Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50502 (Hip)
 7,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cilazapril is the monoethyl ester prodrug form of a potent, specific. long-acting antihypertensive inhibitor of angiotensin-converting enzyme (ACE). The biochemical and pharmacological properties of this compound have been compared with those of captopril and enalapril. In all test systems, cilazapril was the most potent and the longest acting. The active diacid of cilazapril was more potent than the corresponding diacid of enalapril in inhibiting the cleavage of angiotensin I and of Hip-His-Leu by ACE in vitro, in antagonising the angiotensin I-induced contractions of the isolated ileum of the guinea pig, in potentiating the vasodepressor responses to bradykinin, and in reducing the angiotensin I-induced rise in blood pressure of the rat. Parent drug absorption and diacid bioavailability in the rat were higher than for enalapril, and the inhibition of plasma ACE of longer duration. Single doses of cilazapril were more potent than enalapril in lowering the blood pressure of spontaneously hypertensive rats (SHR) and two-kidney renal hypertensive rats. On repeated daily oral dosing to SHR, both compounds had a cumulative antihypertensive effect. The acute antihypertensive effect was enhanced by simultaneous treatment with hydrochlorothiazide.
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PMID:Biological properties of the angiotensin-converting enzyme inhibitor cilazapril. 241 Jun 92

Radioinhibitor binding displacement, a new method for the measurement of angiotensin-converting enzyme (ACE) competitive inhibitors, has been used to assess the relative potency of nine synthetic ACE inhibitors. MK351A, tyrosyl derivative of enalaprilic acid was iodinated with 125I and used as the radioligand. [125I]MK351A bound to human serum ACE in a concentration-dependent manner. It was displaced in a concentration-dependent manner by all ACE inhibitors tested. Fifty percent displacement of bound [125I]MK351A (DD50) for each ACE inhibitor correlated well with inhibitor potency ID50, estimated using an ACE enzymatic activity assay using Hip-His-Leu as substrate (r = 0.96, p less than 0.001; n = 9). The radioinhibitor binding displacement assay was used to measure serum concentration of enalaprilic acid (MK422) in human serum samples. Drug concentration estimated by radioinhibitor binding displacement assay correlated closely (r = 0.96, p less than 0.001; n = 22) with the drug concentration measured by a specific radioimmunoassay. The radioinhibitor binding displacement technique using [125I]MK351A as the ligand for human serum ACE has general application to all competitive ACE inhibitors, allowing comparison of in vitro ACE inhibitor potencies and estimation of serum ACE inhibitor concentrations.
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PMID:Angiotensin-converting enzyme inhibitors: measurement of relative inhibitory potency and serum drug levels by radioinhibitor binding displacement assay. 244 37

The most sensitive nonradiometric routine assay for angiotensin-converting enzyme (ACE) activity uses fluorometry to detect His-Leu released from Hip-His-Leu. Our results indicate that, in contrast to human serum, rat serum and plasma contain large and variable amounts of dipeptidase activity that lead to a subestimation of the ACE activity measured in 0.1 M potassium phosphate buffer, pH 8.3, containing 0.3 M NaCl, the most commonly used assay for human serum and tissue ACE. We describe and validate an assay for 1 to 10 microL rat and human serum or plasma using 5 mM Hip-His-Leu in 500 microL of 0.4 M sodium borate buffer, pH 8.3, containing 0.9 M NaC1 at 37 degrees C that reduced the subestimation error to less than or equal to 3% (rat serum) and less than or equal to 0.1% (human serum) and increased the ACE activity twofold to threefold. The Km and Vmax are reported for rat serum ACE (Hip-His-Leu) and dipeptidase (His-Leu) in borate buffer and phosphate buffer. Rat serum ACE hydrolysis of Hip-His-Leu measured by fluorometry correlated (r = 0.99, p less than 0.05) with the hydrolysis of angiotensin I measured by high-performance liquid chromatography. A direct method based on amino acid analysis is described for evaluating the dipeptidase error of complex mixtures such as tissue extracts and other physiological fluids. We have found that the assay can be used to measure ACE activity in 25 samples (in duplicate) in 2 hours with small intraassay (2.2%) and interassay (3.9%) coefficients of variation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An improved fluorometric assay of rat serum and plasma converting enzyme. 298 18

Thirty-four ACE inhibitors were evaluated to determine the concentration giving 50% inhibition of purified rabbit lung ACE (IC50 microM) using benzyloxycarboxyl-p-NO2-Phe-His-Leu as substrate, to determine the oral dose causing a lowering in blood pressure of 30 mm Hg (ED30 mumol/kg) in acute aortic coarctate (AAC) rats, and to determine inhibition of plasma ACE (PACE) activity in mice after oral dosing. Mouse PACE activity was determined with 14C-Hip-His-Leu as substrate one hour after oral dosing of 3 animals/group with 5 or 50 mumol ACE inhibitor per kg. Data from mice were expressed as percent of control group PACE activity. Least squares regression analysis showed the IC50 data to be poorly correlated with either rat data or mouse PACE data at 50 mumol/kg p.o. However, correlation was significant between log rat ED30 and mouse PACE at 5 (p less than 0.001, r = 0.570) and 50 (p less than 0.025, r = 0.387) mumol/kg p.o. Thus, the simple mouse plasma ACE determination after a dose of 5 mumol/kg is a convenient supplement to the AAC rat model for showing oral activity of ACE inhibitors.
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PMID:Correlation between anti-hypertensive activity in rats and plasma angiotensin I-converting enzyme (ACE) inhibition in mice following oral administration of ACE inhibitors. 298 53

