Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The protection of angiotensin converting enzyme (ACE) inhibitors, captopril and ramiprilat, against free radical-mediated myocardial injury were studied in isolated working rat hearts. Free radicals were generated by electrolysis of Krebs-Henseleit solution with 10 mA direct current for 1 min. Both captopril (360 mumol/l) and ramiprilat (12.5 mumol/l) significantly reduced the decrease of left ventricle dP/dt'max, coronary flow (CF), myocardial superoxide dismutase (SOD) and creatine kinase (CK) activities and the elevation of S-T segment of epicardial ECG as well as the rise of myocardial malondialdehyde (MDA) content caused by electrolysed perfusate. Captopril afforded a dose-dependent protection on cardiac functions with various concentrations of 45, 90, 180 and 360 mumol/l. Iloprost (30 nmol/l), a stable mimetic of prostacyclin, could also alleviate free radical-mediated myocardial injuries. All the beneficial effects of ramiprilat (12.5 mumol/l) were abolished by the administration of indomethacin (5 mumol). In contrast, captopril (90 mumol/l) still exhibited significant protective effects after indomethacin (9 mumol) was administered, though these protective effects were insignificantly weakened. In order to assess the role of sulfhydryl (-SH) group in the effects of captopril, a SH-containing drug S8 and a disulfide DG4, both are deficient in ACE inhibitory properties in vitro, were examined. Data showed that S8 (180 mumol/l) provided a significant protection while DG4 showed no protective effect. It is concluded that ACE inhibitors can protect against free radical-induced myocardial damage. Ramiprilat, a non-SH-containing ACE inhibitor, inhibits free radical-induced damages mainly by stimulation of prostacyclin synthesis and/or release. In addition to this effect, captopril, a SH-containing ACE inhibitor, may exert additional anti-free radical effects by a mechanism which is probably related to the sulfhydryl group.
J Mol Cell Cardiol 1989 Dec
PMID:Captopril and ramiprilat protect against free radical injury in isolated working rat hearts. 269 63

The protective effect of angiotensin-converting enzyme inhibitors (ACEI) on myocardial ischemia and reperfusion damage was estimated in rat hearts, both in vivo and in vitro. Enalapril 2.5 mg/kg ip pretreatment at 24 and 5 h before coronary occlusion, significantly blunted the rise of CPK (445 +/- 151 vs 649 +/- 244 mu/ml, P less than 0.05) and improved electrocardiogram (ECG) 8 h after coronary occlusion. In global ischemia and reperfusion ex vivo, enalapril improved contractility (0.9 +/- 0.2 vs 0.3 +/- 0.3 g, P less than 0.05) and coronary flow (15.6 +/- 3.3 vs 11.9 +/- 3.1 ml/min/g, P less than 0.05), shortened significantly the duration of reperfusion arrhythmia (3.1 +/- 2.7 vs 9.7 +/- 8.1 min, P less than 0.05). In Langendorffs heart, captopril remarkably preserved force of contraction (2.1 +/- 0.4 vs 1.4 +/- 0.4 g, P less than 0.01) and coronary flow (2.7 +/- 0.5 vs 3.6 +/- 0.9 ml/min/g, P less than 0.05) in segmental infarction deteriorated by angiotensin I. Captopril 10(-5) M infusion reduced the release of CPK (435 +/- 112 vs 640 +/- 123 mu/min coronary flow, P less than 0.05). This action was almost completely abolished by pretreating and infusing with indomethacin. As a positive control, prostacyclin 5 X 10(-7) M infusion further reduced the release of CPK to 330 +/- 77 mu/min. It is concluded that angiotensin-converting enzyme inhibitor can protect both myocardial ischemia and reperfusion damage in rat hearts. The mechanism of protection was ascribed to reduced production of angiotensin II by ACE inhibition and increased prostacyclin release in the myocardium.
J Mol Cell Cardiol 1987 Sep
PMID:Protective effects of captopril and enalapril on myocardial ischemia and reperfusion damage of rat. 282 45

