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 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

The action of a kinin-potentiating peptide (KPP) obtained from tryptic digestion of human serum proteins was compared with that of bradykinin-potentiating peptide 9a (BPP9a; obtained from snake venom) and enalaprilat (a synthetic inhibitor of angiotensin-converting enzyme; ACE) as a means of understanding the mechanism of action of KPP on smooth muscle. KPP potentiated bradykinin-induced contractile effects in guinea-pig ileum and rat uterus, but not the bradykinin-induced relaxation of pre-contracted ileum, whereas BPP9a and enalaprilat potentiated both bradykinin effects. The receptor mediating both the contraction and the relaxation elicited by bradykinin in the ileum was found to be of the B2 type. KPP retained its potentiating effect in the presence of enalaprilat in the guinea-pig ileum and rat uterus, whereas the potentiation evoked by BPP9a was abolished. Enalaprilat inhibited the activity of purified ACE, whereas KPP was completely devoid of such an effect. The potentiating effect of KPP, but not that of BPP9a or enalaprilat, was blocked by compounds that inhibit phospholipase A2 and lipoxygenase activity but not by inhibitors of cyclo-oxygenase or phosphodiesterases. The results suggest that the potentiating effect of KPP (i) does not involve inhibition of ACE; (ii) is not due to an increased affinity of the receptor for bradykinin, and (iii) probably involves post-receptor events linked to phospholipase A2 and to the lipoxygenase pathway.
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PMID:Comparative study on the mechanism of bradykinin potentiation induced by bradykinin-potentiating peptide 9a, enalaprilat and kinin-potentiating peptide. 133 May 81

1. This study was designed to investigate whether the angiotensin converting enzyme (ACE) inhibitors, captopril, enalapril and fosinopril have a dose-dependent effect on the production of prostaglandin E2 (PGE2), prostaglandin I2 (prostacyclin, PGI2) and thromboxane A2 (TxA2) by glomeruli isolated from normotensive Wistar-Kyoto rats. 2. Measurements of glomerular prostanoid production were made under basal conditions and in the presence of excess exogenous arachidonic acid. 3. All three ACE inhibitors demonstrated dose-dependent effects upon glomerular prostanoid production which varied with the individual ACE inhibitor. 4. Enalapril induced a dose-dependent increase in the ratio of (PGE2 + PGI2)/TxA2, from 2.17 +/- 0.20 to 5.35 +/- 0.84 and to 10.0 +/- 1.16 with the low and high doses of enalapril respectively. In contrast, the high dose of captopril tended to reduce the ratio when compared to the low dose. 5. The results obtained in this study suggest that although all three ACE inhibitors appear to induce prostacyclin synthetase and/or modulate phospholipase A2 (PLA2) activity, these effects differ with the ACE inhibitor studied and the dose employed. 6. This study has demonstrated dose-dependent effects of three ACE inhibitors on glomerular prostanoid production which may be significant in modulating glomerular haemodynamics and growth characteristics of glomerular cells.
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PMID:Dose-dependent effects of angiotensin converting enzyme (ACE) inhibitors on glomerular prostanoid production by normotensive rats. 844 84