A highly sensitive assay for angiotensin I converting enzyme has been developed by using angiotensin I as a substrate. Angiotensin II generated in the reaction mixture was measured by a newly developed specific radioimmunoassay. To protect against angiotensin II destruction, bestatin, an inhibitor of renin, was also used to inhibit plasma renin activity. The reaction was stopped by adding EDTA and MK-521, inhibitors of angiotensin I converting enzyme. The specificity of the antiserum used for the angiotensin II radioimmunoassay was very high. The cross reactivity with angiotensin I was less than 0.5% and none of the proteolytic enzyme inhibitors crossreacted in the assay. The inhibitory effect of pepstatin on plasma renin activity was very high (more than 80%) under the standard assay conditions employed. Serum angiotensinase activity was completely inhibited by the addition of bestatin. An excellent correlation was obtained between this new method and the spectrophotometric method using a synthetic substrate, Hip-His-Leu. The generation of as little as 12 pM of Angiotensin II can be detected. Such low concentration have not been measurable with the usual spectrophotometric method. This new method will facilitate clinical and experimental studies on this unique enzyme, since very low levels of activity can be determined by this highly sensitive radioimmunoassay for angiotensin II.
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PMID:An improved method for measuring angiotensin I converting enzyme activity using a highly sensitive angiotensin II radioimmunoassay. 300 65

MK351A, a tyrosyl analogue of enalaprilic acid (MK422) is a potent inhibitor of angiotensin-converting enzyme (ACE). MK351A was radioiodinated with 125I and used to develop a radio inhibitor binding assay for human serum ACE. 125I MK351A associated rapidly and reversibly with human serum ACE (T 1/2 = 1/2 h). Bound 125I MK351A was displaced by an excess of cold MK351A, to give non-specific binding of less than 1%. Scatchard analysis of binding was linear (r = -0.99, n = 6, p less than 0.001), indicating a single class of binding site. ACE was estimated in serum from normal patients and patients with sarcoid by the radio inhibitor binding assay and by enzyme kinetic assay using Hip-His-Leu as substrate. The two methods for ACE estimation correlated closely (r = 0.87, n = 82, p less than 0.001). The radio inhibitor binding assay for human serum ACE is a simple, sensitive and specific assay which utilizes novel assay methodology.
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PMID:Angiotensin-converting enzyme (ACE) measurement in human serum using radioinhibitor ligand binding. 301 76

An angiotensin-converting enzyme was isolated from human heart using N[-1(S)-carboxy-5-aminopentyl]glycyl-glycine as an affinity adsorbent. The isolation procedure resulted in an enzyme purified 1650-fold. The enzyme specific activity was 38.0 u./mg protein, Mr = 150 kD. The pH optimum for the angiotensin-converting enzyme towards Hip-His-Leu lies at 7.8, Km = 1.2 mM. The enzyme was inhibited by the substrate (Ks' = 14 mM). The enzyme effectively catalyzed the hydrolysis of angiotensin I (Km = 10 microM; kcat = 250 s-1). NaCl, CaCl2 as well as Na2SO4 in the absence of Cl- activated the enzyme, whereas CH3COONa and NaNO3 did not influence the enzyme activity. It was found that the bradykinin-potentiating factor inhibited the cardiac angiotensin-converting enzyme with IC50 = 4.0 X 10(-8) M.
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PMID:[Isolation and molecular kinetic properties of the angiotensin-converting enzyme from the human heart]. 302 99

Cultured bovine pulmonary artery endothelial cells contain a second peptidyl dipeptidase, distinct from angiotensin-converting enzyme, present in an inactive form associated with a non-dialyzable inhibitor. Partial purification by glycine affinity chromatography separates enzyme from inhibitor to yield a preparation which hydrolyzes angiotensin-1, bradykinin, substance P, atriopeptin-2, enkephalin and Hip-His-Leu. This enzyme is resistant to inhibition by lisinopril, captopril, thiorphan, phosphoramidon, soybean trypsin inhibitor, PMSF and aminopeptidase and carboxypeptidase inhibitors, but is inhibited by EDTA.
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PMID:Conversion of angiotensin-1 to angiotensin-2 by a latent endothelial cell peptidyl dipeptidase that is not angiotensin-converting enzyme. 351 10

Angiotensin I-converting enzyme (ACE) is present in human amniotic fluid. We characterized the enzyme by both its antigenic and enzymatic properties. Using a specific direct radioimmunoassay, ACE was quantified and characterized in each of the 19 samples tested. Mean level was 136 +/- 83 ng/ml. Amniotic ACE completely crossreacted, like that in plasma and kidney, with antibodies raised against the lung enzyme. ACE activity in amniotic fluid averaged 8.7 +/- 5.6 microU/ml using Hip-His-Leu as substrate and was significantly correlated with ACE antigen levels. ACE was not associated with the cells or the free intracellular organelles in amniotic fluid, and the enzyme was present in soluble form. Angiotensinase activity and high levels of kininase activity were found in amniotic fluid. Inhibition studies with captopril and anti-human ACE antibodies suggest that angiotensinases and kininases other than ACE were also present. Because renin, mostly in inactive form, and angiotensinogen were also found in these amniotic fluids, it appears that a complete, although not fully activated, renin angiotensin system is present in amniotic fluid and fetal membranes during pregnancy.
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PMID:Angiotensin I-converting enzyme in amniotic fluid. 609 99

We have studied inhibition of purified canine angiotensin converting enzyme by substance P and its nonapeptide derivative using Hip-His-Leu as the substrate. Kinetic studies indicated that both substance P and its nonapeptide derivative inhibited the hydrolysis of Hip-His-Leu at different concentrations. The mode of inhibition was competitive with a Ki of 1.15 microM for substance P. These results indicate that substance P is a potent inhibitor of angiotensin converting enzyme in vitro.
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PMID:Inhibition of canine lung angiotensin converting enzyme by substance P. 618 2


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