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(Circulation. 1996;94:2915-2922.)
© 1996 American Heart Association, Inc.
Articles |
Long-term Angiotensin-Converting Enzyme Inhibition With Fosinopril Improves Depressed Responsiveness to Ca2+ in Myocytes From Aortic-Banded Rats
the Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory of Beth Israel Hospital and the Department of Medicine (Cardiovascular Division), Beth Israel Hospital and Harvard Medical School, Boston, Mass, and the Division of Cardiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City (W.H.B.).
Correspondence to Beverly H. Lorell, MD, Cardiovascular Division, Beth Israel Hospital, 330 Brookline Ave, Boston, MA 02215.
Background We have previously shown that long-term ACE inhibition with fosinopril prolongs survival and improves ventricular function despite persistent severe left ventricular pressure overload in ascending aortic–banded rats with left ventricular hypertrophy during the transition from compensation to failure.
Methods and Results To study the cellular mechanism of the effects of long-term ACE inhibition on the modification of the transition to failure in pressure-overload hypertrophy, we measured simultaneous intracellular Ca2+ transients and myocyte shortening in isolated left ventricular myocytes from fosinopril-treated aortic-banded rats (n=9), untreated aortic-banded rats (n=9), and normal age-matched control rats (n=10). Fosinopril therapy was begun 6 weeks after banding and was continued until week 21 after banding, when the animals were killed. Collagenase-dissociated myocytes loaded with indo 1-AM were paced at 3 Hz at 36°C and superfused at [Ca2+]o of 0.6, 1.2, and 3.0 mmol/L. In myocytes from untreated aortic-banded rats, peak systolic [Ca2+]i was higher than in control myocytes, and the relationship between myocyte shortening and [Ca2+]i was depressed relative to control myocytes, implicating impaired responsiveness to Ca2+. Long-term fosinopril treatment improved both myocyte shortening and the relationship of shortening to [Ca2+]i (P<.05 versus myocytes from untreated aortic-banded rats). Maximal Ca2+-activated force was depressed in chemically skinned left ventricular fibers from untreated aortic-banded hypertrophied rats relative to age-matched controls but not in the fosinopril-treated aortic-banded rats.
Conclusions Long-term ACE inhibition improves responsiveness to Ca2+ in the presence of normalization of maximal Ca2+-activated force in aortic-banded rats subjected to persistent pressure overload. This may contribute to the favorable effects whereby ACE inhibition modifies the transition from compensated hypertrophy to failure.
Key Words: hypertrophy • heart failure • myocytes • calcium • ventricles
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