Circulation, Vol 87, 1328-1339, Copyright © 1993 by American Heart Association
H Schunkert, B Jackson, SS Tang, FJ Schoen, JF Smits, CS Apstein and BH Lorell
BACKGROUND. The intracardiac conversion rate of angiotensin (Ang) I to Ang
II and the expression of angiotensin converting enzyme (ACE) mRNA are
amplified in rat hearts with left ventricular hypertrophy (LVH). To examine
whether the accelerated intracardiac Ang II generation in LVH is related to
an induction of cardiac ACE, we studied localization and function of
cardiac ACE in hypertrophied rat hearts using specific ACE inhibitors.
METHODS AND RESULTS. Cardiac ACE was localized and quantified in hearts
from male Wistar rats with LVH due to chronic experimental aortic stenosis
and from control rats. With the ACE inhibitor 125I-351A, a derivative of
lisinopril, as a radioligand on coronal sections of LVH and control hearts,
in vitro autoradiography demonstrated ACE binding in aorta, coronary
arteries, atria, and ventricles of both groups. Quantitative analyses
revealed that ACE density (counts per minute per cross-sectional area of
tissue) was twofold higher within the myocardium of hypertrophied left
ventricles compared with controls (p < 0.005). Quantitative morphometry
demonstrated a modest increase in the fractional volume of myocytes as well
as capillary volume without an increase in the fractional volume of
endothelial cells in left ventricular tissue from aortic stenosis rats.
These data suggest that an increase in endothelial cell volume per se
cannot alone account for the observed doubling of ACE density and support
an upregulation of ACE production in hypertrophied tissue. The role of
cardiac ACE in intracardiac conversion of Ang I to Ang II and its specific
inhibition was studied in isolated, isovolumic beating, buffer-perfused LVH
and control hearts. Biochemical conversion rates as well as functional
changes in response to 3 x 10(-7) M Ang I were examined in the absence or
presence of the ACE inhibitor enalaprilat (4 x 10(-6) M). After a brief
stabilization period, groups of LVH and control hearts were subjected to
the following infusion protocols: 15 minutes of vehicle followed by 30
minutes of Ang I plus vehicle, 15 minutes of enalaprilat followed by 30
minutes of Ang I plus enalaprilat (enal/Ang I), or 45 minutes of vehicle
only to allow comparison with a time control. Intracardiac Ang I-to-Ang II
conversion rate was fourfold higher in LVH than in control hearts (p <
0.05). Infusion of enalaprilat reduced the intracardiac Ang I-to-Ang II
conversion rate in LVH hearts by 70% (p < 0.05 versus Ang I). At similar
levels of constant coronary flow per gram, Ang I increased coronary
perfusion pressure by 23 +/- 5 mm Hg (p < 0.01 versus vehicle) in LVH
hearts and by 36 +/- 10 mm Hg (p < 0.005 versus vehicle) in control
hearts. When enalaprilat was infused with Ang I, the increase in perfusion
pressure was limited to 5 +/- 5 mm Hg (NS versus vehicle) in LVH hearts and
12 +/- 3 mm Hg (p < 0.05 versus vehicle) in control hearts and was
significantly lower than in hearts infused with Ang I only (p < 0.05 in
LVH and p < 0.05 in control hearts, respectively). Systolic function was
not affected by either infusion protocol. In contrast, Ang I infusion was
associated with diastolic dysfunction. In LVH hearts, left ventricular
end-diastolic pressure (LVEDP) increased from 10 +/- 1 mm Hg at baseline to
25 +/- 2 mm Hg at the end of the Ang I infusion (p < 0.001 versus
vehicle), which was inhibited by infusion of enalaprilat. In control
hearts, there was a lesser increase in LVEDP from 10 +/- 1 mm Hg to 15 +/-
1 mm Hg in response to Ang I (p < 0.05 versus LVH). Control hearts
treated with enalaprilat with Ang I displayed no increase in LVEDP.
CONCLUSIONS. These observations indicate that ACE protein is increased
within the myocardium of LVH hearts, extending recent findings of increased
cardiac ACE activity and mRNA levels in this model of pressure-overload LVH
in the rat. Blockade of the enzyme by an ACE inhibitor decreases
intracardiac Ang I-to-Ang II conversion rate and prevents the functional
changes of Ang I-to-Ang II activation
ARTICLES
Distribution and functional significance of cardiac angiotensin converting enzyme in hypertrophied rat hearts
Charles A. Dana Research Institute, Boston.
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