(Circulation. 1997;95:1592-1600.)
© 1997 American Heart Association, Inc.
Articles |
Angiotensin AT1 Receptor Inhibition
Effects on Hypertrophic Remodeling and ACE Expression in Rats With Pressure-Overload Hypertrophy due to Ascending Aortic Stenosis
From the Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory and the Department of Medicine (Cardiovascular Division) of Beth Israel Deaconess Medical Center and Harvard Medical School (E.O.W., M.W., K.K.L.H., P.S.D., E.C., B.H.L.), Boston, Mass; the Department of Pathology of the University of Alabama at Birmingham (S.P.B.); Brigham and Women's Hospital and Children's Hospital (M.A.L., K.L.), Boston, Mass; and the University of Texas Health Science Center (C.R.B.), Houston.
Background We tested the hypothesis that long-term administration of the specific angiotensin II subtype 1 (AT1)–receptor blocker BMS-186295 will regress hypertrophy and modify left ventricular angiotensin converting enzyme (ACE) expression in rats with ascending aortic stenosis.
Methods and Results Six weeks after surgery, rats with ascending aortic stenosis were randomized to receive either the AT1-receptor blocker BMS-186295 50 mg·kg-1·d-1 (n=49), amlodipine 2.5 mg·kg-1·d-1 (n=48) as a positive control for systemic vasodilation, or no drug (n=48) and compared with sham-operated rats (n=39). Drug treatment was continued for 15 weeks. Left ventricular ACE mRNA levels were measured by ribonuclease protection assay. The left ventricular/body weight ratio was increased 43% in hearts from rats with untreated left ventricular hypertrophy (LVH) versus control hearts (P<.05). However, there was no difference in either the left ventricular/body weight ratio (2.78±0.08 versus 2.81±0.20 mg/g; P=NS) or myocyte cross-sectional area in the AT1-blocker–treated versus untreated LVH hearts. Amlodipine also showed no effect on regression of hypertrophy. In vivo left ventricular systolic pressure was significantly higher in untreated LVH versus sham-operated rats (193±8 versus 118±4 mm Hg; P<.05), and there was a similar severe elevation of left ventricular systolic pressure in the AT1-blocker– and amlodipine-treated LVH groups (189±9 and 188±16 mm Hg; P=NS versus untreated LVH). In vivo left ventricular end-diastolic pressure was higher in the untreated LVH than in the sham-operated rats (14.8±2.3 versus 7.0±0.5 mm Hg; P<.05). Left ventricular end-diastolic pressure was lower in the AT1-blocker–treated (11.0±1.7 mm Hg) and amlodipine-treated rats (11.5±1.8 mm Hg) and was similar to left ventricular end-diastolic pressure in the sham-operated rats (P=NS). Left ventricular ACE mRNA levels were elevated in untreated LVH rats but were normalized in both the AT1-blocker–treated rats and amlodipine-treated rats.
Conclusions Long-term AT1-receptor blockade did not regress LVH in rats with persistent systolic pressure overload due to ascending aortic stenosis. However, both AT1-receptor blockade and amlodipine improved in vivo left ventricular end-diastolic pressure in association with the normalization of left ventricular ACE mRNA levels.
Key Words: hypertrophy • angiotensin • receptors • stenosis, aortic
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