Bradykinin is a mediator of the protection of myocardium by angiotensin I-converting enzyme/kininase II inhibitors. We reported that the activation of B2 bradykinin receptors in neonatal rat cardiac myocytes in primary culture was followed by hydrolysis of phosphatidylinositol 4,5-bisphosphate and formation of inositol 1,4,5-trisphosphate (IP3). Here we examine the regulation of IP3 formation stimulated by bradykinin. Activation of myocytes with 1 mu/L bradykinin increased IP3 production from 117 +/- 8.3 to 1011 +/- 48.6 pmol/mg protein. Treatment of the cells with 10 mu/L indomethacin or 1 mu/L dexamethasone partially blocked this bradykinin-induced response. Moreover, either U73122, a phospholipase C inhibitor, or (p-amylcinnamoyl) anthranilic acid, a phospholipase A2 inhibitor, blunted the IP3 response to bradykinin. Because thromboxane A2 stimulates inositol bisphosphate metabolism in guinea pig atria, we also investigated the effect of the thromboxane A2 receptor antagonist BM 13177 (1 mu/L), which strongly attenuated the stimulated IP3 production. Since thromboxane A2 appears to partly mediate the IP3 response to bradykinin, we examined the effect of the stable thromboxane A2 mimetic U46619. Control cultures were stimulated more by U46619 than by bradykinin (1629 +/- 14.5 versus 1011 +/- 48.6 pmol IP3/mg protein). This property of U46619 was selectively antagonized by BM 13177. Inhibition of either phospholipase C or phospholipase A2 blunted the IP3 response to U46619. Short-term (30 minutes) activation of protein kinase C with phorbol 12-myristate 13-acetate (10 pmol/L to 1 mu/L) attenuated the IP3 accumulation in response to bradykinin; the effect of phorbol 12-myristate 13-acetate was reversed with 1 mu/L staurosporine, a protein kinase C inhibitor. Treatment with 1 microgram/mL cholera toxin or pertussis toxin for 4 hours amplified the IP3 response to 10 nmol/L bradykinin from 570 +/- 20.0 to 1150 +/- 51.3 and to 1016.7 +/- 21.9 pmol/mg protein. Bradykinin mobilized 9.4% of intracellular calcium stores in cardiomyocytes as assessed by chlortetracycline-based fluorometry, and this effect of bradykinin was blocked by BM 13177 or the B2 bradykinin receptor blocker Hoe 140 by more than 70%. In functional studies, bradykinin (1 mu/L) increased by 12% the twitch contractile force of neonatal rat ventricular strips paced at threshold intensity, but this was unaffected by BM 13177. In conclusion, in cardiomyocytes, bradykinin enhances IP3 production mostly via phospholipase A2 stimulation and thromboxane A2 formation. This prostanoid in turn stimulates its receptor and activates phospholipase C, which then splits phosphatidylinositol 4,5-bisphosphate into IP3 and diacylglycerol. The effect of bradykinin on phospholipase C, via thromboxane A2, is negatively regulated by protein kinase C activation.
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PMID:Thromboxane A2 mediates the stimulation of inositol 1,4,5-trisphosphate production and intracellular calcium mobilization by bradykinin in neonatal rat ventricular cardiomyocytes. 879 31

By means of CM-Sephadex C-25, DEAE-Sephadex A-50, Sephadex G-200, and Sephadex G-75 chromatographies, a lupus anticoagulant like protein (LALP) from Agkistrodon halys brevicaudus was purified. On SDS-PAGE, the purified LALP had a molecular weight of 25,500 daltons under non-reducing condition and 15,000 daltons under reducing condition. The isoelectric point was pH 5.6. Its N terminal amino acid sequencing revealed a mixture of 2 sequences: DCP(P/S)(D/G)WSSYEGH(C/R)(Q/K). It was devoid of phospholipase A, fibrino(geno)lytic, 5'-nucleotidase, L-amino acid oxidase, phosphomonoesterase, phosphodiesterase and thrombin-like activities, which were found in crude venom. In the presence of LALP, PT, aPTT, and dRVVT of human plasma were markedly prolonged and its effects were concentration-dependent but time-independent. The inhibitory effect of LALP on the plasma clotting time was enhanced by decreasing phospholipid concentration in TTI test. The individual clotting factor activity was not affected by LALP when higher dilutions of LALP-plasma mixture were used for assay. Russell's viper venom time was shortened when high phospholipid confirmatory reagent was used. Therefore, the protein has lupus anticoagulant property.
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PMID:Purification and characterization of lupus anticoagulant like protein from Agkistrodon halys brevicaudus venom. 897 23

