Long-term angiotensin-converting enzyme inhibition with fosinopril improves depressed responsiveness to Ca2+ in myocytes from aortic-banded rats

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 degrees 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.