyme by ACE inhibitors resulting in a lower concentration of angiotensin II or blockade of the specific AT1 receptors by AT1 receptor blocking agents should lead to a decrease in both noradrenaline and adrenaline release. It has been demonstrated that ACE inhibition did not influence the net catecholamine overflow during stimulation of the sympathetic nerves in contrast to AT1 antagonists which can specifically and dose dependently diminish noradrenaline and adrenaline release, an effect that could be explained by a compensating mechanism of bradykinin. Bradykinin may accumulate during ACE inhibition and is able to stimulate catecholamine release via B2 receptors. To verify the class effect of AT1 antagonists on presynaptic AT1 receptors, the AT1 antagonist candesartan was investigated regarding its presynaptic effect in pithed spontaneously hypertensive rats. As could be demonstrated with losartan and HR 720, candesartan lowered AT1 receptor mediated angiotensin II-induced noradrenaline release in a dose-dependent manner. It is concluded that AT1 antagonists inhibit angiotensin II mediated catecholamine release on presynaptic sympathetic nerves and the adrenal medulla at the specific AT1 receptor site. The effect can be described as a class effect of these imidazole derivatives.
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PMID:Interactions between the renin-angiotensin system (RAS) and the sympathetic system. 983 58

1. Subcutaneous injection of sodium deoxycholic acid into the anterior of the back of male ddY mice elicited dose-dependent scratching of the injected site with the forepaws and hindpaws. 2. Up to 100 microg of sodium deoxycholic acid induced no significant increase in vascular permeability at the injection site as assessed by a dye leakage method. 3. Bradykinin (BK) B2 receptor antagonists, FR173657 and Hoe140, significantly decreased the frequency of scratching induced by sodium deoxycholic acid. 4. Treatment with aprotinin to inhibit tissue kallikrein reduced the scratching behaviour induced by sodium deoxycholic acid, whereas treatment with soybean trypsin inhibitor to inhibit plasma kallikrein did not. 5. Although injection of kininase II inhibitor, lisinopril together with sodium deoxycholic acid did not alter the scratching behaviour, phosphoramidon, a neutral endopeptidase inhibitor, significantly increased the frequency of scratching. 6. Homogenates of the skin excised from the backs of mice were subjected to gel-filtration column chromatography followed by an assay of kinin release by trypsin from each fraction separated. Less kinin release from the fractions containing kininogen of low molecular weight was observed in the skin injected with sodium deoxycholic acid than in normal skin. 7. The frequency of scratching after the injection of sodium deoxycholic acid in plasma kininogen-deficient Brown Norway Katholiek rats was significantly lower than that in normal rats of the same strain, Brown Norway Kitasato rats. 8. These results indicate that BK released from low-molecular-weight kininogen by tissue kallikrein, but not from high-molecular-weight kininogen by plasma kallikrein, may be involved in the scratching behaviour induced by the injection of sodium deoxycholic acid in the rodent.
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PMID:Reduction of sodium deoxycholic acid-induced scratching behaviour by bradykinin B2 receptor antagonists. 1005 Nov 36

Bradykinin potentiating peptides usually show two different activities, potentiation of bradykinin and inhibition of angiotensin converting enzyme (ACE). Exceptions of this rule have been found suggesting that both effects occur independently. This study of peptide F by means of NMR spectroscopy shows clearly two different main conformations of the molecule. These different conformations may be the reason for the different activities.
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PMID:Spatial structures of the bradykinin potentiating peptide F from Agkistrodon piscivorus piscivoris venom. 1008 65

The dextran-sulfate cellulose (DSC) column used for low-density lipoprotein (LDL) apheresis adsorbs plasma constituents other than LDL that have the following characteristics: proteins containing apolipoprotein B, proteins involved in the initial contact phase of the intrinsic coagulation pathway (coagulation factor XII, high molecular weight kininogen and prekallikrein), factors with lipophilic characteristics (coagulation factor VII, VIII, and vitamin E), and proteins with adhesive or other characters (von Willebrand factor, fibronectin, and serum amyloid P components). Adsorption of these proteins seems to serve in the prevention or regression of atherosclerosis. Moreover, plasma treatment by the DSC column may be useful for treatment of such inexorable diseases as amyloidosis. On the other hand, the column generates bradykinin by activation of the initial contact phase of the intrinsic coagulation pathway. Bradykinin generation may explain hypotension during LDL apheresis observed in patients taking angiotensin converting enzyme (ACE) inhibitors.
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PMID:Plasma constituents other than low-density lipoprotein adsorbed by dextran-sulfate column. 1022 21

