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)

Rats were exposed for 10 months to 60 ppm of Pb (as acetate) in drinking water. Systolic and diastolic blood pressure and cardiac inotropism were increased by the metal, which reduced arterial blood flow and unaffected heart rate. The activities of plasma angiotensin I-converting enzyme (ACE) and kininase II were strongly augmented by Pb, suggesting markedly increased and decreased levels of plasma angiotensin II and bradykinin, respectively. Moreover, the Pb-exposed rats showed a lower increase of the plasma kallikrein and kininase I activities. These results are discussed in the context of the complex relationships linking the renin-angiotensin-aldosterone (RAA), kallikrein-kinin and other autacoidal, neurohumoral (e.g., catecholaminergic) and transductional systems (e.g., nitric oxide (NO)). Pb was confirmed to induce arterial hypertension and cardiovascular alterations at plasma levels similar to those observed in the general population or in subjects with short occupational exposure.
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PMID:Kininergic system and arterial hypertension following chronic exposure to inorganic lead. 1060 32

Studies on bradykinin (BK) have been impeded by the fact that this peptide is rapidly degraded by various kininases. Modifications enacted to stabilize the BK sequence have usually resulted in a loss of agonistic activity. In this study, new structural modifications were investigated with the aim to identify degradation-resistant agonists on the bradykinin B2-receptor. The efficacy and degradation stability of several potentially agonistic derivatives were examined using a B2-receptor model (FURA-stained rat fibroblasts) and rat serum kininases. Modifications of the investigated BK analogues included amino-terminal (D-Arg) or carboxy-terminal (Ile-Tyr) prolongation, various substitutions at positions 2, 5, 7, 8 (tetrahydroisoquinoline-3-carboxylic acid, octahydroindole-2-carboxylic acid, hydroxy-proline, beta-2-thienylalanine, 2,3-dehydro-phenylalanine, erythro-beta-phenylserine, erythro-alpha-amino-beta-phenyl-butyric acid, N-methyl-phenylalanine), or intramolecular cyclization via lactam bridges. Kinin inactivation was investigated in rat serum, where the activities of angiotensin I-converting enzyme (ACE), carboxypeptidase N (CPN), aminopeptidase P (APP) and aminopeptidase M (APM) could be differentiated by selective inhibitors. Analogues derived from phyllokinin (BK-Ile-Tyr-SO4) and cyclic peptides had no receptor affinity. Useful modifications compatible with agonistic activity included D-Arg0 (protects against APP), D-N-methyl-Phe7 and dehydro-Phe5 (protect against ACE), and erythro-phenylserine or erythro-amino-phenyl-butyric acid at position 8 (protect against ACE and CPN). Finally, the kinin derivatives D-Arg0-[Hyp3, Thi5, epsilonSer(betaPh)8]-BK and D-Arg0-[Hyp3, Thi5, epsilonAbu(betaPh)8]-BK proved to be potent B2-agonists with extensive stability against rat serum kininases.
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PMID:Structural requirements for B2-agonists with improved degradation stability. 1061 12

Kinins are vasoactive peptide hormones that can confer protection against the development of hypertension. Because their efficacy is greatly influenced by the rate of enzymatic degradation, the activities of various kininases in plasma and blood of spontaneously hypertensive rats (SHR) were compared with those in normotensive Wistar-Kyoto rats (WKY) to identify pathogenic alterations. Either plasma or whole blood was incubated with bradykinin (10 microM). Bradykinin and kinin metabolites were measured by high-performance liquid chromatography. Kininase activities were determined by cumulative inhibition of angiotensin I-converting enzyme (ACE), carboxypeptidase N (CPN), and aminopeptidase P (APP), using selective inhibitors. Plasma of WKY rats degraded bradykinin at a rate of 13.3 +/- 0.94 micromol x min(-1) x l(-1). The enzymes ACE, APP, and CPN represented 92% of this kininase activity, with relative contributions of 52, 25, and 16%, respectively. Inclusion of blood cells at physiological concentrations did not extend the activities of these plasma kininases further. No differences of kinin degradation were found between WKY and SHR. The identical conditions of kinin degradation in WKY and SHR suggest no pathogenic role of kininases in the SHR model of genetic hypertension.
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PMID:Pathways of bradykinin degradation in blood and plasma of normotensive and hypertensive rats. 1129 20

