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 inactivation of bradykinin on passage across the human foetal placental circulation was investigated in six full-term human placentas. The placentas were perfused with a modified Krebs-Henseleit solution and placenta perfusion pressure was recorded. Samples collected at the arterial inflow and at the venous effluent were assayed on the isolated guinea-pig ileum as an estimation of bradykinin activity. Bradykinin (100 ng ml-1) was infused through the foetal placental vessels before and during captopril 4 X 10(-7) M. Bradykinin produced a transient increase in placental vascular resistance that was not potentiated by captopril. Bradykinin activity was completely abolished after passage through the foetal placental circulation, and the inactivation was blocked by captopril. These data suggest that angiotensin I converting enzyme (kininase II) might occur in the foetal placental vessels.
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PMID:Effect of captopril on bradykinin inactivation by human foetal placental circulation. 351 9

Bradykinin (BK) and two of its C-terminal fragments, namely H-Phe-Ser-Pro-Phe-Arg-OH and H-Ser-Pro-Phe-Arg-OH were found to be potent inhibitors of the chemotaxis of rat polymorphonuclear neutrophils (PMN). The activity of the three peptides was significantly enhanced by SQ 14225, a rather specific inhibitor of kininase II. A shorter C-terminal sequence of BK (Phe-Arg-OH) was inactive. The whole peptide (BK) exerted potent actions on blood pressure and on isolated organs, e.g. the rabbit mesenteric vein or the guinea pig ileum, but none of its fragments showed similar effects. The present findings suggest that rat PMN possess membrane receptors which cannot be considered identical to B1- and B2-receptors, previously characterized on isolated smooth muscles.
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PMID:Effects of bradykinin and some of its fragments on smooth muscles and chemotaxis. 613 67

Bradykinin receptors on cultured human fibroblasts were characterized using [2,3-prolyl-3,4-3H(N)]bradykinin as radioligand. During incubation with intact fibroblasts, intact [3H]bradykinin was lost much more rapidly at 37 degrees than at 4 degrees C as determined by bioassay, high-performance liquid chromatography, and ion-exchange chromatography, and is likely to be degraded. At 4 degrees, but not at 37 degrees C, bradykinin remained intact in the presence of 2 mM bacitracin, but not in the presence of soybean trypsin inhibitor or SQ-20881, an inhibitor of kininase II. Specific binding at 4 degrees C was saturable with a maximum number of binding sites of 230 +/- 18 fmol/mg protein (mean +/- SE, n = 4) and a dissociation constant of 4.6 +/- 0.5 nM (mean +/- SE, n = 4). Linear Scatchard plots, Hill coefficients close to unity (0.95-1.06), and the failure of excess bradykinin to influence dissociation kinetics are consistent with a single component binding system with no significant cooperativity. Na+ at physiological concentrations and Ca++ or Mg++ at 3-10 mM reduced binding by 25%. The relative potencies of bradykinin analogues and unrelated peptides in competing for [3H]bradykinin binding indicated a specificity of the binding sites consistent with that of a B2 type receptor. Potencies of the peptides in displacing [3H]bradykinin correlated with their abilities to release prostacyclin, determined as its metabolite 6-keto-PGF1 alpha. This system, the first in which bradykinin receptors on human cells have been characterized, should prove useful for investigation of the regulation of bradykinin-influenced biological processes.
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PMID:Receptors for bradykinin in intact cultured human fibroblasts. Identification and characterization by direct binding study. 613 11

Bradykinin (BK) initially produced concentration related relaxations of the rabbit basilar artery in vitro under resting tension and when contracted with 5-hydroxytryptamine. Concentration-effect (C-E) curves to BK repeated at 2 h intervals over an 8-10 h period resulted in the production of progressively increased contractile responses. The induction of these contractile responses to BK was prevented by pre-incubation of these tissues with cycloheximide. On tissues which had been challenged with BK at 2 h intervals for 8 h in the absence of cycloheximide the rank order of potency of three kinins to produce contraction was methionyl-lysyl-BK (M-L-BK) greater than BK greater than des-Arg9-BK. On the same tissues the specific B1-receptor antagonist des-Arg9-Leu8-BK inhibited the contractile effects of BK. These results suggest the presence of a B1-receptor mediating contraction. The rank order of potency of the kinins to produce relaxation of tissues preincubated with cycloheximide was BK greater than M-L-BK greater than des-Arg9-BK which suggests the presence of a B2-receptor mediating these responses. Angiotensin I (AI) and angiotensin II (AII) produced concentration related contractions of the tissue. The angiotensin converting enzyme inhibitors captopril, BPP5a and BPP9a inhibited responses to AI but had no effect on contractile C-E curves to BK, AII and 5-HT or on relaxant C-E curves to BK. These results suggest that the rabbit basilar artery in vitro contains two BK receptors, a B1 receptor mediating contraction and a B2 receptor mediating relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Kinin receptors and angiotensin converting enzyme in rabbits basilar arteries. 614 33

