Drugs online research references
Gastroenterology. 1991 Jan;100(1):25-32.
Angiotensin-converting enzyme in the rabbit stomach wall. Identification in the membrane fraction by affinity purification.
Kobayashi R, Sun XY, Walsh JH.
Center for Ulcer Research and Education, University of California, Los Angeles School of Medicine.
To examine the potential role of angiotensin-converting enzyme as a physiological regulator of neuropeptide activity in the alimentary tract, we purified and partially characterized this enzyme from the crude membrane fraction of rabbit gastric muscles. A single-step purification from detergent-solubilized gastric membranes by affinity chromatography, using lisinopril-Sepharose, yielded an electrophoretically homogeneous peptidase composed of 180-kilodalton polypeptide. The purified enzyme represented approximately 2% of [Leu5]enkephalin-degrading activity of the original membrane preparation, and 275-fold purification was achieved. The gastric angiotensin-converting enzyme hydrolyzed synthetic substrates specific to the lung enzyme. It hydrolyzed angiotensin I and several other bioactive peptides, by removing their carboxyl-terminal dipeptides. The activity was completely inhibited with 10(-6) mol/L captopril. The hydrolysis of enkephalin was enhanced twofold by addition of 0.3 mol/L NACl to the assay buffer. These properties were comparable with those reported for the rabbit lung enzyme. Therefore, it was concluded that rabbit gastric muscle tissue contains membrane-bound angiotensin-converting enzyme. The results suggest a role for this enzyme as a local inactivator of bioactive peptides in the stomach wall.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1845758&dopt=Abstract
J Cardiovasc Pharmacol. 1989 Oct;14(4):511-8.
Angiotensin-converting enzyme in rat brain and extraneural tissues visualized by quantitative autoradiography using 3H-trandolaprilate.
Bardelay C, Mach E, Worcel M, Hunt P.
Centre de Recherches Roussel-Uclaf, Romainville, France.
Tritium-labeled trandolaprilate (RU 44403), the active diacid form of the potent and long-acting angiotensin-converting enzyme (ACE) inhibitor trandolapril, has been evaluated as a new autoradiographic marker for the enzyme. The characteristics of 3H-trandolaprilate binding were first determined autoradiographically in tissue sections from rat brain (caudate-putamen) and kidney. 3H-Trandolaprilate binds saturably to these tissues, and with very high affinity (Kd values, 0.36 and 0.13 nM, respectively), and appears to show good selectivity for the enzyme. Due to its high affinity (approximately 100 times that of captopril), the performance of 3H-trandolaprilate as an autoradiographic marker is comparable to that of the recently described 125I-labeled derivative of lisinopril (125I-351A). Saturation and displacement studies in serial sections from a variety of central and peripheral tissues confirmed that the specificity of labeling was similar throughout. The anatomical distribution of ACE visualized with 3H-trandolaprilate in these tissues was close to that described for 3H-captopril and 125I-351A with some minor differences which might arise from difference in the specificity of the ligands.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2478763&dopt=Abstract
Mol Pharmacol. 1992 Aug;42(2):286-93.
Two binding sites on angiotensin-converting enzyme: evidence from radioligand binding studies.
Perich RB, Jackson B, Rogerson F, Mendelsohn FA, Paxton D, Johnston CI.
University of Melbourne, Department of Medicine, Austin Hospital, Heidelberg, Victoria, Australia.
Purified angiotensin-converting enzyme (ACE) from rat lung and testis, membrane preparations of ACE from lung, kidney, and testis, and ACE from plasma were used in radioligand binding studies, to seek evidence for two binding sites in ACE of somatic origin, as predicted by molecular biology studies. 125I-Ro 31-8472, a radioiodinated hydroxy derivative of cilazaprilat, and 125I-351A, a radioiodinated p-hydroxybenzamidine analogue of lisinopril, were used as radioligands. Autoradiographic study of renal ACE using 125I-Ro 31-8472 or 125I-351A showed the same distribution of radioligand binding across kidney sections and identical radioligand binding for purified lung and testis ACE by Western blot, confirming that the same protein bound both radioligands. Analysis of displacement of 125I-Ro 31-8472 binding from ACE by ACE inhibitors 351A and lisinopril yielded biphasic curves for pulmonary, renal, and plasma ACE and a monophasic curve for ACE from the testis. Analysis by LIGAND suggested two binding sites in ACE from plasma or somatic sources and one binding site in ACE of testicular origin, as predicted by molecular biology studies. Displacement of 125I-351A binding from lung and testis ACE by Ro 31-8472 and 351A was monophasic. LIGAND analysis revealed interaction with a single class of binding sites on lung and testis ACE, in agreement with previous studies using 125I-351A. Equilibrium dissociation constants (Kd) for the carboxyl-terminal (KdI) and amino-terminal (KdII) binding sites of purified ACE, using 125I-Ro 31-8472, were similar for Ro 31-8472 (lung kdI, 65 +/- 7 pM; KdII, 175 +/- 38 pM) but were clearly different for 351A (lung KdI, 19 +/- 2 pM; KdII, 2771 +/- 489 pM; p less than 0.01). Cell membrane-associated somatic ACE and plasma ACE, which is devoid of a carboxyl-terminal hydrophobic anchor region, had similar absolute values and differences in 351A binding affinities at the two ACE binding sites. Kd in testis was 46 +/- 6 pM for Ro 31-8472 and 16 +/- 3 pM for 351A, corresponding to estimates at the carboxyl-terminal binding site of somatic ACE. The 65-200-fold reduction in 351A binding affinity at the amino binding site may limit the detection of two binding sites on somatic ACE by 125I-351A radioligand binding analysis.(ABSTRACT TRUNCATED AT 400 WORDS)
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1325031&dopt=Abstract
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