Bradykinin is a small peptide that acts mainly as a hormone by activating specific receptors that confer protection against the development of hypertension. The efficacy of bradykinin is influenced by the activities of various kininases present in plasma and blood. In this study, both human and rat plasma were incubated with a labelled form of bradykinin (at 4 and 12.5 microM), that will be referred to as bromobradykinin. The metabolic fate of bromobradykinin was monitored by liquid chromatography coupled to an orthogonal acceleration time-of-flight mass spectrometer (oaTOF). Quantification measurements of the bromine-containing metabolites were performed on-line, via flow splitting, by inductively coupled plasma mass spectrometry (ICPMS). The data obtained highlighted that the mechanism(s) of bradykinin metabolism in human and rat plasma are different, with the metabolism of bradykinin in rat plasma being much more aggressive than that observed in human plasma. In addition to the known bradykinin metabolites, e.g. [1,5], [1,7] from ACE, [1,8] from carboxypeptidase and [2,9] from aminopeptidase activity, we have identified the presence of new bradykinin metabolites in both human and rat plasma. These have been identified as fragment [5], the amino acid phenylalanine, which was present in both the human and rat plasma and the fragments [2,8] and [4,8] in rat plasma. To our knowledge it is the first time that these fragments have been recorded in human and rat plasma. The occurrence of these new fragments provides evidence for the presence of potentially new enzymes and mechanisms of bradykinin metabolism. The method described here provides a powerful technique for monitoring the activity of the many kininases involved in bradykinin metabolism such as ACE (angiotensin I converting enzyme), carboxypeptidase N and aminopeptidase P. In addition, this procedure could be used as a screening assay for selecting and monitoring the actions of inhibitors of the enzymes implicated in bradykinin metabolism directly in plasma or serum.
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PMID:Study of bradykinin metabolism in human and rat plasma by liquid chromatography with inductively coupled plasma mass spectrometry and orthogonal acceleration time-of-flight mass spectrometry. 1180 44

Bradykinin and substance P have been implicated as mediators in angiotensin-converting enzyme inhibitor (ACEI)-associated angioedema. Studies investigating the metabolism of bradykinin in sera from patients with a history of ACEI-associated angioedema and controls suggest that there is a defect in a non-ACE, non-kininase I pathway of bradykinin degradation, such as the aminopeptidase P (APP)/dipeptidyl peptidase IV (DPPIV) pathway. This study tested the hypothesis that serum APP or DPPIV activity is decreased in patients with ACEI-associated angioedema. APP and DPPIV activity were measured in sera collected from patients during ACEI-associated angioedema, from patients with a remote history of ACEI-associated angioedema, and from normotensive and untreated hypertensive controls. The effects of acute and chronic ACEI and corticosteroid treatment on serum DPPIV activity were also assessed. DPPIV activity was similar in normotensive volunteers (37.8 +/- 6.3 nmol/mL per min), in untreated hypertensive subjects who had been exposed previously to ACEI without angioedema (36.2 +/- 4.3 nmol/mL per min), in hypertensive patients with a remote history of angioedema (35.1 +/-8.5 nmol/mL per min), and in chronically ACEI-treated hypertensive subjects (36.1 +/- 5.6 nmol/mL per min). DPPIV activity decreased with increasing age (R(2)=0.10, P=0.016). Subject group significantly affected DPPIV activity (F=6.208, P=0.016) such that DPPIV activity was significantly lower in patients with ACEI-associated angioedema (26.9 +/- 4.1 nmol/mL per min) than in normotensive controls, in previously ACEI-exposed untreated hypertensive volunteers, or in ACEI-treated hypertensive volunteers, even after controlling for age. There was no effect of acute ACE inhibition or corticosteroids on DPPIV activity. With respect to APP activity, there was no difference between groups. These results suggest that DPPIV activity is depressed in individuals with hypertension during acute ACEI-associated angioedema.
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PMID:Dipeptidyl peptidase IV activity in patients with ACE-inhibitor-associated angioedema. 1188 90