To study the roles played by cardiac valvular endothelium in normal and pathologic conditions, we have established and characterized a system of bovine valvular endothelial cells (VEC) in culture. Viable VEC from calf atrioventricular valves were obtained by a non-enzymatic procedure using 3 mM ethylenediamine-tetraacetic acid (EDTA) as dissociating agent. The cells grown in Dulbecco's modified Eagle's medium supplemented with non-essential amino acids, vitamins and 20% fetal calf serum, developed as monolayers of closely apposed polygonal cells which were subcultured for up to seven passages. VEC maintained in culture the general ultrastructure displayed in vivo, expressed von Willebrand factor, presented angiotensin converting enzyme activity and synthesized a rich extracellular matrix. VEC preserved the cell surface anionic sites (detected with cationized ferritin, pI 8.4) and cationic sites (visualized with haemeundecapeptide pI 4.85), and took up, especially by adsorptive endocytosis, albumin-gold conjugate. The cells were coupled by functional communicating (gap) junctions, as demonstrated by microinjection of 6-carboxyfluorescein. VEC in culture produced fibronectin, prostacyclin, hyaluronic acid and heparin-like glycosaminoglycans (identified by electrophoresis, enzyme digestion, and deaminative cleavage of molecules). These properties render cultured VEC a suitable model for investigating their functions and involvement in normal and pathologic heart valves.
J Mol Cell Cardiol 1988 Feb
PMID:Calf cardiac valvular endothelial cells in culture: production of glycosaminoglycans, prostacyclin and fibronectin. 284 May 11

The proteolytic degradation of the enkephalin-containing heptapeptide Tyr-Gly-Gly-Phe-Met-Arg-Phe (YGGFMRF) was investigated by incubating the peptide with synaptic membranes from mouse whole brain and characterizing the formed products. The degradation products were derivatized with 4-dimethylaminoazobenzene-4'-isothiocyanate and then analyzed by high pressure liquid chromatography and by amino-terminal analysis. The incubation of YGGFMRF with synaptic membranes yielded YGGFM and RF as the degradation products. The angiotensin-converting enzyme (ACE) inhibitors, MK-422 and captopril, potently inhibited the formation of YGGFM and RF with IC50 values of 8 nM and 95 nM, respectively. The "enkephalinase A" inhibitor, thiorphan, weakly inhibited this dipeptidyl carboxypeptidase activity with an IC50 greater than 1 microM. YGGFMRF, MK-422, captopril, and thiorphan all produced a dose-dependent analgesic response in the mouse hot plate test when administered intracerebroventricularly. However, when subanalgesic doses of inhibitors were co-administered with a subanalgesic dose of YGGFMRF, only the ACE inhibitors, MK-422 and captopril, potentiated the analgesic response of the peptide. These data provide in vitro and in vivo evidence that ACE is the primary enzyme involved in the proteolytic degradation of YGGFMRF in the mouse brain.
Mol Pharmacol 1985 Dec
PMID:Angiotensin-converting enzyme inhibitors potentiate the analgesic activity of [Met]-enkephalin-Arg6-Phe7 by inhibiting its degradation in mouse brain. 300 97

We demonstrate that [3H]captopril selectively labels angiotensin converting enzyme (EC 3.14.15.1) (ACE) and employ this technique to probe enzyme-inhibitor interactions. [3H]Captopril binding sites copurify with ACE activity from rat lung or rat brain. At each stage of the purification the Vmax/Bmax ratio, or kcat is 17,000 min-1 with hippuryl-L-histidyl-L-leucine as substrate. The specificity of [3H]captopril binding is apparent in the similar pharmacologic profile of inhibition in crude and pure enzyme preparations. Furthermore, binding sites and enzyme activity comigrate in gel filtration and sucrose gradient sedimentation experiments. Equilibrium analysis of [3H]captopril binding to purified ACE reveals a Bmax of 6 nmol/mg of protein (KD = 2 nM), demonstrating the presence of one inhibitor binding site per polypeptide chain. The kinetics of [3H]captopril binding are characterized by monophasic association and dissociation rate constants of 0.026 nM-1 min-1 and 0.034 min-1, respectively. The affinity of ACE for both [3H] captopril and enalaprilat is greater at 37 degrees than at 0 degree, demonstrating that these interactions are entropically driven, perhaps by an isomerization of the enzyme molecule. The ionic requirements for [3H]captopril binding and substrate catalysis differ. Chloride and bromide ion, but not fluoride, are about 100-fold more potent stimulators of binding than catalysis. When the active site Zn2+ ion is replaced by Co2+, catalysis was stimulated 2-fold, whereas binding activity was decreased by 70%.
Mol Pharmacol 1986 Feb
PMID:Characterization of angiotensin converting enzyme by [3H]captopril binding. 300 26

