Published Online
on September 22, 2003

A more recent version of this article appeared on October 7, 2003

This Article Full Text (PDF) All Versions of this Article: 108/14/1679    most recent 01.CIR.0000094733.61689.D4v1 Alert me when this article is cited Alert me if a correction is posted 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 Zisman, L. S. Articles by Canver, C. C. Search for Related Content PubMed PubMed Citation Articles by Zisman, L. S. Articles by Canver, C. C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Cardio-renal physiology/pathophysiology Other heart failure Congestive ACE/Angiotension receptors Heart failure - basic studies Hypertrophy Myocardial cardiomyopathy disease Pulmonary circulation and disease

Submitted on January 7, 2003
Revised on August 8, 2003
Accepted on August 11, 2003

Angiotensin-(1-7) Formation in the Intact Human Heart. In Vivo Dependence on Angiotensin II as Substrate

Lawrence S. Zisman MD^*, Glenn E. Meixell PhD, Michael R. Bristow MD, PhD, and Charles C. Canver MD

From The Heart Institute, Albany Medical Center, Albany, NY (L.S.Z., C.C.C.), and The University of Colorado Health Sciences Center, Denver (G.E.M., M.R.B.).

^* To whom correspondence should be addressed. E-mail: zismanl{at}mail.amc.edu.

Background--Several enzymes that hydrolyze angiotensin I (Ang I) and Ang II to Ang-(1-7) have been identified, but their relative importance in the intact human heart is not known.

Methods and Results--Intracoronary (IC) ¹²³I-Ang I was administered to 4 heart transplantation recipients. Arterial and coronary sinus (CS) samples were taken before and after coadministration of IC enalaprilat. ¹²³I-Ang metabolites were separated by high-pressure liquid chromatography, and ¹²³I-Ang-(1-7) and ¹²³I-Ang II were quantified across the myocardial circulation. ¹²³I-Ang II formation (as measured by fractional conversion) at steady state was 0.43±0.05 and was reduced to 0.042±0.02 after IC enalaprilat (P<0.01). The fractional conversion of ¹²³I-Ang-(1-7) was 0.198±0.032 but was reduced to 0.06±0.01 during IC enalaprilat (P<0.01). Net Ang II production at steady state was 2720±704 pg/min. Ang-(1-7) production was 3489±768 pg/min. After IC enalaprilat, Ang II production fell to 436±66.8 pg/min (P<0.05 versus Ang II production). After suppression of Ang II production with enalaprilat, there was net uptake of Ang-(1-7): -289±144 pg/min (P<0.05).

Conclusions--Ang-(1-7) was formed in the intact human myocardial circulation and was decreased when Ang II formation was suppressed. These data indicate that the major pathway for Ang-(1-7) generation in the intact human heart was dependent on substrate availability of Ang II. Ang-(1-7)-forming enzymes that demonstrate substrate preference for Ang II are likely to play an important role in the regulation of Ang-(1-7) formation in the intact human heart.

Key words: angiotensin • enzymes • cardiomyopathy

This article has been cited by other articles:

				I. Falcao-Pires, N. Goncalves, T. Henriques-Coelho, D. Moreira-Goncalves, R. Roncon-Albuquerque Jr., and A. F. Leite-Moreira Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary hypertension Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H2007 - H2014. [Abstract] [Full Text] [PDF]

				P. E. Gallagher, C. M. Ferrario, and E. A. Tallant Regulation of ACE2 in cardiac myocytes and fibroblasts Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2373 - H2379. [Abstract] [Full Text] [PDF]

				P. E. Gallagher, C. M. Ferrario, and E. A. Tallant MAP kinase/phosphatase pathway mediates the regulation of ACE2 by angiotensin peptides Am J Physiol Cell Physiol, November 1, 2008; 295(5): C1169 - C1174. [Abstract] [Full Text] [PDF]