Accelerated coronary artery disease (CAD) is the leading cause of late mortality following cardiac transplantation. The vascular lesions are characterized by myointimal proliferation and perivascular mononuclear inflammatory infiltrates. Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent phospholipid mediator produced by inflammatory cells and activated endothelial cells. Angiotensin II is known to activate phospholipase A2, a critical enzyme in PAF synthesis. Using a rat heterotopic cardiac transplant model known to induce graft CAD, we previously reported that chronic administration of captopril, an angiotensin converting enzyme inhibitor, reduces intimal proliferation and maintains luminal patency. The purpose of the current study was to determine if captopril regulates vascular remodeling by suppressing PAF synthesis and whether administration of a PAF antagonist ameliorates graft CAD. Captopril was found to decrease levels of PAF and PAF-like compounds as well as reduce intimal lesions, decrease cellular rejection grade, and diminish allograft heart weights. Treatment with a PAF antagonist significantly decreased proliferation of the intimal component of the vasculopathy and caused regression of the cardiac hypertrophy, but had no significant effect on cellular rejection. In contrast, untreated animals had elevated plasma PAF levels, elevated heart weights, and severe myointimal proliferation with luminal stenosis 21 days post-transplantation. These observations suggest that graft CAD is mediated, in part, by PAF and PAF-like compounds, and suppression of endogenous PAF may prevent cardiac allograft vasculopathy.
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PMID:Captopril and platelet-activating factor (PAF) antagonist prevent cardiac allograft vasculopathy in rats: role of endogenous PAF and PAF-like compounds. 1036 92

The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.
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PMID:International union of pharmacology. XXIII. The angiotensin II receptors. 1097 69

Our in vivo assay for thrombolysis consisted of recording the weight of platelet-rich thrombi adhering to a collagen strip that was superfused with arterial blood in extracorporal circulation of anaesthetised Wistar rats. Immediate thrombolysis occurred in response to intravenously administrated angiotensin-converting enzyme inhibitor (ACE-I) at non-hypotensive doses of 3-30 microg kg(-1) (captopril<perindopril<quinapril). The thrombolytic response lasted up to 3 h with maximum reduction of the weight of thrombus by 75%. Pretreatment with COX-1 and COX-3 inhibitors (aspirin at a low dose of 1 mg kg(-1), SC 560 and acetaminophen, 0.3-3 mg kg(-1)) slightly augmented thrombolysis by ACE-I, while COX-2 inhibitors (nimesulide and coxibs at doses <1 mg kg(-1) and aspirin at a high dose of 50 mg kg(-1)) or a kinin B2 receptor antagonist (icatibant) abolished it. NOS inhibition by L-NAME blunted and delayed thrombolysis by ACE-I. In parallel to maximum thrombolysis by quinapril (30 microg kg(-1)), plasma levels of 6-keto-PGF1alpha rose significantly from 40 +/- 7 to 554 +/- 91 pg ml(-1) (n=5, mean +/- S.D.), while basal levels of PGE2 (12 +/- 3 pg ml(-1)) and TXB2 (47 +/- 11 pg ml(-1)) remained essentially unchanged. Pretreatment with celecoxib (0.1-1.0 mg kg(-1)) abolished not only thrombolysis by quinapril but also the quinapril-induced rise in plasma 6-keto-PGF1alpha. In cultured bovine aortic endothelial cells, perindoprilate (30 microM) increased cytosolic free calcium [Ca2+]i, but this effect was by three to four orders of magnitude weaker than that of bradykinin (Bk). In aortas of Wistar rats, the transcripts of COX-2 and PGI-S were overexpressed as compared to COX-1. Thus, in blood vessels of Wistar rats, the preferable route of the PGI2 generation might lead through the COX-2 pathway. We conclude that in Wistar rats, ACE-I induces thrombolysis via accumulation of endogenous kinins over the endothelium and a subsequent activation of B2 receptors followed by the release of prostacyclin and nitric oxide. Thrombolysis by ACE-I seems to be mediated mainly through prostacyclin that is made by COX-2. It may well be that an increase in endothelial [Ca2+]i by ACE-I activates phospholipase A2, which supplies COX-2 with the substrate for making thrombolytic prostacyclin.
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PMID:Mechanisms of angiotensin-converting enzyme inhibitor induced thrombolysis in Wistar rats. 1459 56

