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(Circulation. 1998;98:1735-1741.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Differential Regulation of Cardiac Angiotensin Converting Enzyme Binding Sites and AT₁ Receptor Density in the Failing Human Heart

Lawrence S. Zisman, MD; Koji Asano, MD, PhD; Darrin L. Dutcher, BS; Anthony Ferdensi, BS; Alastair D. Robertson, PhD; Matthew Jenkin, BS; Erik W. Bush, BS; Teresa Bohlmeyer, MD; M. Benjamin Perryman, PhD; ; Michael R. Bristow, MD, PhD

From the Department of Medicine, Division of Cardiology, University of Colorado Health Sciences Center, Denver.

Correspondence to Lawrence S. Zisman, MD, Center for Pulmonary Heart Disease, The Rush Heart Institute, 1725 W Harrison St, Suite 020, Chicago, IL 60612. E-mail lzisman{at}rush.edu

Background—The regulation and interaction of ACE and the angiotensin II (Ang II) type I (AT₁) receptor in the failing human heart are not understood.

Methods and Results—Radioligand binding with ³H-ramiprilat was used to measure ACE protein in membrane preparations of hearts obtained from 36 subjects with idiopathic dilated cardiomyopathy (IDC), 8 subjects with primary pulmonary hypertension (PPH), and 32 organ donors with normal cardiac function (NF hearts). ¹²⁵I-Ang II formation was measured in a subset of hearts. Saralasin (¹²⁵I-{Sar¹,Ile⁸}-Ang II) was used to measure total Ang II receptor density. AT₁ and AT₂ receptor binding were determined with the AT₁ receptor antagonist losartan. Maximal ACE binding (B_max) was 578±47 fmol/mg in IDC left ventricle (LV), 713±97 fmol/mg in PPH LV, and 325±27 fmol/mg in NF LV (P<0.001, IDC or PPH versus NF). In IDC, PPH, and NF right ventricles (RV), ACE B_max was 737±78, 638±137, and 422±49 fmol/mg, respectively (P=0.02, IDC versus NF; P=0.08, PPH versus NF). ¹²⁵I-Ang II formation correlated with ACE binding sites (r=0.60, P=0.00005). There was selective downregulation of the AT₁ receptor subtype in failing PPH ventricles: 6.41±1.23 fmol/mg in PPH LV, 2.37±0.50 fmol/mg in PPH RV, 5.38±0.53 fmol/mg in NF LV, and 7.30±1.10 fmol/mg in NF RV (P=0.01, PPH RV versus PPH LV; P=0.0006, PPH RV versus NF RV).

Conclusions—ACE binding sites are increased in both failing IDC and nonfailing PPH ventricles. In PPH hearts, the AT₁ receptor is downregulated only in the failing RV.

Key Words: angiotensin • cardiomyopathy • pulmonary heart disease

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