The hypotheses that glandular kallikrein (KK) potentiate the conversion of angiotensin I (AI) to angiotensin II (AII) was tested on isolated mesenteric artery from rabbit. Cumulative additions of A1 in concentrations 10(-8), 5 X 10(-8) and 10(-7) M gave dose-related contractions of the artery. Due to tachyphylaxis second dose-response run was used for comparison. KK, 0.4 U/ml, potentiated these contractions. Addition of captopril (C, 10(-5) M) to inhibit angiotensin converting enzyme (ACE) reduced the AI responses markedly and tachyphylaxis almost completely. The responses of the KK induced potentiation of AI was the same regardless of the presence of captopril. KK, 0.01 U/ml or 0.4 U/ml, produced the same effects. Saralasin (S, 10(-5) M), an AII receptor antagonist, completely abolished the responses following C+KK+AI. Thus, these results indicate that the KK induced potentiation of the AI response is due to a conversion to AII. Bradykinin (BK, 10(-7), 10(-5) M) did not mimic the KK potentiation of AI. Three different kallikrein inhibitors, S-2441 (H-D-Pro-Phe-Arg-NH-heptyl X 2HCl), Trasylol and amiloride, reduced the KK potentiation of AI. Phentolamine, an alpha-adrenergic receptor antagonist added for inhibition of AII adrenergic facilitation, also reduced the KK induced potentiation of AI. In conclusion, these results indicate that KK potentiate the conversion of AI to AII and thereby induces vasopressor effects.
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PMID:Kallikrein potentiation of angiotensin I-induced contraction on isolated mesenteric artery. 619 Mar 76

Captopril, an inhibitor of angiotensin converting enzyme, was administered twice daily to 13 hypertensive patients for a mean period of 9 weeks. Continuous blood pressure control in the ambulatory patients was established with a portable blood pressure recorder. Notwithstanding, in eight patients with normal renal function, plasma converting enzyme was found to resume normal activity before administration of the morning dose of captopril. Only in 5 patients with impaired renal function did some blockade of plasma converting enzyme persist for more than 12 hours. Measured plasma converting enzyme activity seemed to reflect total conversion of angiotensin I, including conversion in the pulmonary vascular bed, since changes in its activity were closely paralled by changes in plasma aldosterone levels. Bradykinin accumulation seems unlikely when converting enzyme and thus, presumably, kininase II has resumed normal activity. Captopril administration does not seem to alter plasma epinephrine or norepinephrine levels. Blood pressure reduction in the face of normal angiotensin converting enzyme activity is probably due to hyporesponsiveness of the arterioles to pressor hormones, which may be due to specific renin-related and/or nonspecific effects of captopril.
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PMID:Discrepancy between antihypertensive effect and angiotensin converting enzyme inhibition by captopril. 624 69

We purified peptidyl-dipeptidase (converting enzyme, EC 3.4.15.1) to homogeneity from the membrane fraction of human lung and for comparison, from human and hog kidney. The membrane-bound lung enzyme was purified 1800-fold with 19% yield, and the kidney enzyme 640-fold with 10% yield. The specific activities with Bz-Gly-His-Leu were 81 mumol/min/mg for the lung and 65 for the kidney enzyme. The lung enzyme was homogeneous in gel electrophoresis with Mr = 155,000 and Sw,20 = 8.0 in ultracentrifugation. Antibodies elicited against lung or kidney enzyme cross-reacted with enzyme from other organ, but not with the hog enzyme. In isoelectric focusing both human enzymes had a major form with a pI of 5.2. The lung preparation also contained more acidic forms (pI = 4--5), which were eliminated by treatment with neuraminidase. Lung and kidney converting enzyme hydrolyzed bradykinin, angiotensin I, and enkephalins and had similar kinetic constants. Bradykinin was the best substrate, as indicated by its kcat/Km, but Met5-enkephalin had the highest turnover number. The hydrolysis of Bz-Gly-His-Leu was inhibited by captopril (SQ 14225) competitively, and by Keto-ACE, a non-peptide derivative of Bz-Phe-Gly-Pro, non-competitively.
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PMID:Purification and characterization of human converting enzyme (kininase II). 627 Jun 33