				J. F. Giani, M. M. Gironacci, M. C. Munoz, D. Turyn, and F. P. Dominici Angiotensin-(1-7) has a dual role on growth-promoting signalling pathways in rat heart in vivo by stimulating STAT3 and STAT5a/b phosphorylation and inhibiting angiotensin II-stimulated ERK1/2 and Rho kinase activity Exp Physiol, May 1, 2008; 93(5): 570 - 578. [Abstract] [Full Text] [PDF]

				A. G. Filho, A. J. Ferreira, S. H. S. Santos, S. R. S. Neves, E. R. Silva Camargos, L. K. Becker, H. A. Belchior, M. F. Dias-Peixoto, S. V. B. Pinheiro, and R. A. S. Santos Selective increase of angiotensin(1-7) and its receptor in hearts of spontaneously hypertensive rats subjected to physical training Exp Physiol, May 1, 2008; 93(5): 589 - 598. [Abstract] [Full Text] [PDF]

				R. A. S. Santos, A. J. Ferreira, and A. C. Simoes e Silva Recent advances in the angiotensin-converting enzyme 2-angiotensin(1-7)-Mas axis Exp Physiol, May 1, 2008; 93(5): 519 - 527. [Abstract] [Full Text] [PDF]

				A. J. Trask, J. A. Jessup, M. C. Chappell, and C. M. Ferrario Angiotensin-(1-12) is an alternate substrate for angiotensin peptide production in the heart Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2242 - H2247. [Abstract] [Full Text] [PDF]

				J. C. Q. Velez, A. M. Bland, J. M. Arthur, J. R. Raymond, and M. G. Janech Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes Am J Physiol Renal Physiol, July 1, 2007; 293(1): F398 - F407. [Abstract] [Full Text] [PDF]

				A. J. Trask, D. B. Averill, D. Ganten, M. C. Chappell, and C. M. Ferrario Primary role of angiotensin-converting enzyme-2 in cardiac production of angiotensin-(1-7) in transgenic Ren-2 hypertensive rats Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3019 - H3024. [Abstract] [Full Text] [PDF]

				S. Keidar, M. Kaplan, and A. Gamliel-Lazarovich ACE2 of the heart: From angiotensin I to angiotensin (1-7) Cardiovasc Res, February 1, 2007; 73(3): 463 - 469. [Abstract] [Full Text] [PDF]

				T. L. Reudelhuber A Place in Our Hearts for the Lowly Angiotensin 1-7 Peptide? Hypertension, May 1, 2006; 47(5): 811 - 815. [Full Text] [PDF]

				F. J. Warner, R. A. Lew, A. I. Smith, D. W. Lambert, N. M. Hooper, and A. J. Turner Angiotensin-converting Enzyme 2 (ACE2), But Not ACE, Is Preferentially Localized to the Apical Surface of Polarized Kidney Cells J. Biol. Chem., November 25, 2005; 280(47): 39353 - 39362. [Abstract] [Full Text] [PDF]

				E. A. Tallant, C. M. Ferrario, and P. E. Gallagher Angiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the mas receptor Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1560 - H1566. [Abstract] [Full Text] [PDF]

				C. M. Ferrario, J. Jessup, M. C. Chappell, D. B. Averill, K. B. Brosnihan, E. A. Tallant, D. I. Diz, and P. E. Gallagher Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2 Circulation, May 24, 2005; 111(20): 2605 - 2610. [Abstract] [Full Text] [PDF]

				L. S. Zisman ACE and ACE2: a tale of two enzymes Eur. Heart J., February 2, 2005; 26(4): 322 - 324. [Full Text] [PDF]

				N. Li, J. Zimpelmann, K. Cheng, J. A. Wilkins, and K. D. Burns The role of angiotensin converting enzyme 2 in the generation of angiotensin 1-7 by rat proximal tubules Am J Physiol Renal Physiol, February 1, 2005; 288(2): F353 - F362. [Abstract] [Full Text] [PDF]