In this study we determined whether hypoxia could promote vasoactivator thromboxane (TX) and prostacyclin (PGI2) as well as phospholipase A2 (PLA2) production by placental trophoblast cells (TCs) from normal and preeclamptic (PE) pregnancies. Placentas were obtained immediately after delivery from normal (n=9) and preeclamptic (n=9) pregnancies. TCs were isolated by dispase digestion of villous tissue and purified by Percoll gradient centrifugation. TCs (5x10(6) cells/well) were cultured with Dulbecco's Modified Eagles Medium (DMEM) under hypoxia condition (2% O2/5% CO2/93% N2) for 48 h. TCs cultured under normoxia condition (5% CO2/air) were used as control. Culture medium was collected at the end of incubation. Productions for TX, PGI2 and PLA2 were measured by ACE competitive enzyme immunoassay (EIA). Comparisons were made using the Mann-Whitney U test or paired t-test and the data are expressed as mean+/-SE (pg/microg cellular protein). Significance was set at a p-value of <0.05. We found: (1) PE-TCs produced more TXB2 and PLA2 than normal-TCs under normoxia conditions, TXB2: 4.33+/-1.03 vs. 1.84+/-0.29 pg/microg protein, p<0.05; PLA2: 0.38+/-0.08 vs. 0.21+/-0.03 pg/microg protein, p<0.05, respectively. (2) Hypoxia promoted both PE- and normal-TCs to generate more TXB2 and PLA2, TXB2: 6.36+/-1.72 vs. 3.05+/-0.45 pg/microg; PLA2: 0.52+/-0.10 vs. 0.30+/-0.04 pg/microg, respectively. (3) No change in 6-keto PGF1alpha production was observed for normal-TCs or PE-TCs when compared under normoxia vs. hypoxia condition, normal-TCs: 0.20+/-0.05 vs. 0.21+/-0.05 pg/microg; PE-TCs: 0.38+/-0.05 vs. 0.36+/-0.04 pg/microg, respectively. We concluded that hypoxia promotes both PLA2 and TX, but not PGI2, production by placental trophoblast cells cultured under hypoxia condition. These results suggest that increased PLA2 release may alter the arachidonic acid cascade and promote TX synthesis. Relative hypoxia could contribute to the increase in TX production and result in vasoconstriction in placental vasculature in preeclampsia.
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PMID:Increased phospholipase A2 and thromboxane but not prostacyclin production by placental trophoblast cells from normal and preeclamptic pregnancies cultured under hypoxia condition. 1585 Jun 45

Causal relationship between sodium and hypertension has been proposed and various changes in Na+,K+-ATPase (sodium pump) activity have been described in established primary hypertension. A number of direct vascular effects of estradiol have been reported, including its impact on the regulation of sodium pump activity and vasomotor tone. The effects of estradiol involve the activation of multiple signaling cascades, including phosphatydil inositol-3 kinase (PI3K) and p42/44 mitogen-activated protein kinase (p42/44(MAPK)). In addition, some of the effects of estradiol have been linked to activity of cytosolic phospholipase A(2) (cPLA(2)). One possible cardioprotective mechanism of estradiol involves of the interaction between estradiol and the rennin-angiotensin system (RAS). Elevated circulating and tissue levels of angiotensin II (Ang II) have been implicated in the development of hypertension and heart failure. The aim of our investigation was to elucidate the signaling mechanisms employed by estradiol and Ang II in mediating sodium pump, in vascular smooth muscle cells (VSMC). The aim of our investigation was to elucidate the signaling mechanisms employed by estradiol and Ang II in mediating sodium pump activity/expression in VSMC, with particular emphasis on PI3K/cPLA(2)/p42/44(MAPK) signaling pathways. Our primary hypothesis is that estradiol stimulates sodium pump activity/expression in VSMC via PI3K/cPLA(2)/p42/44(MAPK) dependent mechanism and, that impaired estradiol-stimulated sodium pump activity/expression in hypertensive rodent models (i.e. SHR), Ang II-mediated vascular impairment of estradiol is related to a decrease ability of estradiol to stimulate the PI3K/cPLA(2)/p42/44(MAPK) signaling pathways. An important corollary to this hypothesis is that in hypertensive state (i.e. SHR rats) the decreasing in ACE enzyme activity and/or AT1 receptor expression caused by administration of estradiol is accompanying with abrogated ability of Ang II to decrease IRS-1/PI3K association, and consequent PI3K/cPLA(2)/p42/44(MAPK) activity and associated sodium pump activity/expression. A clear characterization of how Ang II attenuates estradiol signaling may lead to a better understanding of the molecular mechanism(s) underlying pathophysiological conditions such as hypertension and to understanding how certain pathophysiological situations affect sodium pump activity/expression in VSMC.
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PMID:Hypothetical mechanism of sodium pump regulation by estradiol under primary hypertension. 1830 83


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