LONG-TERM ANGIOTENSIN-CONVERTING ENZYME-INHIBITION WITH FOSINOPRIL IMPROVES DEPRESSED RESPONSIVENESS TO CA2-BANDED RATS( IN MYOCYTES FROM AORTIC)

Background We have previously shown that long-term ACE inhibition with fosinopril prolongs survival and improves ventricular function despit e persistent severe left Ventricular pressure overload in ascending ao rtic-banded rats with left ventricular hypertrophy during the transiti on from compensation to failure.Methods and Results To study the cellu lar mechanism of the effects of long-term ACE inhibition on the modifi cation of the transition to failure in pressure-overload hypertrophy, we measured simultaneous intracellular Ca2+ transients and myocyte sho rtening in isolated left Ventricular myocytes from fosinopril-treated aortic-banded rats (n=9), untreated aortic-banded rats (n=9), and norm al age-matched control rats (n=10). Fosinopril therapy was begun 6 wee ks after banding and was continued until week 21 after banding, when t he animals were killed. Collagenase-dissociated myocytes loaded with i ndo 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-bande d rats, peak systolic [Ca2+](i) was higher than in control myocytes, a nd the relationship between myocyte shortening and [Ca2+](i) was depre ssed relative to control myocytes, implicating impaired responsiveness to Ca2+. Long-term fosinopril treatment improved both myocyte shorten ing and the relationship of shortening to [Ca2+](i) (P<.05 versus myoc ytes from untreated aortic-banded rats). Maximal Ca2+-activated force was depressed in chemically skinned left ventricular fibers from untre ated aortic-banded hypertrophied rats relative to age-matched controls but not in the fosinopril-treated aortic-banded rats. Conclusions Lon g-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.