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)

Kinins and prostaglandins of the E series (PGE) have the capacity to influence renal hemodynamic and excretory events and may interact intrarenally so as to reinforce one another. Thus, in the isolated Krebs-perfused rabbit kidney we showed that addition of either bradykinin or kininogen to the perfusing fluid augments the release of a PGE-like substance and that aprotinin, a kallikrein inhibitor, reduces the release of prostaglandins evoked by kininogen but not by bradykinin. Moreover, we have observed that deoxycorticosterone, an agent which increases urinary kallikrein, enhances the urinary excretion of PGE-like substance, and that this effect is prevented by simultaneous treatment with aprotinin. These observations and our demonstration that enhanced intrarenal activity of the kallikrein-kinin system, consequent to kininase II inhibition, is associated with renal vasodilation, diuresis, and natriuresis, suggest that a coupling of kinins and prostaglandins intrarenally may be directed towards the facilitation of salt-water excretion. The interdigitation of prostaglandins and the kallikrein-kinin system may thereby constitute the essential operation of a regulatory system in which the complementary actions of these hormones antagonize the sodium retaining effect of mineralocorticoids in those states in which salt-water balance is positive.
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PMID:Interaction of mineralocorticoids, renal prostaglandins and the renal kallikrein-kinin system. 76 63

Bradykinin is very efficiently inactivated on passage through the pulmonary circulation by enzymes on the vascular walls. Several different cleavages of the bradykinin molecule have been observed; one appears to be due to angiotensin converting enzyme. Several types of inhibitors have been useful in the study of these pulmonary peptidases and have helped increase understanding of the functioning of the angiotensin and plasma kinin systems.
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PMID:Inactivation of bradykinin the plumonary circulation. 96 47

Exsanguinated rat liver preparations perfused in situ with oxygenated saline solutions inactivated recirculating bradykinin (BK) at rates of 2.3 to 9.1 and isoleucyl5 angiotensin II (AII) at rates of 2.8 to 15.0 nmoles X min-1 X g-1 of liver, depending on the initial concentration of the peptides in the perfusion fluid (3.1 to 18.9 X 10(-6) M for BK and 8.5 to 17.0 X 10(-6) M for AII). On the other hand, at similar concentrations, recirculation of isoleucyl5 Angiotensin I (AI) for 8 min did not lead to decrease of its biological activity when assayed on the isolated rat uterus. Following a single passage through liver, picomole amounts of both BK and AII were inactivated by about 90% as revealed by assays on a superfused rat uterus. The potency ratio AI:AII, assayed on a superfused rat uterus was 1:22 and changed to 1:5 following a single passage of both peptides through liver. This finding and the separation of 4.9% of AII on carboxymethylcellulose columns following recirculation of AI through rat liver indicate a conversion of AI into AII. The dipeptides Phe-Arg, Ser-Pro and Gly-Phe were identified among the hydrolysis products of perfused BK. A peptidyldipeptide hydrolase (EC 3.4.15) may be responsible for both the BK inactivation and AI conversion. The inactivation of AII cannot be attributed to the same enzyme.
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PMID:Catabolism of vasoactive polypeptides by perfused rat liver. 100 40

In the present study, the synthesis and degradation of several potent vasoactive substances influencing coronary resistance were characterized in the isolated perfused rabbit heart. Prostaglandin synthetase activity, angiotensin converting enzyme activity, and bradykininase activity (without angiotensinase) were observed. A prostaglandin E2-like substance appeared to be the ednogenous mediator of the coronary vasodilation produced by bradykinin and angiotensin II (AII). (1) The concentration of this prostaglandinlike substance in the coronary venous effluent was directly proportional to the concentration of the coronary vasocilator stimulus (bradykinin or AII). (2) The prostaglandinlike substance released and the coronary dilation produced by the agonists correlated temporally and quantitatively. (3). Abolition of cardiac biosynthesis of the prostaglandinlike substance by indomethacin also abolished the decrease in coronary resistance produced by the agonists. AII, the most potent naturally occurring vasoconstrictor substance, produced a paradoxical coronary vasodilation because it stimulated cardiac prostaglandin biosynthesis, but the direct coronary vasoconstrictor action of AII could be readily unmasked by indomethacin, which blocks prostaglandin synthesis. The nonapeptide SQ-20881 blocked cardiac biosynthesis of AII (from angiotensin I) and enhanced the coronary vascular effects of bradykinin by interfering with bradykininase activity. Similarly, the AII-receptor antagonist, 1-Sar-8-Ile-AII, blocked the coronary vascular effect of AII.
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PMID:Hormone interactions in the isolated rabbit heart. Synthesis and coronary vasomotor effects of prostaglandins, angiotensin, and bradykinin. 119 72

