Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/9557
Title: Variation in angiotensin-converting enzyme (ACE) inhibitor affinity at two binding sites on rat pulmonary ACE: influence on bradykinin hydrolysis.
Authors: Perich, R B;Jackson, B;Johnston, Colin I
Affiliation: Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.
Issue Date: 1-May-1992
Citation: Clinical and Experimental Pharmacology & Physiology; 19(5): 353-7
Abstract: 1. ACE from rat lung and testis was characterized by radioligand binding studies using [125I]-Ro 31-8472, the radioiodinated hydroxy derivative of the potent ACE inhibitor cilazaprilat. 2. Analysis of the displacement of [125I]-Ro 31-8472 from ACE by ACE inhibitors of different structure by the LIGAND program was best fitted by a two binding site model for lung ACE and a one binding site model for testis ACE. 3. There was marked variation in ACE inhibitor binding affinity at the two binding sites of lung ACE across the panel of ACE inhibitors studied (equilibrium dissociation constant; Kd; pmol/L) for site one vs site two: cilazaprilat 40 +/- 3 vs 430 +/- 92*; lisinopril 25 +/- 1 vs 848 +/- 107**; and quinaprilat 4 +/- 1 vs 1869 +/- 720; *P less than 0.05; **P less than 0.005, t-test, n = 3). Reduction in binding affinity at site two of lung ACE was related to an increase in ACE inhibitor side chain length or complexity of carboxyl terminal moiety. ACE inhibitor binding affinity at the testis ACE binding site resembled site one of lung ACE. 4. Inhibition of bradykinin hydrolysis by lung ACE in the presence of increasing concentrations of cilazaprilat or quinaprilat was similar (F = 0.64; P greater than 0.05), suggesting that bradykinin cleavage predominates at ACE active site one. 5. The differences in ACE inhibitor affinity at the two ACE active sites has implications in physiological substrate selectivity, and may influence the pharmacodynamic effects of different ACE inhibitors.
Internal ID Number: 1325885
URI: http://ahro.austin.org.au/austinjspui/handle/1/9557
URL: http://www.ncbi.nlm.nih.gov/pubmed/1325885
Type: Journal Article
Subjects: Angiotensin-Converting Enzyme Inhibitors.metabolism
Animals
Binding Sites
Bradykinin.metabolism
Genetic Variation
Hydrolysis.drug effects
Iodine Radioisotopes
Kinetics
Lung.enzymology
Male
Peptidyl-Dipeptidase A.drug effects.metabolism
Pyridazines.metabolism
Radioligand Assay
Rats
Rats, Inbred Strains
Structure-Activity Relationship
Testis.enzymology
Appears in Collections:Journal articles

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