The hydrolysis of substance P is catalyzed by purified rabbit lung angiotensin-converting enzyme (peptidyldipeptide hydrolase, EC 3.4.15.1). The kcat/Km for the reaction at 37 degrees is 3.3 +/- 0.3 X 10(3) M-1 sec-1, which is 60 times less than that which has been reported for the hydrolysis of angiotensin I. The initial site of hydrolysis is the antipenultimate peptide bond, which generates the tripeptide amide (Gly-Leu-Met-NH2). This hydrolysis is inhibited by the angiotensin-converting enzyme inhibitors captopril, MK-422, and EDTA, and is dependent on the concentration of chloride ion. Both captopril and MK-422 potentiate the substance P-induced stimulation of salivation in rats. Thus, angiotensin-converting enzyme may be one of the enzymes that degrade substance P in vivo.
Mol Pharmacol 1984 Mar
PMID:Carboxyl-terminal tripeptidyl hydrolysis of substance P by purified rabbit lung angiotensin-converting enzyme and the potentiation of substance P activity in vivo by captopril and MK-422. 619 59

This review summarizes our knowledge of pituitary endopeptidases. Emphasis has been placed on well-characterized enzymes and their potential roles in proteolytic processes of the pituitary. Because of space limitations, degradation of biologically active peptide by crude preparations has generally not been discussed. Only a few proteolytic enzymes are at present adequately characterized, and knowledge of their physiological function in vivo is insufficient. Among the many functions of proteolytic enzymes, those that are specific for the pituitary as an endocrine gland are of primary interest. Such functions include inactivation of neuropeptides and factors that control the secretory function of the pituitary, processing of precursors destined for secretion, selective cleavage of prohormones into active fragments, and degradation of inactive fragments. While some of the enzymes described here, such as cathepsin D, could be expected to have primarily a degradative function, others could potentially be involved in hormonal metabolism, since they exhibit trypsin-like, chymotrypsin-like, and dipeptidyl carboxypeptidase-like activities, all potentially useful in hormonal conversions. Data suggestive of the presence in the pituitary of enzymes involved in removal of the 'signal sequence', and enzymes involved in hormone processing by cleavage of bonds after a pair of basic residues and in the subsequent removal of these residues by a carboxypeptidase B-like activity have been published. None of these enzymes, however, has been isolated or purified to a degree that would allow determination of its specificity, mechanisms of action, physicochemical properties, and susceptibility to specific inhibitors. Questions that remain unresolved ask whether differences in the processing pathways in various anatomical parts of the pituitary are due to the presence of proteases with different specificities, or to different disposition of these enzymes, and factors, such as conformation of the substrate and its secondary modification, for example by glycosylation or phosphorylation. Proof of a functional involvement of a protease in hormonal processing should include demonstration that inhibition of activity results in inhibition of processing in the intact cell. Specific inhibitors of processing enzymes could potentially be used to modulate pituitary function, and thus have pharmacological interest. Although there are few answers to the above problems at present, the questions are well defined, and it can be expected that the rapidly expanding research on pituitary proteases will soon provide some of the answers.
Mol Cell Biochem 1983
PMID:Pituitary endopeptidases. 634 52

