This Article Full Text Full Text (PDF) All Versions of this Article: 23/2/251    most recent 01.ATV.0000051875.41849.25v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tom, B. Articles by Danser, A.H. J. Search for Related Content PubMed PubMed Citation Articles by Tom, B. Articles by Danser, A.H. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CAPTOPRIL Related Collections Health policy and outcome research ACE/Angiotension receptors Fibrinolysis CV surgery: transplantation, ventricular assistance, cardiomyopathy Cardiac development

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:251.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

ACE- Versus Chymase-Dependent Angiotensin II Generation in Human Coronary Arteries

A Matter of Efficiency?

Beril Tom; Ingrid M. Garrelds; Elizabeth Scalbert; Alexander P.A. Stegmann; Frans Boomsma; Pramod R. Saxena; A.H. Jan Danser

From the Department of Pharmacology, Thoracic Surgery and Heart Valve Bank (A.P.A.S.), and Internal Medicine (F.B.), Erasmus MC, Rotterdam, The Netherlands and Institut de Recherches Internationales Servier (E.S.), Courbevoie, France.

Correspondence to Dr A.H.J. Danser, Department of Pharmacology, Room EE1418b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail danser{at}farma.fgg.eur.nl

Objective— The objective of this study was to investigate ACE- and chymase-dependent angiotensin I-to-II conversion in human coronary arteries (HCAs).

Methods and Results— HCA rings were mounted in organ baths, and concentration-response curves to angiotensin II, angiotensin I, and the chymase-specific substrate Pro¹¹-D-Ala¹²–angiotensin I (PA–angiotensin I) were constructed. All angiotensins displayed similar efficacy. For a given vasoconstriction, bath (but not interstitial) angiotensin II during angiotensin I and PA–angiotensin I was lower than during angiotensin II, indicating that interstitial (and not bath) angiotensin II determines vasoconstriction. PA–angiotensin I increased interstitial angiotensin II less efficiently than angiotensin I. Separate inhibition of ACE (with captopril) and chymase (with C41 or chymostatin) shifted the angiotensin I concentration-response curve 5-fold to the right, whereas a 10-fold shift occurred during combined ACE and chymase inhibition. Chymostatin, but not captopril and/or C41, reduced bath angiotensin II and abolished PA–Ang I–induced vasoconstriction. Perfused HCA segments, exposed luminally or adventitially to angiotensin I, released angiotensin II into the luminal and adventitial fluid, respectively, and this release was blocked by chymostatin.

Conclusions— Both ACE and chymase contribute to the generation of functionally active angiotensin II in HCAs. However, because angiotensin II loss in the organ bath is chymase-dependent, ACE-mediated conversion occurs more efficiently (ie, closer to AT₁ receptors) than chymase-mediated conversion.

Key Words: angiotensin • angiotensin-converting enzyme • chymase • human coronary artery • Pro¹¹-D-Ala¹²–angiotensin I

This article has been cited by other articles:

				M. Wang, J. Zhang, L.-Q. Jiang, G. Spinetti, G. Pintus, R. Monticone, F. D. Kolodgie, R. Virmani, and E. G. Lakatta Proinflammatory Profile Within the Grossly Normal Aged Human Aortic Wall Hypertension, July 1, 2007; 50(1): 219 - 227. [Abstract] [Full Text] [PDF]

				A. H. Jan Danser, W. W. Batenburg, and J. H. M. van Esch Prorenin and the (pro)renin receptor--an update Nephrol. Dial. Transplant., May 1, 2007; 22(5): 1288 - 1292. [Full Text] [PDF]

				C. A. Burckle, A.H. Jan Danser, D. N. Muller, I. M. Garrelds, J.-M. Gasc, E. Popova, R. Plehm, J. Peters, M. Bader, and G. Nguyen Elevated Blood Pressure and Heart Rate in Human Renin Receptor Transgenic Rats Hypertension, March 1, 2006; 47(3): 552 - 556. [Abstract] [Full Text] [PDF]

				W. Chai, I. M. Garrelds, R. de Vries, W. W. Batenburg, J. P. van Kats, and A.H. Jan Danser Nongenomic Effects of Aldosterone in the Human Heart: Interaction With Angiotensin II Hypertension, October 1, 2005; 46(4): 701 - 706. [Abstract] [Full Text] [PDF]

				J. H.M. van Esch, B. Tom, V. Dive, W. W. Batenburg, D. Georgiadis, A. Yiotakis, J. M.G. van Gool, R. J.A. de Bruijn, R. de Vries, and A.H. J. Danser Selective Angiotensin-Converting Enzyme C-Domain Inhibition Is Sufficient to Prevent Angiotensin I-Induced Vasoconstriction Hypertension, January 1, 2005; 45(1): 120 - 125. [Abstract] [Full Text] [PDF]

				W. W. Batenburg, I. M. Garrelds, C. C. Bernasconi, L. Juillerat-Jeanneret, J. P. van Kats, P. R. Saxena, and A.H. J. Danser Angiotensin II Type 2 Receptor-Mediated Vasodilation in Human Coronary Microarteries Circulation, May 18, 2004; 109(19): 2296 - 2301. [Abstract] [Full Text] [PDF]

				S. A Doggrell and J. C Wanstall Vascular chymase: pathophysiological role and therapeutic potential of inhibition Cardiovasc Res, March 1, 2004; 61(4): 653 - 662. [Abstract] [Full Text] [PDF]