Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The blood-bathed organ technique was used to study the release of catecholamines, angiotensin II and prostaglandin-like (PL) substances into the circulation during hypercapnia and after haemorrhage in anaesthetized dogs. 2. Elevated blood concentrations of noradrenaline, angiotensin II and prostaglandin-like substances have been detected during both experimental conditions. 3. The rise of arterial blood pressure during hypercapnia and after haemorrhage was associated with elevated concentrations of angiotensin II in the blood and could be abolished by inhibition of the angiotensin I-converting enzyme with SQ 20881. 4. The compensation of arterial pressure during both stresses was significantly impaired by release of prostaglandin-like substances; it could be restored by inhibition of prostaglandin biosynthesis with indomethacin. 5. The results indicate that activation of the renin-angiotensin system represents the major humoral mechanism for the maintenance of arterial pressure during hypercapnic acidosis and after haemorrhage.
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PMID:Humoral response and blood pressure regulation during hypercapnia and haemorrhage in dogs. 107 98

Polymerase chain amplification experiments indicate that the germinal specific promoter of the angiotensin I-converting enzyme (ACE) is completely extinguished in somatic tissues. Despite this very strict specificity of expression, the germinal ACE promoter is active in transient transfection experiments in two somatic cell lines and one cell line of germinal origin. The analysis of the promoter shows the existence two regulatory elements within the first 350 bp: a proximal positive element and a distal negative element.
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PMID:Functional study of the germinal angiotensin I-converting enzyme promoter. 128 Apr 15

Protein sequencing and molecular cloning of human endothelial angiotensin I-converting enzyme (ACE; kininase II), have led to a description of the structure of the enzyme and to several questions concerning the intracellular maturation of ACE and the mechanisms of enzyme action. With the help of recombinant ACE expression in mammalian cells and site-directed mutagenesis, a model for the maturation of ACE in endothelial cells has been proposed. This model comprises transmembrane anchoring of the membrane-bound ACE near its carboxyterminal extremity, and post-translational cleavage of the anchor in the secreted form. The endothelial ACE displays a high degree of internal homology between two large peptidic domains that each bears a consensus sequence for zinc binding and therefore a putative active site. The testicular ACE, however, encoded from the same gene by a shorter mRNA, contains only the carboxyterminal half of endothelial ACE and therefore a single active site. Expression of ACE mutants with only one intact homologous domain, however, indicates that in endothelial ACE both domains are enzymatically active. Further characterization of these two active sites of endothelial ACE is in progress. In humans, population studies have indicated that the large interindividual variability in plasma ACE levels is partly genetically determined and under the influence of a major gene effect. This was later confirmed and extended by the observation of an insertion-deletion polymorphism of the ACE gene that is associated with the level of ACE in plasma. The clinical implications of these observations are discussed.
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PMID:The angiotensin I-converting enzyme (kininase II): molecular organization and regulation of its expression in humans. 128 23

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 present studies examine the effect of the nonpeptide angiotensin II (AII) type 1 receptor antagonist, DuP 753, on water intake in rats treated with dipsogenic stimuli, which are thought to induce drinking via release of renin and subsequent formation of AII. Subcutaneous administration of DuP 753 in doses that are known to inhibit drinking induced by AII failed to inhibit the water intake of rats following subcutaneous administration of the beta-adrenoceptor agonist isoproterenol. The peptide antagonist1 Sar, 8Ileu-AII, which blocks both AII type 1 and AII type 2 receptors, also failed to inhibit isoproterenol-induced drinking, suggesting that neither subtype is involved in this drinking response. Additional studies verified previous reports that acute subcutaneous administration of both the beta-adrenoceptor antagonist propranolol and the angiotensin I-converting enzyme inhibitor captopril could block the drinking response to subcutaneous administration of isoproterenol. Subcutaneous administration of DuP 753 also failed to inhibit the drinking responses to subcutaneous administration of serotonin, 5-hydroxytryptophan, hypertonic saline, and polyethylene glycol. However, central intraventricular administration of DuP 753 inhibited the drinking response to subcutaneous administration of isoproterenol. The results are discussed in terms of the importance of AII in mediating isoproterenol-, serotonin-, and 5-hydroxytryptophan-induced water intake and suggest a need to readdress this mechanism.
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PMID:Effect of DuP 753, a nonpeptide angiotensin II receptor antagonist, on the drinking responses to acutely administered dipsogenic agents in rats. 131 Nov 3

The purpose of this study was to measure angiotensin I-converting activity in heart, kidney, lung and cheek pouch tissue homogenates of spontaneously hypertensive and normotensive hamsters. We also determined inhibitor sensitivity and the effects of chloride anion concentration on kidney angiotensin I-converting activity in these animals. We found no significant differences in angiotensin I-converting activity between hypertensive and normotensive hamsters in all tissues tested. Inhibitor sensitivity of kidney angiotensin I-converting activity with captopril and lisonopril was similar in both groups. Finally, kidney angiotensin I-converting activity increased significantly in both groups as chloride anion concentration in the assay buffer increased. Substituting chloride anion for citrate abrogated the increase in angiotensin I-converting enzyme activity.
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PMID:Tissue angiotensin I-converting enzyme activity in spontaneously hypertensive hamsters. 131 75

