This Article Full Text Full Text (PDF) 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 van Kats, J. P. Articles by Danser, A. H. J. Search for Related Content PubMed PubMed Citation Articles by van Kats, J. P. Articles by Danser, A. H. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CAPTOPRIL Medline Plus Health Information Heart Attack Related Collections Biochemistry and metabolism Chronic ischemic heart disease Cardio-renal physiology/pathophysiology Cardiovascular Pharmacology ACE/Angiotension receptors Animal models of human disease

(Circulation. 2000;102:1556.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade Prevent Cardiac Remodeling in Pigs After Myocardial Infarction

Role of Tissue Angiotensin II

Jorge P. van Kats, PhD; Dirk J. Duncker, MD, PhD; David B. Haitsma, MD; Martin P. Schuijt, MSc; Remko Niebuur, MSc; René Stubenitsky, MSc; Frans Boomsma, PhD; Maarten A. D. H. Schalekamp, MD, PhD; Pieter D. Verdouw, PhD; A. H. Jan Danser, PhD

From the Departments of Internal Medicine I (J.P.v.K., M.P.S., F.B., M.A.D.H.S.), Experimental Cardiology (J.P.v.K., D.J.D., D.B.H., R.N., R.S., P.D.V.), and Pharmacology (M.P.S., A.H.J.D.), Erasmus University Rotterdam, Rotterdam, the Netherlands.

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

Background—The mechanisms behind the beneficial effects of renin-angiotensin system blockade after myocardial infarction (MI) are not fully elucidated but may include interference with tissue angiotensin II (Ang II).

Methods and Results—Forty-nine pigs underwent coronary artery ligation or sham operation and were studied up to 6 weeks. To determine coronary angiotensin I (Ang I) to Ang II conversion and to distinguish plasma-derived Ang II from locally synthesized Ang II, ¹²⁵I-labeled and endogenous Ang I and II were measured in plasma and in infarcted and noninfarcted left ventricle (LV) during ¹²⁵I-Ang I infusion. Ang II type 1 (AT₁) receptor–mediated uptake of circulating ¹²⁵I-Ang II was increased at 1 and 3 weeks in noninfarcted LV, and this uptake was the main cause of the transient elevation in Ang II levels in the noninfarcted LV at 1 week. Ang II levels and AT₁ receptor–mediated uptake of circulating Ang II were reduced in the infarct area at all time points. Coronary Ang I to Ang II conversion was unaffected by MI. Captopril and the AT₁ receptor antagonist eprosartan attenuated postinfarct remodeling, although both drugs increased cardiac Ang II production. Captopril blocked coronary conversion by >80% and normalized Ang II uptake in the noninfarcted LV. Eprosartan did not affect coronary conversion and blocked cardiac Ang II uptake by >90%.

Conclusions—Both circulating and locally generated Ang II contribute to remodeling after MI. The rise in tissue Ang II production during angiotensin-converting enzyme inhibition and AT₁ receptor blockade suggests that the antihypertrophic effects of these drugs result not only from diminished AT₁ receptor stimulation but also from increased stimulation of growth-inhibitory Ang II type 2 receptors.

Key Words: angiotensin • inhibitors • receptors • myocardial infarction • hypertrophy

This article has been cited by other articles:

				O. Sorop, D. Merkus, V. J. de Beer, B. Houweling, A. Pistea, E. O. McFalls, F. Boomsma, H. M. van Beusekom, W. J. van der Giessen, E. VanBavel, et al. Functional and Structural Adaptations of Coronary Microvessels Distal to a Chronic Coronary Artery Stenosis Circ. Res., April 11, 2008; 102(7): 795 - 803. [Abstract] [Full Text] [PDF]

				D. Merkus, D. B. Haitsma, O. Sorop, F. Boomsma, V. J. de Beer, J. M. J. Lamers, P. D. Verdouw, and D. J. Duncker Coronary vasoconstrictor influence of angiotensin II is reduced in remodeled myocardium after myocardial infarction Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2082 - H2089. [Abstract] [Full Text] [PDF]

				B. Houweling, D. Merkus, O. Sorop, F. Boomsma, and D. J. Duncker Role of endothelin receptor activation in secondary pulmonary hypertension in awake swine after myocardial infarction J. Physiol., July 15, 2006; 574(2): 615 - 626. [Abstract] [Full Text] [PDF]

				M. E. Dickson and C. D. Sigmund Genetic Basis of Hypertension: Revisiting Angiotensinogen Hypertension, July 1, 2006; 48(1): 14 - 20. [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]