The relative contribution of nitric oxide (NO) and cyclo-oxygenase products in the dilator response to equieffective doses of acetylcholine (ACh) and bradykinin (Bk) was studied in the isolated, saline-perfused rabbit heart under constant flow conditions. ACh (1 microM) and Bk (10 nM) induced a similar vasodilation, with a maximum reduction in coronary perfusion pressure (CPP) of 27 +/- 2%. The vasodilation induced by both agonists was associated with an enhanced release of 6-keto-PGF1 alpha from the coronary bed, with the Bk-induced increase in 6-keto-PGF1 alpha being threefold greater than that induced by ACh. The angiotensin converting enzyme (ACE) inhibitor ramiprilat (0.3 microM) selectively enhanced both the 6-keto-PGF1 alpha outflow and the dilator response to Bk. The B2-receptor antagonist Hoe 140 (0.1 microM) blocked both Bk effects. The cyclo-oxygenase inhibitor diclofenac (1 microM) halved the dilator response to Bk, but did not affect the vasodilation to ACh. Both agonists induced the release of NO, as assessed by the increase in cyclic GMP content of platelets passing through the vascular bed. However, ACh induced a 2.5-fold greater increase in platelet cyclic GMP content, compared to Bk. Treatment of hearts with NG-nitro-L-arginine (L-NNA, 30 microM) halved the ACh- and Bk-induced maximum reduction in CPP. Combined infusion of L-NNA and diclofenac completely blocked the dilator response to Bk, and inhibited the vasodilation to ACh more efficiently than L-NNA alone. We conclude that both NO and PGI2 contribute to the coronary dilator response to Bk and ACh in the rabbit Langendorff heart.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostacyclin and nitric oxide contribute to the vasodilator action of acetylcholine and bradykinin in the intact rabbit coronary bed. 128 Jul 23

The role of angiotensin-converting enzyme (ACE), neutral endopeptidase 24.11 (NEP), and other peptidases in the endothelial degradation of bradykinin was investigated in cultured human umbilical vein endothelial cells (HUVEC). The major part of the kininase II activity on intact cells was attributed to ACE activity, the minor part to NEP activity. Amastatin, as aminopeptidase inhibitor, and DL-2-mercaptomethyl-3-guanidinoethyl-thiopropionic acid (MGTA), an inhibitor of kininase I, did not affect endothelial kininase activity. The decline of the bradykinin concentrations in the supernatant of intact endothelial monolayer indicated a total kininase activity of 289 +/- 27 fmol/min/dish. The calculated activity of ACE was 223 fmol/min/dish and the neutral endopeptidase activity was 51 fmol/min/dish. Thus, ACE and neutral endopeptidase are the main kininases in the degradation of bradykinin by intact endothelial cells. In contrast to the intact endothelial monolayers, in homogenates additional kininase activity was found which was not affected by either ACE and NEP inhibitors nor by amastatin and MGTA.
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PMID:Bradykinin degrading activity in cultured human endothelial cells. 128 24

Because converting enzyme and kininase II are identical enzymes and probably influence both the biosynthesis of angiotensin II and the metabolism of bradykinin, we investigated the effects of bradykinin and desArg-bradykinin on the sympathetic outflow of pithed spontaneously hypertensive rats (SHRs) before and after acute or chronic inhibition of the converting enzyme by ramipril. Sympathetic outflow was induced by preganglionic electrical stimulation of the spinal cord and measured as circulating, stimulation dependent norepinephrine and epinephrine by high-performance liquid chromatography (HPLC) and electrochemical detection. Bradykinin increased dose-dependently norepinephrine and epinephrine release, particularly when converting enzyme was inhibited. DesArg-bradykinin did not influence norepinephrine outflow but caused a dose-dependent increase in epinephrine release only after converting-enzyme inhibition. It is suggested that both bradykinin and desArg-bradykinin could compensate for the lack of effect of angiotensin II on sympathetic outflow.
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PMID:Changes in peripheral sympathetic outflow of pithed spontaneously hypertensive rats after bradykinin and DesArg-bradykinin infusions: influence of converting-enzyme inhibition. 128 27