Carrageenan-induced edema of rat paw was greatly potentiated by orally or locally administered angiotensin converting enzyme (CE, identical with kininase II) inhibitor, (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid (YS980). The potentiative effect of YS980 was observed by the administration not only prior to but also 3 hr after the carrageenan injection. The vascular permeability test showed the same potentiative effect of YS980 in the inflamed tissue of carrageenan edema. Bradykinin potentiating peptide-B (BPP-B) and 1,10-phenanthroline also potentiated the edema and the effects of these compounds were in order of YS980 greater than BPP-B greater than 1,10-phenanthroline. The order was in accordance with that of inhibitory potencies against kininase II activity of rat serum in vitro. However, the activity of kininase I was not affected by YS980 and BPP-B. In addition, among various experimental models of acute paw edema, the potentiative effects of YS980 were restricted to the inflammations mediated by kinins such as carrageenan, cellulose sulfate, kaolin and bradykinin-induced edema. These results suggest that the potentiative effect of YS980 on carrageenan edema is mainly based on its inhibitory effect on kininase II in the inflamed site.
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PMID:[Potentiative effects of angiotensin converting enzyme inhibitors on carrageenan-induced edema in rats]. 629 82

Bradykinin (BK) and [des-Arg9]-bradykinin (-9BK) concentrations in blood and urine samples from 18 normotensive subjects and 23 patients with low-renin essential hypertension were determined by radioimmunoassay. BK and -9BK levels in venous blood from normotensive subjects were 67.1 +/- 60.8 pg/ml and 204.1 +/- 44.5 (mean +/- S.D.), respectively, and levels in urine from normotensive subjects were 5.3 +/- 5.3 ng/ml and 1.6 +/- 1.2, respectively. The blood and urinary levels of BK and -9BK in low-renin essential hypertensives were not significantly different from those of normotensives and did not change when the hypertensives were treated with the new orally active angiotensin I-converting enzyme (ACE) inhibitor, enalapril (MK421). It has been proposed that BK levels do not change with ACE inhibition because under these conditions BK might be metabolized to -9BK by kininase I. Since -9BK levels did not increase with MK421 treatment, this possibility can be excluded. The absence of elevations in blood and urine BK and -9BK after administration of MK421 does not support an involvement of kinins in the mechanism of antihypertensive action of MK421 in these patients. On the basis of the data, it is not possible to exclude such an involvement, however, because local changes in kinin concentrations could occur that are not reflected by changes in circulating or urinary kinin levels.
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PMID:Immunoreactive bradykinin and [des-Arg9]-bradykinin in low-renin essential hypertension--before and after treatment with enalapril (MK 421). 631 33

The effects of cardiovascular drugs on endothelium and vascular smooth muscle function are important for the prevention of cardiovascular disease. Changes in endothelial function are an early event in most forms of cardiovascular disease and, later in the disease process, vascular smooth muscle cells are functionally altered and begin to migrate to and proliferate in the intima. Calcium antagonists and angiotensin converting enzyme (ACE) inhibitors are widely used in patients with cardiovascular disease and are thought to have vascular protective effects. ACE, an enzyme located in the endothelial cell membrane, activates angiotensin I and angiotensin II, and deactivates bradykinin. Bradykinin activates endothelial bradykinin (B2) receptors, which results in the formation of nitric oxide and prostacyclin. Hence, ACE inhibitors not only prevent the formation of angiotensin II, but also increase the local levels of bradykinin and in turn nitric oxide and prostacyclin. These compounds are vasodilators and potent inhibitors of platelet function, and therefore may mediate important protective effects of ACE inhibitors. Furthermore, nitric oxide may have antiproliferative effects in vascular smooth muscle cells. Calcium antagonists do not appear to affect the release of endothelium-derived relaxing factors or any other endothelial product. However, they facilitate endothelium-dependent relaxation and reduce the contracting effects of endothelin-1 at the level of smooth muscle. Indeed, in some blood vessels, e.g. the large coronary arteries and the human forearm circulation, verapamil and nifedipine antagonise endothelin-induced contractions. In addition, calcium antagonists inhibit the effects of platelet-derived growth factor and may have antiproliferative effects in vascular smooth muscle cells. In conditions involving progressive dysfunction of the endothelium, vascular deposition of platelets increases the local levels of platelet-derived growth factor, and the antiproliferative effects of calcium antagonists may thus be particularly important.
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PMID:Calcium antagonists and ACE inhibitors. Effect on endothelium and vascular smooth muscle. 751 65


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