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)

A model of congestive heart failure (CHF) was produced in rats approximately 76 days following surgical occlusion of the left coronary artery. In rats with healed myocardial infarction (MI size = 45% LV), hemodynamic variables were predictably elevated (LVEDP greater than 20 mm Hg) or depressed LV dP/dtmax (5200 mm Hg/sec). The hemodynamic response (MAP, HR, LVEDP, and dP/dtmax) to intravenous infusion of Mil (54 to 347 micrograms/kg) was measured on two occasions, separated by a 7-12 day period of oral treatment (2 mg/kg/day). Enalaprilat was tested in a similar design with the infusion phase (70 micrograms/kg, total dose) separated by oral enalapril (Enal), 1 mg/kg/day. The hemodynamic response to Mil was also examined in rats treated with the ACE inhibitor. At low doses, Mil modestly elevated HR (+17 beats/min) and dose-dependently increased (P less than 0.05) LV contractility by approximately 25%. Higher doses of Mil reduced preload (LVEDP) and afterload (MAP). Oral Mil produced little hemodynamic improvement except modest elevation (+9%) in LV contractility. There was no evidence of tachyphylaxis to i.v. Mil. In contrast, enalaprilat reduced MAP and preload without altering HR or contractility, effects observed after oral treatment. In the presence of the ACE inhibitor, Mil's hemodynamic actions were not enhanced. These experiments demonstrate that ACE inhibition improves ventricular performance by reducing preload and afterload. In this model, Mil improves performance by a direct inotropic mechanism as well as a reduction in afterload.
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PMID:Acute and subacute hemodynamic effects of enalaprilat, milrinone and combination therapy in rats with chronic left ventricular dysfunction. 303 90

It has been proposed that the contribution of myocardial tissue angiotensin converting enzyme (ACE) to angiotensin II (Ang II) formation in the human heart is low compared with non-ACE pathways. However, little is known about the actual in vivo contribution of these pathways to Ang II formation in the human heart. To examine angiotensin II formation in the intact human heart, we administered intracoronary 123I-labeled angiotensin I (Ang I) with and without intracoronary enalaprilat to orthotopic heart transplant recipients. The fractional conversion of Ang I to Ang II, calculated after separation of angiotensin peptides by HPLC, was 0.415 +/- 0.104 (n = 5, mean +/- SD). Enalaprilat reduced fractional conversion by 89%, to a value of 0.044 +/- 0.053 (n = 4, P = 0.002). In a separate study of explanted hearts, a newly developed in vitro Ang II-forming assay was used to examine cardiac tissue ACE activity independent of circulating components. ACE activity in solubilized left ventricular membrane preparations from failing hearts was 49.6 +/- 5.3 fmol 125I-Ang II formed per minute per milligram of protein (n = 8, +/- SE), and 35.9 +/- 4.8 fmol/min/mg from nonfailing human hearts (n = 7, P = 0.08). In the presence of 1 microM enalaprilat, ACE activity was reduced by 85%, to 7.3 +/- 1.4 fmol/min/mg in the failing group and to 4.6 +/- 1.3 fmol/min/mg in the nonfailing group (P < 0.001). We conclude that the predominant pathway for angiotensin II formation in the human heart is through ACE.
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PMID:Angiotensin II formation in the intact human heart. Predominance of the angiotensin-converting enzyme pathway. 765 20

