We investigated the binding characteristics of angiotensin receptors and used this assay to determine the predominant enzyme capable of converting angiotensin I in the human left ventricle. In homogenates of human left ventricle, 125I-[Sar1,Ile8]angiotensin II bound with sub-nanomolar affinity, with a corresponding KD of 0.42±0.09nM, a Bmax of 11.2±2.3fmolċmg-1 protein and a Hill slope of 1.04±0.04. The rank order of inhibitory potency of competing ligands for the 125I-[Sar1,Ile8]angiotensin II binding site was CGP42112 > angiotensin II⩾ angiotensin III = angiotensin I > losartan. The angiotensin type II (AT2) receptor predominated in the human left ventricle over the angiotensin type I (AT1) receptor, with an approximate AT1/AT2 receptor ratio of 35:65. No specific 125I-angiotensin IV binding sites could be detected in the human left ventricle. Using competitive radioligand binding assays, we were able to demonstrate that the chymase/cathepsin G enzyme inhibitor chymostatin was more potent than the angiotensin-converting enzyme (ACE) inhibitor captopril at inhibiting the conversion of angiotensin I in the human left ventricle. Aprotonin (an inhibitor of cathepsin G but of not chymase) had no effect on angiotensin I conversion, suggesting that the majority of the conversion was mediated by chymase. Thus, although the current therapies used for the renin-angiotensin system have focused on ACE inhibitors and AT1 receptor antagonists, the left ventricle of the human heart expresses mainly AT2 receptors and the tissue-specific conversion of angiotensin I occurs predominantly via chymase rather than ACE.
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Research Article|
November 28 2001
Radioligand binding reveals chymase as the predominant enzyme for mediating tissue conversion of angiotensin I in the normal human heart
Sidath D. KATUGAMPOLA;
Sidath D. KATUGAMPOLA
1Clinical Pharmacology Unit, University of Cambridge, Level 6, Centre for Clinical Investigations, Box 110, Addenbrooke's Hospital, Cambridge CB2 2QQ, U.K.
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Anthony P. DAVENPORT
1Clinical Pharmacology Unit, University of Cambridge, Level 6, Centre for Clinical Investigations, Box 110, Addenbrooke's Hospital, Cambridge CB2 2QQ, U.K.
Correspondence: Dr Anthony P. Davenport (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
March 20 2001
Revision Received:
June 06 2001
Accepted:
August 28 2001
Online ISSN: 1470-8736
Print ISSN: 0143-5221
The Biochemical Society and the Medical Research Society © 2002
2002
Clin Sci (Lond) (2002) 102 (1): 15–21.
Article history
Received:
March 20 2001
Revision Received:
June 06 2001
Accepted:
August 28 2001
Citation
Sidath D. KATUGAMPOLA, Anthony P. DAVENPORT; Radioligand binding reveals chymase as the predominant enzyme for mediating tissue conversion of angiotensin I in the normal human heart. Clin Sci (Lond) 1 January 2002; 102 (1): 15–21. doi: https://doi.org/10.1042/cs1020015
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