Fasting leads to an increase in insulin binding to isolated rat hepatocytes from 12 to 17%. This increase was accounted for by changes in the affinity of insulin receptors without alteration in their number. In contrast, the responsiveness of hepatocytes to insulin was markedly diminished in fasted rats. Both basal and insulin-stimulated rates of 14C-glucose incorporation into glycogen were significantly decreased in fasted animals. When insulin-induced 14C-glucose incorporation into glycogen was expressed as a percent above the basal rate, hepatocytes isolated both from control and fasted animals showed the same magnitude of maximal response (66 +/- 13% in fed and 59 +/- 12% in fasted animals, respectively). However, more insulin must be bound to hepatocytes isolated from fasted animals in order to elicit the same percent of insulin's maximal effect. Incubation of 'fed' hepatocytes in the serum obtained from fasted rats significantly diminished their responsiveness to insulin. An addition of insulin (100 ng/ml), glucose (10 mM) and antibodies to glucagon (1:100) eliminated the inhibitory effect of 'fasted' serum on 'fed' hepatocytes. A 48-hour fast increased significantly the microviscosity (decreased fluidity) of hepatocyte plasma membranes and altered membrane phospholipid composition. These changes correlated with enhanced insulin binding to isolated membranes. Moreover, in response to insulin, plasma membranes isolated from 'fasted' hepatocytes generated only one half the amount of the second messenger (PDH activator) observed in membranes of fed animals. The amount of PDH activator generated by incubation of plasma membranes with insulin correlated inversely with both insulin binding and membrane microviscosity. We conclude that 1) fasting induces both coupling defect and post-receptor changes in insulin's action; 2) both extracellular and intracellular factors contribute to fasting-induced dissociation of insulin binding from insulin action; 3) insulin/glucagon ratio may influence hepatocyte responsiveness to insulin; 4) alterations in plasma membrane fluidity and phospholipid composition may alter insulin binding and contribute to its dissociation from the subsequent action; 5) membranes isolated from 'fasted' hepatocytes generate less mediator of insulin action than do membranes isolated from 'fed' hepatocytes.
Mol Cell Biochem 1984 Apr
PMID:Mechanisms of the fasting-induced dissociation of insulin binding from its action in isolated rat hepatocytes. 637 42

Quantitative cytochemical and microfluorimetric techniques were employed to compare mural intermediary metabolism--endothelial macromolecular uptake changes in spontaneous aortic-arteriosclerotic lesions of normolipemic New Zealand White rabbits. Specifically, mural succinic (SDH), lactic (LDH), and glucose-6-phosphate (G-6-PDH) dehydrogenase activities and luminal surface uptake of fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA) were measured in lesion sites abnormally resistant (calcified) and susceptible (proliferative) to dietary hypercholesterolemia. Calcified lesions exhibited severe (55-66%) diminution of SDH, LDH, and G-6-PDH activities within the involved inner mural zone and a comparable (68%) decline in luminal FITC-BSA uptake. Concomitant reductions in FITC-BSA uptake (30%) and marker enzymes of the predominant energy transducing pathways in arterial tissue, i.e., SDH (30%) and LDH (31%), were evidenced in proliferative foci, whereas G-6-PDH was augmented (52%) in comparison to nonlesioned aortic segments. These data lend additional support to the concept that endothelial uptake of plasma-borne macromolecules is coupled to oxidizable substrate requirements of inner avascular compartments of the arterial wall. It is postulated that diminished macromolecular transport in these degenerative lesions stems from reduced mural metabolic demands, and that pharmacologic reduction of vascular smooth muscle metabolism may depress uptake of sclerogenic macromolecules.
Exp Mol Pathol 1984 Feb
PMID:Cytochemical correlates of atherosclerosis-resistant and susceptible lesions of the normal rabbit aorta. 669 4

The opioid peptides methionine-enkephalin and leucine-enkephalin appear to exert their biological effects through a receptor mediated mechanism. There appears to be three potential mechanisms for enkephalin degradation which could serve to control enkephalin levels in the vicinity of enkephalin receptors. These are, 1) cleavage of the tyrosyl-glycine bond by aminopeptidases, 2) cleavage of the glycl-glycine bond by a dipeptidyl aminopeptidase, and 3) cleavage of the glycyl-phenylalanine bond by a dipeptidyl carboxypeptidase. In this review the biochemical properties of these potential enkephalinases are described, and the evidence for each acting as an enkephalinase is reviewed.
Mol Cell Biochem 1982 Aug 20
PMID:Degradation of enkephalins: the search for an enkephalinase. 675 92


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