The affinity of three substrates for the intestinal peptide carrier is explained based on their three-dimensional (3D) structural data. The kinetic transport parameters of three ACE-inhibitors, enalapril, enalaprilat, and lisinopril, have been determined in an in vivo system using rat intestine. The observed kinetic transport parameters (+/- asymptotic standard error) of enalapril are: 0.81 (+/- 0.23) mM, 0.58 (+/- 0.37) mumol/h per cm2, and 0.56 (+/- 0.04) cm/h for the half-maximal transport concentration (KT), the maximal transport flux (Jmax) and the passive permeability constant (Pm). Enalaprilat was transported by passive diffusional with a Pm of 0.51 (+/- 0.04) cm/h. For lisinopril the kinetic transport parameters were 0.38 (+/- 0.19) mM, 0.12 (+/- 0.07) mumol/h per cm2, and 0.18 (+/- 0.02) cm/h for KT, Jmax, and Pm, respectively. The affinity of the ACE-inhibitors for the intestinal peptide carrier has been evaluated based on their ability to inhibit the transport rate of cephalexin. The inhibition constants (Ki) of enalapril, enalaprilat and lisinopril were 0.15, 0.28 and 0.39 mM, respectively. 3D structural analysis of lisinopril using molecular modelling techniques reveals that intramolecular hydrogen bond formation is responsible for decreased carrier affinity.
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PMID:Molecular mechanism for the relative binding affinity to the intestinal peptide carrier. Comparison of three ACE-inhibitors: enalapril, enalaprilat, and lisinopril. 779 53

Enalapril effectively decreases hematocrits in patients with postrenal transplant erythrocytosis (PTE). We studied the effect of enalapril withdrawal on erythropoiesis in 18 patients with PTE who had been treated for 13 +/- 8 months. Hematocrit, reticulocyte count, plasma erythropoietin, and plasma insulin-like growth factor I were measured biweekly for six weeks. Red cell mass, plasma volume, transferrin saturation, and plasma angiotensin II were measured at withdrawal and six weeks later. Hematocrit increased by at least 0.04 in 13 patients ('responders') but changed by -0.08 to 0.01 in five patients ('nonresponders'). In the responder subgroup, hematocrit increased from 0.43 +/- 0.05 to 0.51 +/- 0.05 (P < 0.001), red cell mass increased from 25.4 +/- 5.9 to 28.9 +/- 5.9 ml/kg body weight (P < 0.001), and transferrin saturation decreased from 41 +/- 16 to 27 +/- 9 percent (P < 0.01). Reticulocyte count increased two weeks after withdrawal of enalapril. Plasma volume did not change significantly. No measurement changed in the nonresponder subgroup. Plasma levels of erythropoietin, total erythroid stimulating activity, insulin-like growth factor I, and angiotensin II did not change significantly in either subgroup. Enalaprilat did not inhibit erythropoiesis in cell culture. Thus, erythropoiesis increased in 13 of 18 patients after stopping enalapril and was independent of changes in circulating concentrations of several erythropoietic factors, including erythropoietin. The pathogenesis of PTE and mechanism underlying the beneficial effect of angiotensin converting enzyme inhibition remain undetermined.
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PMID:Erythropoiesis after withdrawal of enalapril in post-transplant erythrocytosis. 785

Greater protein intake increases glomerular eicosanoid production in rats. Bilateral ureteral obstruction (BUO) also enhances glomerular eicosanoid production in experimental animals. To examine the effects of dietary protein intake on glomerular eicosanoid production in ureteral obstruction, we measured the in vitro production of the vasodilatory prostaglandins, PGE2, and 6-keto PGF1 alpha, and the vasoconstrictor, TxB2, and the mass of cyclooxygenase in glomeruli of sham-operated control (SOC) rats and rats with BUO of 24 hr duration fed a low- (6% casein) or a high- (40% casein) protein diet for approximately 4 weeks. The animals were pretreated or not with the angiotensin converting enzyme inhibitor, enalaprilat, prior to sham-operation or ureteral obstruction. Glomeruli from SOC rats fed a high-protein diet produced significantly greater amounts of PGE2, 6-keto PGF1 alpha, and TxB2, and had substantially increased mass of cyclooxygenase when compared with glomeruli from SOC rats fed a low-protein diet. Pretreatment of animals with enalaprilat prior to sham operation prevented the increase in glomerular eicosanoid production and cyclooxygenase content in SOC rats fed a high-protein diet and the levels observed were similar to those in SOC rats fed a low-protein diet. Both eicosanoid production and cyclooxygenase mass were further increased in glomeruli from rats with BUO fed a high-protein diet when compared with glomeruli of SOC rats fed the same diet. The increased levels of these measurements in BUO rats fed a high-protein diet fell markedly when the rats were pretreated with enalaprilat in vivo. The values were essentially comparable to those of SOC rats fed a low-protein diet. By contrast, there was no substantial increase in the production of PGE2, 6-keto PGF1 alpha, and TxB2 and in the mass of cycloxygenase in glomeruli of BUO versus SOC rats fed a low-protein diet. Enalaprilat did not affect glomerular eicosanoid production or cyclooxygenase content in SOC and BUO rats fed a low-protein diet. Taken together, the present study indicates that dietary protein affects BUO-induced increases in glomerular eicosanoid production by altering the activity of the cyclooxygenase pathway mainly via the reninangiotensin system. Thus, protein content in a diet may modify an alteration in renal hemodynamics caused by BUO by changing the glomerular production of eicosanoids and the activity of the renin-angiotensin system.
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PMID:Effects of dietary protein on glomerular eicosanoid production in rats with bilateral ureteral obstruction. 793 55