				D. J. Duncker, D. B. Haitsma, D. A. Liem, P. D. Verdouw, and D. Merkus Exercise unmasks autonomic dysfunction in swine with a recent myocardial infarction Cardiovasc Res, March 1, 2005; 65(4): 889 - 896. [Abstract] [Full Text] [PDF]

				D. Merkus, B. Houweling, A. H. van den Meiracker, F. Boomsma, and D. J. Duncker Contribution of endothelin to coronary vasomotor tone is abolished after myocardial infarction Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H871 - H880. [Abstract] [Full Text] [PDF]

				J. van der Velden, D. Merkus, B.R. Klarenbeek, A.T. James, N.M. Boontje, D.H.W. Dekkers, G.J.M. Stienen, J.M.J. Lamers, and D.J. Duncker Alterations in Myofilament Function Contribute to Left Ventricular Dysfunction in Pigs Early After Myocardial Infarction Circ. Res., November 26, 2004; 95(11): e85 - e95. [Abstract] [Full Text]

				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]

				M. J. Ryan and C. D. Sigmund ACE, ACE Inhibitors, and Other JNK Circ. Res., January 9, 2004; 94(1): 1 - 3. [Full Text] [PDF]

				H. Thai, J. Wollmuth, S. Goldman, and M. Gaballa Angiotensin Subtype 1 Receptor (AT1) Blockade Improves Vasorelaxation in Heart Failure by Up-Regulation of Endothelial Nitric-Oxide Synthase via Activation of the AT2 Receptor J. Pharmacol. Exp. Ther., December 1, 2003; 307(3): 1171 - 1178. [Abstract] [Full Text] [PDF]

				B. Tom, I. M. Garrelds, E. Scalbert, A. P.A. Stegmann, F. Boomsma, P. R. Saxena, and A.H. J. Danser ACE- Versus Chymase-Dependent Angiotensin II Generation in Human Coronary Arteries: A Matter of Efficiency? Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 251 - 256. [Abstract] [Full Text] [PDF]

				D. L. Brutsaert Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity Physiol Rev, January 1, 2003; 83(1): 59 - 115. [Abstract] [Full Text] [PDF]

				T. W. Lameris, S. de Zeeuw, D. J. Duncker, G. Alberts, F. Boomsma, P. D. Verdouw, and A. H. van den Meiracker Exogenous Angiotensin II Does Not Facilitate Norepinephrine Release in the Heart Hypertension, October 1, 2002; 40(4): 491 - 497. [Abstract] [Full Text] [PDF]

				M. P. Schuijt, M. Basdew, R. van Veghel, R. de Vries, P. R. Saxena, R. G. Schoemaker, and A. H. Jan Danser AT2 receptor-mediated vasodilation in the heart: effect of myocardial infarction Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2590 - H2596. [Abstract] [Full Text] [PDF]

				D. B Haitsma, D. Bac, N. Raja, F. Boomsma, P. D Verdouw, and D. J Duncker Minimal impairment of myocardial blood flow responses to exercise in the remodeled left ventricle early after myocardial infarction, despite significant hemodynamic and neurohumoral alterations Cardiovasc Res, December 1, 2001; 52(3): 417 - 428. [Abstract] [Full Text] [PDF]

				S. Lee, C. M. Kramer, S. Mankad, S.-e. Yoo, and K. Sandberg Combined angiotensin converting enzyme inhibition and angiotensin AT1 receptor blockade up-regulates myocardial AT2 receptors in remodeled myocardium post-infarction Cardiovasc Res, July 1, 2001; 51(1): 131 - 139. [Abstract] [Full Text] [PDF]

				L. H. Opie and M. N. Sack Enhanced Angiotensin II Activity in Heart Failure : Reevaluation of the Counterregulatory Hypothesis of Receptor Subtypes Circ. Res., April 13, 2001; 88(7): 654 - 658. [Abstract] [Full Text] [PDF]

				J. J. Saris, F. H. M. Derkx, J. M. J. Lamers, P. R. Saxena, M. A. D. H. Schalekamp, and A. H. J. Danser Cardiomyocytes Bind and Activate Native Human Prorenin : Role of Soluble Mannose 6-Phosphate Receptors Hypertension, February 1, 2001; 37(2): 710 - 715. [Abstract] [Full Text] [PDF]

				D. B. Haitsma, D. Merkus, J. Vermeulen, P. D. Verdouw, and D. J. Duncker Nitric oxide production is maintained in exercising swine with chronic left ventricular dysfunction Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2198 - H2209. [Abstract] [Full Text] [PDF]