Bradykinin is susceptible to degradation by a variety of endo- and exopeptidases. These include aminopeptidase P, meprin, endopeptidase 24.15, prolyl endopeptidase, neutral endopeptidase 24.11, angiotensin I-converting enzyme, carboxypeptidase N, carboxypeptidase M, and deamidase. These peptidases are widely distributed in various tissues and cells in the body, and their subcellular locations vary as well. Because bradykinin is inactivated (for binding the B2 receptor) when any of its peptide bonds are cleaved, all of these enzymes qualify as potential "kininases" in vivo; however, the importance of a particular enzyme as a kininase will depend on its localization, access to bradykinin, and the presence of other peptidases. In addition, these peptidases can cleave a variety of other peptide hormone substrates. Determination of the importance of a peptidase in the inactivation of bradykinin during a particular physiological response can be difficult, but specific peptidase inhibitors and kinin receptor antagonists are useful tools in investigating these questions.
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PMID:Bradykinin-degrading enzymes: structure, function, distribution, and potential roles in cardiovascular pharmacology. 128 29

The cardiovascular effects of bradykinin require additional vasoactive mediators for a fully balanced response. This includes arachidonic acid (eicosatetraenoic acid) and its metabolites, the eicosanoids (prostaglandins, leukotrienes, thromboxanes, and others). Eicosanoid generation by bradykinin is started by binding of the peptide to specific B2 receptors at the plasma membrane. This initiates G-protein coupled stimulation of phospholipase C, IP3-induced increases in cytosolic Ca2+, and stimulation of protein kinase C. Arachidonic acid is liberated from membrane phospholipids primarily via Ca(2+)-induced stimulation of phospholipase A2 and converted into tissue-specific eicosanoids by enzymes in the vicinity. In vascular tissue, most of the available arachidonic acid is converted into vasodilator prostaglandins, i.e., prostacyclin (PGI2) and prostaglandin E2 (PGE2). These prostaglandins are involved in vasodilator actions of the kinins. There is also some evidence for generation of vasoconstrictor eicosanoids, such as thromboxane A2, under certain conditions. The biological significance of kinin-related prostaglandin formation becomes apparent after inhibition of kinin breakdown by ACE inhibitors. These compounds prevent generation of vasoconstrictor angiotensin II and stimulate endothelial eicosanoid formation via local kinin accumulation. There is evidence suggesting that kinin-induced prostaglandin generation contributes to anti-ischemic, inotropic, and blood pressure-lowering effects of the compounds. This also includes inhibition of polymorphonuclear leukocyte (PMN) accumulation in injured myocardial tissue, which is antagonized by PGI2-related pathways, stimulated by ACE inhibition and/or bradykinin.
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PMID:Role of prostaglandins in the cardiovascular effects of bradykinin and angiotensin-converting enzyme inhibitors. 128 33

Angiotensin-converting enzyme (ACE) inhibitors exert their beneficial effects not only via endocrine mechanisms, but most probably also via interference with autocrine-paracrine actions involving local renin-angiotensin and kallikrein-kinin systems with subsequent autacoid release. Inhibition of ACE (kininase II) results in the reduction of angiotensin II generation and kinin degradation, leading to beneficial cardiovascular effects. Bradykinin and prostacyclin release from isolated rat hearts was increased by local ACE inhibitions with ramiprilat. In different models the bradykinin-mediated effects of ACE inhibition were abolished with the specific B2 kinin-receptor antagonist Hoe 140: The cardioprotective effects of ramiprilat or ramipril such as reduction of postischemic reperfusion injuries in isolated rat hearts or the reduction in infarct size in dogs and rabbits were abolished by coadministration of Hoe 140. Furthermore, left ventricular hypertrophy in rats with aortic banding could be prevented or regression was induced when the ACE inhibitor was given in a non-blood pressure-lowering dose. These beneficial effects were also abolished by Hoe 140. In conclusion, in different experimental models, ACE inhibitors exert cardioprotective effects. An enhancement of endothelial autacoid formation (nitric oxide and prostacyclin) by inhibiting degradation of bradykinin may contribute to these effects.
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PMID:Role of bradykinin in the cardiac effects of angiotensin-converting enzyme inhibitors. 128 35


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