The purpose of this study was to examine whether neutral endopeptidase and angiotensin I-converting enzyme, two membrane-bound metalloenzymes that are widely distributed in the microcirculation, play a role in bradykinin-induced increase in vascular permeability in the hamster cheek pouch. Changes in vascular permeability were quantified by counting the number of leaky sites and by calculating the clearance of fluorescein isothiocyanate (FITC)-dextran (molecular mass, 70,000 d) during suffusion of the cheek pouch with bradykinin. Bradykinin produced a concentration- and time-dependent increase in the number of leaky sites and clearance of FITC-dextran. The selective, active site-directed neutral endopeptidase inhibitors phosphoramidon (1.0 microM) and thiorphan (10.0 microM) and the selective angiotensin I-converting enzyme inhibitor captopril (10.0 microM) each shifted the concentration-response curve to bradykinin significantly to the left. During suffusion with bradykinin (1.0 microM) and phosphoramidon, the number of leaky sites increased significantly from 17 +/- 2 to 27 +/- 4 sites per 0.11 cm2 (mean +/- SEM, p less than 0.05), and FITC-dextran clearance increased significantly from 1.0 +/- 0.2 to 2.1 +/- 0.3 ml/sex x 10(-6).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of peptidases in bradykinin-induced increase in vascular permeability in vivo. 131 17

1. Serum, tissue and urine angiotensin I-converting enzyme (ACE) activity was estimated in the following groups of rats: saline-injected rats (controls); captopril-treated (CAP) control animals (CONTROL-CAP); puromycin aminonucleoside (PAN)-induced nephrotic syndrome (NS); and CAP-treated animals with NS (NS-CAP). 2. Serum ACE activity increased in the CONTROL-CAP, NS, and NS-CAP groups. The increase in the NS-CAP group was significantly higher compared with the NS or CONTROL-CAP groups. 3. In the CONTROL-CAP group, tissue ACE decreased in brain, heart and adrenal glands, and remained unchanged in the lung, testis, kidney, small intestine and liver. In the NS group, tissue ACE activity increased in the lung and testis, decreased in the brain and heart, and remained unchanged in the small intestine, adrenal glands, kidney and liver. Tissue ACE activity increased significantly in the NS-CAP group compared with the other groups. This increase in tissue ACE may contribute to an increase in the serum ACE activity in the NS-CAP group compared with the NS group. 4. Urine ACE activity increased in the NS and NS-CAP groups, although the rise in the NS-CAP group was significantly higher. The urine ACE correlated significantly with the circulating levels of this enzyme in the NS and NS-CAP groups. The loss of ACE in the urine in the presence of an increased serum ACE activity indicates that the biosynthesis of tissue ACE and its release into the bloodstream must be elevated.
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PMID:Captopril magnifies the increase in angiotensin I-converting enzyme activity in rats with aminonucleoside nephrosis. 131 8

The hypothesis of a genetic control of plasma angiotensin I-converting enzyme (ACE) level has been suggested both by segregation analysis and by the identification of an insertion/deletion (I/D) polymorphism of the ACE gene, a polymorphism contributing much to the variability of ACE level. To elucidate whether the I/D polymorphism was directly involved in the genetic regulation, plasma ACE activity and genotype for the I/D polymorphism were both measured in a sample of 98 healthy nuclear families. The pattern of familial correlations of ACE level was compatible with a zero correlation between spouses and equal parent-offspring and sib-sib correlations (.24 +/- .04). A segregation analysis indicated that this familial resemblance could be entirely explained by the transmission of a codominant major gene. The I/D polymorphism was associated with marked differences of ACE levels, although these differences were less pronounced than those observed in the segregation analysis. After adjustment for the polymorphism effects, the residual heritability (.280 +/- .096) was significant. Finally, a combined segregation and linkage analysis provided evidence that the major-gene effect was due to a variant of the ACE gene, in strong linkage disequilibrium with the I/D polymorphism. The marker allele I appeared always associated with the major-gene allele s characterized by lower ACE levels. The frequency of allele I was .431 +/- .025, and that of major allele s was .557 +/- .041. The major gene had codominant effects equal to 1.3 residual SDs and accounted for 44% of the total variability of ACE level, as compared with 28% for the I/D polymorphism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. 131 14

The endothelial angiotensin I-converting enzyme (ACE; EC 3.4.15.1) has recently been shown to contain two large homologous domains (called here the N and C domains), each being a zinc-dependent dipeptidyl carboxypeptidase. To further characterize the two active sites of ACE, we have investigated their interaction with four competitive ACE inhibitors, which are all potent antihypertensive drugs. The binding of [3H] trandolaprilat to the two active sites was examined using the wild-type ACE and four ACE mutants each containing only one intact domain, the other domain being either deleted or inactivated by point mutation of the zinc-coordinating histidines. In contrast with all the previous studies, which suggested the presence of a single high affinity inhibitor binding site in ACE, the present study shows that both the N and C domains of ACE contain a high affinity inhibitor binding site (KD = 3 and 1 X 10(-10) M, respectively, at pH 7.5, 4 degrees C, and 100 mM NaCl). Chloride stabilizes the enzyme-inhibitor complex for each domain primarily by slowing its dissociation rate, as the k-1 values of the N and C domains are markedly decreased (about 30- and 1100-fold, respectively) by 300 mM NaCl. At high chloride concentrations, the chloride effect is much greater for the C domain than for the N domain resulting in a higher affinity of this inhibitor for the C domain. In addition, the inhibitory potency of captopril (C), enalaprilat (E), and lisinopril (L) for each domain was assayed by hydrolysis of Hip-His-Leu. Their Ki values for the two domains are all within the nanomolar range, indicating that they are all highly potent inhibitors for both domains. However, their relative potencies are different for the C domain (L greater than E greater than C) and the N domain (C greater than E greater than L). The different inhibitor binding properties of the two domains observed in the present study provide strong evidence for the presence of structural differences between the two active sites of ACE.
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PMID:The two homologous domains of human angiotensin I-converting enzyme interact differently with competitive inhibitors. 132 19


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