Chronic exposure to low levels of lead causes hypertension in humans and experimental animals. Several mechanisms have been shown to contribute to the pathogenesis of lead-induced hypertension: (1) avid oxidation and inactivation of endogenous nitric oxide (NO) by reactive oxygen species leading to functional NO deficiency; (2) increased sympathetic activity and circulating noradrenaline coupled with decreased vascular and elevated renal beta-adrenergic receptor density; (3) increased angiotensin-converting enzyme (ACE) activity and elevated plasma renin, angiotensin II and aldosterone levels; (4) heightened kininase I and kininase II activities; (5) possible increase in endothelin and thromboxane production; and (6) lead-mediated inhibition of vascular smooth muscle Na(+)-K+ ATPase leading to a rise in cellular Na+ and hence Ca2+ stores. This paper provides an overview of the epidemiology of lead-induced hypertension followed by a review of the available data on the above-mentioned topics.
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PMID:Pathogenesis of lead-induced hypertension: role of oxidative stress. 1218 52

Trypanosoma cruzi, the protozoan that causes Chagas' heart disease, invades endothelial cells in vitro by activating the B2 kinin receptor (B2R). Here, we demonstrate that mice infected with trypomastigotes develop potent edema after treatment with the angiotensin-converting enzyme (ACE) (or kininase II) inhibitor captopril. Experiments performed with specific kinin receptor (B2R/B1R) antagonists and knockout mice revealed that the early-phase (3-h) edema is mediated by the constitutive B2R, whereas the late-phase (24-h) response depends on stimulation of the up-regulated B1R. Given previous evidence that parasite invasion of cells expressing B2R is potentiated by captopril, we investigated the prerequisites for in vitro infection of Chinese hamster ovary cells overexpressing either B1R or B2R, human umbilical vein endothelial cells activated by lipopolysaccharide, and neonatal rat cardiomyocytes. Our results indicate that captopril potentiates parasite invasion regardless of the kinin (B2/B1) activation pathways, whereas DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid (MGTA), an inhibitor of kininase I (carboxypeptidase M/N), selectively decreases parasite infectivity for B1R-expressing cells. These data suggest that formation of the B1R agonist, i.e., [des-Arg] kinins, critically depends on the processing action of kininase I, here proposed as a potential pathogenesis cofactor. Collectively, our data suggest that fluctuations in the levels of kininases may modulate parasite infectivity and pathological outcome in Chagas' disease.
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PMID:Trypanosoma cruzi induces edematogenic responses in mice and invades cardiomyocytes and endothelial cells in vitro by activating distinct kinin receptor (B1/B2) subtypes. 1242 28