1. Isolated perfused rat tail artery preparations were used to investigate the effects of the angiotensin converting enzyme inhibitor enalaprilat on the actions of a series of alpha-adrenoceptor antagonists. The agonist used was phenylephrine. 2. Enalaprilat (1 mumol/L) potentiated the competitive alpha 1-adrenoceptor antagonist actions of phentolamine (10-100 nmol/L) and yohimbine (0.3-3.0 mumol/L) as well as the non-competitive antagonist action of phenoxybenzamine (50-100 pmol/L). 3. The competitive alpha 1-adrenoceptor antagonist action of prazosin (1-10 nmol/L) was not affected by enalaprilat. 4. For the competitive alpha 1-adrenoceptor antagonists, including prazosin, there appeared to be an inverse relationship between antagonist potency and the extent of potentiation by enalaprilat. 5. The results support the hypothesis and angiotensin II modulates vascular smooth muscle alpha 1-adrenoceptor function.
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PMID:The interaction between enalaprilat and selected alpha-adrenoceptor antagonists in isolated rat tail arteries. 795 51

In this study, the acute haemodynamic effects of angiotensin converting enzyme (ACE) inhibition with intravenous enalaprilat alone or in combination with preload restoration were determined in patients with severe heart failure complicating acute myocardial infarction. Ten patients with raised pulmonary arterial wedge pressure (PAWP > or = 18 mmHg) were first studied during constant conventional vasodilation with diuretic and inotropic medication, by monitoring central haemodynamics and arterial blood gases. The same variables were measured before enalaprilat infusion, after preload reduction with enalaprilat (1 mg.h-1, rate doubled every 30 min until PAWP decreased > or = 25% or up to total cumulative dose of 10 mg) and after preload restoration with fluid loading (4% albumin given 15 ml.min-1 to restore PAWP to baseline) during continuous low dose enalaprilat infusion. Enalaprilat alone (median dose 0.9 mg) reduced significantly the PAWP (from 25 to 17 mmHg; P = 0.004), the mean arterial pressure (from 87 to 83 mmHg; P = 0.008), the mean pulmonary arterial pressure and the right atrial pressure. The cardiac index, stroke volume index and systemic vascular resistance index remained unchanged. Preload restoration during continuous enalaprilat infusion (median dose of 4% albumin 230 ml, and enalaprilat 0.2 mg) did not further enhance left ventricular function; rather, there was a nearly significant decrease in myocardial perfusion pressure. Arterial oxygenation remained unchanged throughout the study. In conclusion, adding intravenous enalaprilat to conventional therapy makes it possible to relieve pulmonary congestion while maintaining the cardiac function and arterial oxygenation. Preload restoration during continuous ACE inhibition offers no further advantages, and may have adverse effects, since the myocardial perfusion pressure may fall.
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PMID:Haemodynamic effects of enalaprilat and preload in acute severe heart failure complicating myocardial infarction. 807 Apr 80

