Abstract
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 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.
Original language | English |
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Pages (from-to) | 2915-2922 |
Number of pages | 8 |
Journal | Circulation |
Volume | 94 |
Issue number | 11 |
DOIs | |
State | Published - 1996 |
Keywords
- calcium
- heart failure
- hypertrophy
- myocytes
- ventricles