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 (Bmax) 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
Bmax 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.
© 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
Key Words: angiotensin • cardiomyopathy • pulmonary heart disease
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