A series of trifluoromethyl-containing analogs of captopril as well as analogs and homologs of enalaprilat were synthesized and evaluated for inhibition of angiotensin converting enzyme (ACE). It was found that direct substitution of trifluoromethyl for methyl produced a very potent captopril analog with an IC50 of 3 x 10(-10) M in vitro. Hydrophobicity and conformational effects of trifluoromethyl group are among the reasons accounting for this activity. Structure-activity relationship is studied based on molecular mechanics calculations using a II-SCF-molecular mechanics program (PIMM) as well as SYBYL molecular mechanics program. It was found that simultaneous incorporation of trifluoromethyl and an indoline residue unexpectedly yielded a less potent captopril analog (IC50 = 8 x 10(-8) M). Enalaprilat analogs derived from replacement of the alanine residue with trifluoronorvaline and trifluoronorleucine residues gave moderately potent compounds (IC50 = 2-6 x 10(-8) M). The structure-activity relationship for these fluoroenalaprilat analogs is discussed in comparison with known analogs.
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PMID:Design, synthesis and enzyme inhibitory activities of new trifluoromethyl-containing inhibitors for angiotensin converting enzyme. 807 3

The effects of captopril on the response of cytosolic free Ca2+ concentration in cultured vascular smooth muscle cells of aortas from Wistar-Kyoto and spontaneously hypertensive rats to angiotensin II (Ang II) and bradykinin were studied using fura 2. Incubation with captopril for longer than 10 minutes caused a decreased response of cytosolic free Ca2+ to Ang II and bradykinin. Maximal effects of captopril were observed after a 40-minute incubation. The inhibitory effect of captopril was abolished in Ca(2+)-free medium, suggesting that captopril acts by blocking Ca2+ influx. Similar effects were observed with enalaprilat. Isometric contraction of aortic strips induced by Ang II in normotensive rats was reduced from 6.5 +/- 2.5 to 1.8 +/- 0.6 mN by a 40-minute incubation with 1 mumol/L captopril (P = .016). Enalaprilat similarly decreased the Ang II-induced contraction. Besides the inhibition of the angiotensin converting enzyme, direct effects of Ang II converting enzyme inhibitors on vascular contraction and Ca2+ influx in vascular smooth muscle cells may be of therapeutic relevance.
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PMID:Effect of captopril on vasoconstriction and Ca2+ fluxes in aortic smooth muscle. 824 13

Bradykinin (BK) affects a variety of smooth muscle types, including uterus. These effects are generally short-lived due to metabolism by a variety of enzymes including angiotensin converting enzyme (ACE), endopeptidase 24.11 (EP-24.11) and endopeptidase 24.15 (EP-24.15). The uterotonic action of BK and the limitation of that action by peptidases were examined using isolated rat uterus. BK contracted the estrus, diestrus and day 22 pregnant rat uterus. N-[1(R,S)-carboxy-3-phenylpropyl]-Phe-p-aminobenzoate (10(-7) M), a specific inhibitor of EP-24.11, and N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate (10(-6) M), a specific inhibitor of EP-24.15, enhanced BK-induced contraction in the estrus and pregnant uterus. Enalaprilat (6 x 10(-8) M), an inhibitor of ACE, also enhanced BK-induced contraction. The enzyme inhibitors alone did not contract the uterus. Bradykinin B2 receptor antagonism blocked the effects of the inhibitors. ACE is present in the rat uterus, but there are no reports of EP-24.11 or EP-24.15. Here we report that EP-24.11 and EP-24.15 activities are present in the estrus and pregnant rat uterus. Partially purified uterine homogenates metabolized specific model substrates for EP-24.11 and EP-24.15. The enzyme activities were inhibited by N-[1(R,S)-carboxy-3-phenylpropyl]-Phe-p-aminobenzoate and N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate, respectively, and increased 5- to 8-fold at term pregnancy as compared to estrus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulatory effect of endopeptidase inhibitors on bradykinin-induced contraction of rat uterus. 839 14


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