Background-Our objective for this study was to investigate whether nitric oxide (NO) modulates tissue respiration in the failing human myocardium. Methods and Results-Left ventricular free wall and right ventricular tissue samples were taken from 14 failing explanted human hearts at the time of transplantation. Tissue oxygen consumption was measured with a Clark-type oxygen electrode in an airtight stirred bath containing Krebs solution buffered with HEPES at 37 degrees C (pH 7.4). Rate of decrease in oxygen concentration was expressed as a percentage of the baseline, and results of the highest dose are indicated. Bradykinin (10(-4) mol/L, -21+/-5%), amlodipine (10(-5) mol/L, -14+/-5%), the ACE inhibitor ramiprilat (10(-4) mol/L, -21+/-2%), and the neutral endopeptidase inhibitor thiorphan (10(-4) mol/L, -16+/-5%) all caused concentration-dependent decreases in tissue oxygen consumption. Responses to bradykinin (-2+/-6%), amlodipine (-2+/-4%), ramiprilat (-5+/-6%), and thiorphan (-4+/-7%) were significantly attenuated after NO synthase blockade with N-nitro-L-arginine methyl ester (10(-4) mol/L; all P<0.05). NO-releasing compounds S-nitroso-N-acetyl-penicillamine (10(-4) mol/L, -34+/-5%) and nitroglycerin (10(-4) mol/L, -21+/-5%), also decreased tissue oxygen consumption in a concentration-dependent manner. However, the reduction in tissue oxygen consumption in response to S-nitroso-N-acetyl-penicillamine (-35+/-7%) or nitroglycerin (-16+/-5%) was not significantly affected by N-nitro-L-arginine methyl ester. Conclusions-These results indicate that the modulation of oxygen consumption by both endogenous and exogenous NO is preserved in the failing human myocardium and that the inhibition of kinin degradation plays an important role in the regulation of mitochondrial respiration.
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PMID:Nitric oxide modulates mitochondrial respiration in failing human heart. 1049 73

Angiotensin-converting enzyme (ACE) inhibitor associated angioedema was detected in 39 subjects (17%) of 231 consecutive patients examined in the last 5 years at our out-patient clinic for symptoms of angioedema without urticaria. In these patients, angioedema was most commonly localized to the face. The duration of ACE-inhibitor treatment at the onset of angioedema ranged from 1 day to 8 years with a median of 6 months. The time elapsed between onset of angioedema and withdrawal of ACE-inhibitor ranged from 1 day to 10 years with a median of 10 months. Delayed diagnosis is explained by the unusual characteristics of this adverse reaction: angioedema may start years after beginning the treatment and then it recurs irregularly. In fact, ACE-inhibitors seem to facilitate angioedema in predisposed subjects, rather than causing it with an allergic or idiosyncratic mechanism. Thus, while Cl-inhibitor levels are usually normal in subjects developing ACE-inhibitor-dependent angioedema, we found that ACE-inhibitors caused angioedema in Cl-inhibitor-deficient patients. Because the main inactivator of bradykinin is kininase II, which is identical with ACE, it is believed that bradykinin mediates ACE-inhibitor-dependent angioedema. We had the possibility to examine the plasma bradykinin levels in one ACE-inhibitor-treated patient during an angioedema attack and we found very high levels, but we did not find an increase of break-down products of high-molecular-weight-kininogen as observed during acute attacks in hereditary angioedema. Bradykinin fell to normal levels during remission after withdrawal of the drug. These observations indicate that in ACE-inhibitor-induced angioedema, contrary to hereditary angioedema, the reduction of bradykinin catabolic rate plays a predominant role.
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PMID:Angioedema due to angiotensin-converting enzyme inhibitors. 1060 20


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