Our investigations started when synthetic bradykinin became available and we could characterize two enzymes that cleaved it: kininase I or plasma carboxypeptidase N and kininase II, a peptidyl dipeptide hydrolase that we later found to be identical with the angiotensin I converting enzyme (ACE). When we noticed that ACE can cleave peptides without a free C-terminal carboxyl group (e.g., with a C-terminal nitrobenzylamine), we investigated inactivation of substance P, which has a C-terminal Met(11)-NH(2). The studies were extended to the hydrolysis of the neuropeptide, neurotensin and to compare hydrolysis of the same peptides by neprilysin (neutral endopeptidase 24.11, CD10, NEP). Our publication in 1984 dealt with ACE and NEP purified to homogeneity from human kidney. NEP cleaved substance P (SP) at Gln(6)-Phe(7), Phe(7)[see text]-Phe(8), and Gly(9)-Leu(10) and neurotensin (NT) at Pro(10)-Tyr(11) and Tyr(11)-Ile(12). Purified ACE also rapidly inactivated SP as measured in bioassay. HPLC analysis showed that ACE cleaved SP at Phe(8)-Gly(9) and Gly(9)-Leu(10) to release C-terminal tri- and dipeptide (ratio = 4:1). The hydrolysis was Cl(-) dependent and inhibited by captopril. ACE released only dipeptide from SP free acid. ACE hydrolyzed NT at Tyr(11)-Ile(12) to release Ile(12)-Leu(13). Then peptide substrates were used to inhibit ACE hydrolyzing Fa-Phe-Gly-Gly and NEP cleaving Leu(5)-enkephalin. The K(i) values in microM were as follows: for ACE, bradykinin = 0.4, angiotensin I = 4, SP = 25, SP free acid = 2, NT = 14, and Met(5)-enkephalin = 450, and for NEP, bradykinin = 162, angiotensin I = 36, SP = 190, NT = 39, Met(5)-enkephalin = 22. These studies showed that ACE and NEP, two enzymes widely distributed in the body, are involved in the metabolism of SP and NT. Below we briefly survey how NEP and ACE in two decades have gained the reputation as very important factors in health and disease. This is due to the discovery of more endogenous substrates of the enzymes and to the very broad and beneficial therapeutic applications of ACE inhibitors.
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PMID:Angiotensin converting enzyme (ACE) and neprilysin hydrolyze neuropeptides: a brief history, the beginning and follow-ups to early studies. 1513 71

Chronic, low-level lead exposure causes hypertension in both animals and humans. The pathogenesis of lead-induced hypertension is multifactorial, including such diverse mechanisms as: inactivation of endogenous nitric oxide and downregulation of soluble guanylate cyclase by reactive oxygen species (ROS), leading to a functional deficiency in nitric oxide; heightened sympathetic activity and plasma norepinephrine together with depressed vascular and elevated renal beta-adrenergic receptor density; elevated plasma angiotensin-converting enzyme (ACE) activity, plasma renin activity (PRA), angiotensin II (Ang-II), and aldosterone levels; increased kininase I and kininase II activities; lead-induced inhibition of vascular smooth muscle Na(+)-K+ ATPase, leading to a rise in cellular Na+ and, hence, Ca2+; and a possible rise in endothelin and thromboxane generation. In this article, we present an overview of the epidemiology and proposed underlying mechanisms of lead-induced hypertension.
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PMID:Lead-induced hypertension: role of oxidative stress. 1525 67

Angiotensin-converting enzyme (kininase II [ACE]) inhibitors are capable of potentiating bradykinin (BK) effects by enhancing the actions of bradykinin on B(2) receptors independent of blocking its inactivation. To investigate further the importance of ACE kininase activity on BK-induced vasodilation, we investigated the effect of inhibiting ACE, as well as other kininases, on both BK metabolism and vasodilator effect in preparations that exhibit increased ACE activity. Mesenteric arterial beds obtained from 1-kidney, 1-clip hypertensive rats presented augmented ACE and angiotensin I converting activities compared with normotensive rats. The isolated and perfused mesenteric beds were exposed to BK for 15 minutes in the absence or in the presence of kininase inhibitors; then, the perfusate was collected for analysis of the products of BK metabolism by high-performance liquid chromatography. BK was metabolized to the fragments BK(1-8), BK(1-7), and BK(1-5), and the recovery of intact BK was reduced by 47% in the hypertensive group. Recovery of BK was increased in both groups in the presence of a kininase I inhibitor and in the hypertensive group by neutral endopeptidase 24.11 inhibitor; however, ACE inhibition did not affect BK metabolism in both groups. In contrast, only the ACE inhibitor potentiated the vasodilator effect of BK in a mesenteric bed preconstricted with phenylephrine; the increase in BK effect, nevertheless, was not greater in arteries from hypertensive rats that presented an increased ACE activity when compared with those in the normotensive group. These data demonstrated that ACE inhibitor-induced potentiation of BK vasodilator effects is not related to their actions on BK degradation.
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PMID:Potentiation of bradykinin effect by angiotensin-converting enzyme inhibition does not correlate with angiotensin-converting enzyme activity in the rat mesenteric arteries. 1747 Jul 24


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